CML

Photo by Rhoda Baer

Countries with the lowest opportunities for natural selection have higher cancer rates than countries with the highest opportunities for natural selection, according to a study published in Evolutionary Applications.

Researchers said this is because modern medicine is enabling people to survive cancers, and their genetic backgrounds are passing from one generation to the next.

The team said the rate of some cancers has doubled and even quadrupled over the past 100 to 150 years, and human evolution has moved away from “survival of the fittest.”

“Modern medicine has enabled the human species to live much longer than would otherwise be expected in the natural world,” said study author Maciej Henneberg, PhD, DSc, of the University of Adelaide in South Australia.

“Besides the obvious benefits that modern medicine gives, it also brings with it an unexpected side-effect—allowing genetic material to be passed from one generation to the next that predisposes people to have poor health, such as type 1 diabetes or cancer.”

“Because of the quality of our healthcare in western society, we have almost removed natural selection as the ‘janitor of the gene pool.’ Unfortunately, the accumulation of genetic mutations over time and across multiple generations is like a delayed death sentence.”

Country comparison

The researchers studied global cancer data from the World Health Organization as well as other health and socioeconomic data from the United Nations and the World Bank of 173 countries. The team compared the top 10 countries with the highest opportunities for natural selection to the 10 countries with the lowest opportunities for natural selection.

“We looked at countries that offered the greatest opportunity to survive cancer compared with those that didn’t,” said study author Wenpeng You, a PhD student at the University of Adelaide. “This does not only take into account factors such as socioeconomic status, urbanization, and quality of medical services but also low mortality and fertility rates, which are the 2 distinguishing features in the ‘better’ world.”

“Countries with low mortality rates may allow more people with cancer genetic background to reproduce and pass cancer genes/mutations to the next generation. Meanwhile, low fertility rates in these countries may not be able to have diverse biological variations to provide the opportunity for selecting a naturally fit population—for example, people without or with less cancer genetic background. Low mortality rate and low fertility rate in the ‘better’ world may have formed a self-reinforcing cycle which has accumulated cancer genetic background at a greater rate than previously thought.”

Based on the researchers’ analysis, the 20 countries are:

Cancer incidence

The researchers found the rates of most cancers were higher in the 10 countries with the lowest opportunities for natural selection. The incidence of all cancers was 2.326 times higher in the low-opportunity countries than the high-opportunity ones.

The increased incidences of hematologic malignancies were as follows:

• Non-Hodgkin lymphoma—2.019 times higher in the low-opportunity countries
• Hodgkin lymphoma—3.314 times higher in the low-opportunity countries
• Leukemia—3.574 times higher in the low-opportunity countries
• Multiple myeloma—4.257 times higher in the low-opportunity countries .

Dr Henneberg said that, having removed natural selection as the “janitor of the gene pool,” our modern society is faced with a controversial issue.

“It may be that the only way humankind can be rid of cancer once and for all is through genetic engineering—to repair our genes and take cancer out of the equation,” he said.

Photo by Rhoda Baer

Countries with the lowest opportunities for natural selection have higher cancer rates than countries with the highest opportunities for natural selection, according to a study published in Evolutionary Applications.

Researchers said this is because modern medicine is enabling people to survive cancers, and their genetic backgrounds are passing from one generation to the next.

The team said the rate of some cancers has doubled and even quadrupled over the past 100 to 150 years, and human evolution has moved away from “survival of the fittest.”

“Modern medicine has enabled the human species to live much longer than would otherwise be expected in the natural world,” said study author Maciej Henneberg, PhD, DSc, of the University of Adelaide in South Australia.

“Besides the obvious benefits that modern medicine gives, it also brings with it an unexpected side-effect—allowing genetic material to be passed from one generation to the next that predisposes people to have poor health, such as type 1 diabetes or cancer.”

“Because of the quality of our healthcare in western society, we have almost removed natural selection as the ‘janitor of the gene pool.’ Unfortunately, the accumulation of genetic mutations over time and across multiple generations is like a delayed death sentence.”

Country comparison

The researchers studied global cancer data from the World Health Organization as well as other health and socioeconomic data from the United Nations and the World Bank of 173 countries. The team compared the top 10 countries with the highest opportunities for natural selection to the 10 countries with the lowest opportunities for natural selection.

“We looked at countries that offered the greatest opportunity to survive cancer compared with those that didn’t,” said study author Wenpeng You, a PhD student at the University of Adelaide. “This does not only take into account factors such as socioeconomic status, urbanization, and quality of medical services but also low mortality and fertility rates, which are the 2 distinguishing features in the ‘better’ world.”

“Countries with low mortality rates may allow more people with cancer genetic background to reproduce and pass cancer genes/mutations to the next generation. Meanwhile, low fertility rates in these countries may not be able to have diverse biological variations to provide the opportunity for selecting a naturally fit population—for example, people without or with less cancer genetic background. Low mortality rate and low fertility rate in the ‘better’ world may have formed a self-reinforcing cycle which has accumulated cancer genetic background at a greater rate than previously thought.”

Based on the researchers’ analysis, the 20 countries are:

Cancer incidence

The researchers found the rates of most cancers were higher in the 10 countries with the lowest opportunities for natural selection. The incidence of all cancers was 2.326 times higher in the low-opportunity countries than the high-opportunity ones.

The increased incidences of hematologic malignancies were as follows:

• Non-Hodgkin lymphoma—2.019 times higher in the low-opportunity countries
• Hodgkin lymphoma—3.314 times higher in the low-opportunity countries
• Leukemia—3.574 times higher in the low-opportunity countries
• Multiple myeloma—4.257 times higher in the low-opportunity countries .

Dr Henneberg said that, having removed natural selection as the “janitor of the gene pool,” our modern society is faced with a controversial issue.

“It may be that the only way humankind can be rid of cancer once and for all is through genetic engineering—to repair our genes and take cancer out of the equation,” he said.

Photo by Rhoda Baer

Countries with the lowest opportunities for natural selection have higher cancer rates than countries with the highest opportunities for natural selection, according to a study published in Evolutionary Applications.

Researchers said this is because modern medicine is enabling people to survive cancers, and their genetic backgrounds are passing from one generation to the next.

The team said the rate of some cancers has doubled and even quadrupled over the past 100 to 150 years, and human evolution has moved away from “survival of the fittest.”

“Modern medicine has enabled the human species to live much longer than would otherwise be expected in the natural world,” said study author Maciej Henneberg, PhD, DSc, of the University of Adelaide in South Australia.

“Besides the obvious benefits that modern medicine gives, it also brings with it an unexpected side-effect—allowing genetic material to be passed from one generation to the next that predisposes people to have poor health, such as type 1 diabetes or cancer.”

“Because of the quality of our healthcare in western society, we have almost removed natural selection as the ‘janitor of the gene pool.’ Unfortunately, the accumulation of genetic mutations over time and across multiple generations is like a delayed death sentence.”

Country comparison

The researchers studied global cancer data from the World Health Organization as well as other health and socioeconomic data from the United Nations and the World Bank of 173 countries. The team compared the top 10 countries with the highest opportunities for natural selection to the 10 countries with the lowest opportunities for natural selection.

“We looked at countries that offered the greatest opportunity to survive cancer compared with those that didn’t,” said study author Wenpeng You, a PhD student at the University of Adelaide. “This does not only take into account factors such as socioeconomic status, urbanization, and quality of medical services but also low mortality and fertility rates, which are the 2 distinguishing features in the ‘better’ world.”

“Countries with low mortality rates may allow more people with cancer genetic background to reproduce and pass cancer genes/mutations to the next generation. Meanwhile, low fertility rates in these countries may not be able to have diverse biological variations to provide the opportunity for selecting a naturally fit population—for example, people without or with less cancer genetic background. Low mortality rate and low fertility rate in the ‘better’ world may have formed a self-reinforcing cycle which has accumulated cancer genetic background at a greater rate than previously thought.”

Based on the researchers’ analysis, the 20 countries are:

Cancer incidence

The researchers found the rates of most cancers were higher in the 10 countries with the lowest opportunities for natural selection. The incidence of all cancers was 2.326 times higher in the low-opportunity countries than the high-opportunity ones.

The increased incidences of hematologic malignancies were as follows:

• Non-Hodgkin lymphoma—2.019 times higher in the low-opportunity countries
• Hodgkin lymphoma—3.314 times higher in the low-opportunity countries
• Leukemia—3.574 times higher in the low-opportunity countries
• Multiple myeloma—4.257 times higher in the low-opportunity countries .

Dr Henneberg said that, having removed natural selection as the “janitor of the gene pool,” our modern society is faced with a controversial issue.

“It may be that the only way humankind can be rid of cancer once and for all is through genetic engineering—to repair our genes and take cancer out of the equation,” he said.

Photo by Bill Branson

A study of cancer drugs approved by the European Commission from 2009 to 2013 showed that few hematology drugs were known to provide a benefit in overall survival (OS) or quality of life (QOL) over existing treatments.

Of 12 drugs approved for 17 hematology indications, 3 drugs had been shown to provide a benefit in OS (for 3 indications) at the time of approval.

None of the other hematology drugs were known to provide an OS benefit even after a median follow-up of 5.4 years.

Two hematology drugs were shown to provide a benefit in QOL (for 2 indications) after approval, but none of the drugs were known to provide a QOL benefit at the time of approval.

These findings were published in The BMJ alongside a related editorial, feature article, and patient commentary.

All cancer drugs

Researchers analyzed reports on all cancer drug approvals by the European Commission from 2009 to 2013.

There were 48 drugs approved for 68 cancer indications during this period. Fifty-one of the indications were for solid tumor malignancies, and 17 were for hematologic malignancies.

For 24 indications (35%), research had demonstrated a significant improvement in OS at the time of the drugs’ approval. For 3 indications, an improvement in OS was demonstrated after approval.

There was a known improvement in QOL for 7 of the indications (10%) at the time of approval and for 5 indications after approval.

The median follow-up was 5.4 years (range, 3.3 years to 8.1 years).

Overall, there was a significant improvement in OS or QOL during the study period for 51% of the indications (35/68). For the other half (49%, n=33), it wasn’t clear if the drugs provide any benefits in OS or QOL.

All cancer trials

The 68 approvals of cancer drugs were supported by 72 clinical trials.

Sixty approvals (88%) were supported by at least 1 randomized, controlled trial. Eight approvals (12%) were based on a single-arm study. This included 6 of 10 conditional marketing authorizations and 2 of 58 regular marketing authorizations.

Eighteen of the approvals (26%) were supported by a pivotal study powered to evaluate OS as the primary endpoint. And 37 of the approvals (54%) had a supporting pivotal trial evaluating QOL, but results were not reported for 2 of these trials.

Hematology trials and drugs

Of the 12 drugs approved for 17 hematology indications, 4 were regular approvals, 5 were conditional approvals, and 8 had orphan drug designation.

The approvals were supported by data from 18 trials—13 randomized and 5 single-arm trials.

The study drug was compared to an active comparator in 9 of the trials. The drug was evaluated as an add-on treatment in 4 trials. And the drug was not compared to anything in 5 trials (the single-arm trials).

OS was the primary endpoint in 1 of the trials, and 17 trials had OS or QOL as a secondary endpoint.

There were 3 drugs that had demonstrated an OS benefit at the time of approval but no QOL benefit at any time:

• Decitabine used for first-line treatment of acute myeloid leukemia in adults 65 and older who are ineligible for chemotherapy
• Pomalidomide in combination with dexamethasone as third-line therapy for relapsed/refractory multiple myeloma (MM)
• Rituximab plus chemotherapy for first-line treatment of chronic lymphocytic leukemia (CLL).

There were 2 drugs that had demonstrated a QOL benefit, only after approval, but they were not known to provide an OS benefit at any time:

• Nilotinib as a treatment for adults with newly diagnosed, chronic phase, Ph+ chronic myeloid leukemia (CML)
• Ofatumumab for CLL that is refractory to fludarabine and alemtuzumab

For the remaining drugs, there was no evidence of an OS or QOL benefit at any time during the period studied. The drugs included:

• Bortezomib given alone or in combination with doxorubicin or dexamethasone as second-line therapy for MM patients ineligible for hematopoietic stem cell transplant (HSCT)
• Bortezomib plus dexamethasone with or without thalidomide as first-line therapy in MM patients eligible for HSCT
• Bosutinib as second- or third-line treatment of Ph+ CML (any phase)
• Brentuximab vedotin for relapsed or refractory systemic anaplastic large-cell lymphoma
• Brentuximab vedotin for relapsed or refractory, CD30+ Hodgkin lymphoma after autologous HSCT or as third-line treatment for patients ineligible for autologous HSCT
• Dasatinib for first-line treatment of chronic phase, Ph+ CML
• Pixantrone for multiply relapsed or refractory B-cell non-Hodgkin lymphoma
• Ponatinib for patients with Ph+ acute lymphoblastic leukemia who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib or characterized by T315I mutation
• Ponatinib for patients with any phase of CML who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib/nilotinib or characterized by T315I mutation
• Rituximab as maintenance after induction for patients with follicular lymphoma
• Rituximab plus chemotherapy for relapsed or refractory CLL
• Temsirolimus for relapsed or refractory mantle cell lymphoma.
  

Photo by Bill Branson

A study of cancer drugs approved by the European Commission from 2009 to 2013 showed that few hematology drugs were known to provide a benefit in overall survival (OS) or quality of life (QOL) over existing treatments.

Of 12 drugs approved for 17 hematology indications, 3 drugs had been shown to provide a benefit in OS (for 3 indications) at the time of approval.

None of the other hematology drugs were known to provide an OS benefit even after a median follow-up of 5.4 years.

Two hematology drugs were shown to provide a benefit in QOL (for 2 indications) after approval, but none of the drugs were known to provide a QOL benefit at the time of approval.

These findings were published in The BMJ alongside a related editorial, feature article, and patient commentary.

All cancer drugs

Researchers analyzed reports on all cancer drug approvals by the European Commission from 2009 to 2013.

There were 48 drugs approved for 68 cancer indications during this period. Fifty-one of the indications were for solid tumor malignancies, and 17 were for hematologic malignancies.

For 24 indications (35%), research had demonstrated a significant improvement in OS at the time of the drugs’ approval. For 3 indications, an improvement in OS was demonstrated after approval.

There was a known improvement in QOL for 7 of the indications (10%) at the time of approval and for 5 indications after approval.

The median follow-up was 5.4 years (range, 3.3 years to 8.1 years).

Overall, there was a significant improvement in OS or QOL during the study period for 51% of the indications (35/68). For the other half (49%, n=33), it wasn’t clear if the drugs provide any benefits in OS or QOL.

All cancer trials

The 68 approvals of cancer drugs were supported by 72 clinical trials.

Sixty approvals (88%) were supported by at least 1 randomized, controlled trial. Eight approvals (12%) were based on a single-arm study. This included 6 of 10 conditional marketing authorizations and 2 of 58 regular marketing authorizations.

Eighteen of the approvals (26%) were supported by a pivotal study powered to evaluate OS as the primary endpoint. And 37 of the approvals (54%) had a supporting pivotal trial evaluating QOL, but results were not reported for 2 of these trials.

Hematology trials and drugs

Of the 12 drugs approved for 17 hematology indications, 4 were regular approvals, 5 were conditional approvals, and 8 had orphan drug designation.

The approvals were supported by data from 18 trials—13 randomized and 5 single-arm trials.

The study drug was compared to an active comparator in 9 of the trials. The drug was evaluated as an add-on treatment in 4 trials. And the drug was not compared to anything in 5 trials (the single-arm trials).

OS was the primary endpoint in 1 of the trials, and 17 trials had OS or QOL as a secondary endpoint.

There were 3 drugs that had demonstrated an OS benefit at the time of approval but no QOL benefit at any time:

• Decitabine used for first-line treatment of acute myeloid leukemia in adults 65 and older who are ineligible for chemotherapy
• Pomalidomide in combination with dexamethasone as third-line therapy for relapsed/refractory multiple myeloma (MM)
• Rituximab plus chemotherapy for first-line treatment of chronic lymphocytic leukemia (CLL).

There were 2 drugs that had demonstrated a QOL benefit, only after approval, but they were not known to provide an OS benefit at any time:

• Nilotinib as a treatment for adults with newly diagnosed, chronic phase, Ph+ chronic myeloid leukemia (CML)
• Ofatumumab for CLL that is refractory to fludarabine and alemtuzumab

For the remaining drugs, there was no evidence of an OS or QOL benefit at any time during the period studied. The drugs included:

• Bortezomib given alone or in combination with doxorubicin or dexamethasone as second-line therapy for MM patients ineligible for hematopoietic stem cell transplant (HSCT)
• Bortezomib plus dexamethasone with or without thalidomide as first-line therapy in MM patients eligible for HSCT
• Bosutinib as second- or third-line treatment of Ph+ CML (any phase)
• Brentuximab vedotin for relapsed or refractory systemic anaplastic large-cell lymphoma
• Brentuximab vedotin for relapsed or refractory, CD30+ Hodgkin lymphoma after autologous HSCT or as third-line treatment for patients ineligible for autologous HSCT
• Dasatinib for first-line treatment of chronic phase, Ph+ CML
• Pixantrone for multiply relapsed or refractory B-cell non-Hodgkin lymphoma
• Ponatinib for patients with Ph+ acute lymphoblastic leukemia who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib or characterized by T315I mutation
• Ponatinib for patients with any phase of CML who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib/nilotinib or characterized by T315I mutation
• Rituximab as maintenance after induction for patients with follicular lymphoma
• Rituximab plus chemotherapy for relapsed or refractory CLL
• Temsirolimus for relapsed or refractory mantle cell lymphoma.
  

Photo by Bill Branson

A study of cancer drugs approved by the European Commission from 2009 to 2013 showed that few hematology drugs were known to provide a benefit in overall survival (OS) or quality of life (QOL) over existing treatments.

Of 12 drugs approved for 17 hematology indications, 3 drugs had been shown to provide a benefit in OS (for 3 indications) at the time of approval.

None of the other hematology drugs were known to provide an OS benefit even after a median follow-up of 5.4 years.

Two hematology drugs were shown to provide a benefit in QOL (for 2 indications) after approval, but none of the drugs were known to provide a QOL benefit at the time of approval.

These findings were published in The BMJ alongside a related editorial, feature article, and patient commentary.

All cancer drugs

Researchers analyzed reports on all cancer drug approvals by the European Commission from 2009 to 2013.

There were 48 drugs approved for 68 cancer indications during this period. Fifty-one of the indications were for solid tumor malignancies, and 17 were for hematologic malignancies.

For 24 indications (35%), research had demonstrated a significant improvement in OS at the time of the drugs’ approval. For 3 indications, an improvement in OS was demonstrated after approval.

There was a known improvement in QOL for 7 of the indications (10%) at the time of approval and for 5 indications after approval.

The median follow-up was 5.4 years (range, 3.3 years to 8.1 years).

Overall, there was a significant improvement in OS or QOL during the study period for 51% of the indications (35/68). For the other half (49%, n=33), it wasn’t clear if the drugs provide any benefits in OS or QOL.

All cancer trials

The 68 approvals of cancer drugs were supported by 72 clinical trials.

Sixty approvals (88%) were supported by at least 1 randomized, controlled trial. Eight approvals (12%) were based on a single-arm study. This included 6 of 10 conditional marketing authorizations and 2 of 58 regular marketing authorizations.

Eighteen of the approvals (26%) were supported by a pivotal study powered to evaluate OS as the primary endpoint. And 37 of the approvals (54%) had a supporting pivotal trial evaluating QOL, but results were not reported for 2 of these trials.

Hematology trials and drugs

Of the 12 drugs approved for 17 hematology indications, 4 were regular approvals, 5 were conditional approvals, and 8 had orphan drug designation.

The approvals were supported by data from 18 trials—13 randomized and 5 single-arm trials.

The study drug was compared to an active comparator in 9 of the trials. The drug was evaluated as an add-on treatment in 4 trials. And the drug was not compared to anything in 5 trials (the single-arm trials).

OS was the primary endpoint in 1 of the trials, and 17 trials had OS or QOL as a secondary endpoint.

There were 3 drugs that had demonstrated an OS benefit at the time of approval but no QOL benefit at any time:

• Decitabine used for first-line treatment of acute myeloid leukemia in adults 65 and older who are ineligible for chemotherapy
• Pomalidomide in combination with dexamethasone as third-line therapy for relapsed/refractory multiple myeloma (MM)
• Rituximab plus chemotherapy for first-line treatment of chronic lymphocytic leukemia (CLL).

There were 2 drugs that had demonstrated a QOL benefit, only after approval, but they were not known to provide an OS benefit at any time:

• Nilotinib as a treatment for adults with newly diagnosed, chronic phase, Ph+ chronic myeloid leukemia (CML)
• Ofatumumab for CLL that is refractory to fludarabine and alemtuzumab

For the remaining drugs, there was no evidence of an OS or QOL benefit at any time during the period studied. The drugs included:

• Bortezomib given alone or in combination with doxorubicin or dexamethasone as second-line therapy for MM patients ineligible for hematopoietic stem cell transplant (HSCT)
• Bortezomib plus dexamethasone with or without thalidomide as first-line therapy in MM patients eligible for HSCT
• Bosutinib as second- or third-line treatment of Ph+ CML (any phase)
• Brentuximab vedotin for relapsed or refractory systemic anaplastic large-cell lymphoma
• Brentuximab vedotin for relapsed or refractory, CD30+ Hodgkin lymphoma after autologous HSCT or as third-line treatment for patients ineligible for autologous HSCT
• Dasatinib for first-line treatment of chronic phase, Ph+ CML
• Pixantrone for multiply relapsed or refractory B-cell non-Hodgkin lymphoma
• Ponatinib for patients with Ph+ acute lymphoblastic leukemia who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib or characterized by T315I mutation
• Ponatinib for patients with any phase of CML who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib/nilotinib or characterized by T315I mutation
• Rituximab as maintenance after induction for patients with follicular lymphoma
• Rituximab plus chemotherapy for relapsed or refractory CLL
• Temsirolimus for relapsed or refractory mantle cell lymphoma.
  

Photo from St. Jude Children’s Research Hospital

Researchers say they have determined how the structure of Abl kinase regulates its activity, enabling the enzyme to switch itself on and off.

The team believes these findings will pave the way to new treatment strategies that can overcome drug resistance in chronic myeloid leukemia (CML) and other malignancies.

Charalampos Kalodimos, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described this research in Nature Structural & Molecular Biology.

The researchers sought to understand how Abl manages to switch itself on and off by altering its shape. Abl controls this switching through allosteric regulation, in which a part of the molecule distant from its kinase domain somehow inhibits or activates Abl.

“We knew we had these 2 functional states, but we had no idea about the conditions under which Abl switched from one to another,” Dr Kalodimos said.

“We also didn’t understand how external molecules that regulate Abl acted on these 2 states. Nor did we understand how mutations that confer drug resistance affected the states.”

To investigate, the researchers used NMR spectroscopy to view Abl’s structure and watch the kinase change. The team explored how the region of Abl called the allosteric regulatory module interacted with the kinase domain to control it.

The research revealed that, in its shape-shifting, Abl was precisely balanced between its inhibition and activation states.

“We saw this very fast ‘breathing’ motion of several thousand times a second, in which the molecule goes on and off, on and off,” Dr Kalodimos said. “This motion is important because it allows other molecules that regulate Abl to adjust its activity one way or the other in a graded manner—like turning a rheostat up or down.”

Such regulation would involve pushing the Abl molecule toward either the inhibited or activated state, Dr Kalodimos said.

Newfound activator region

The researchers also discovered new details about how Abl’s structure affects its activation state. For example, the team’s experiments revealed a previously unknown activator region within Abl.

The researchers noted that the Abl regulatory module consists of 5 regions:

• An unstructured N-terminal region called the cap (residues 1–80)
• The SH3 domain (residues 85–138)
• A short linker called the connector^SH3/2 (residues 139–152), which links the SH3 and SH2 domains
• The SH2 domain (residues 153–237)
• A linker (linker^SH2–KD; residues 238–250) that connects SH2 to the kinase domain (residues 255–534).

The previously unknown activator region the researchers identified is part of the cap region comprising residues 14 to 20 (cap^PxxP), which carries a PxxP sequence motif, a preferred binding site of the SH3 domain.

The team found that cap^PxxP is an SH3-binding site that can compete with and displace the linker^SH2–KD from the SH3 domain, thereby destabilizing the inhibiting state.

The researchers said they believe the recently reported A19V drug-resistance mutation exerts its function by promoting the activated state of Abl by means of cap^PxxP.

Implications for treatment

The researchers also analyzed mutations in Bcr-Abl that allow it to become resistant to imatinib. The drug has proven effective in treating CML by plugging into the kinase domain of the over-activated Abl enzyme and shutting it down. However, in many patients, a mutation in the gene that produces Abl renders it drug-resistant.

While many of the mutations block imatinib from plugging into the kinase domain, others appear to interfere with the allosteric regulation. In effect, they may “warp” the enzyme to keep it activated.

In analyzing the structure of these allosteric mutants, Dr Kalodimos and his colleagues discovered the mutants altered Abl’s shape to activate it and did not interfere with how imatinib plugs into the kinase domain.

This finding points the way to new treatments to overcome such resistance, according to Dr Kalodimos.

“There is now a new generation of drugs that bind to the allosteric pocket to inhibit its activity,” he said. “These could be combined with [imatinib] to overcome allosteric mutations to shift Abl into an inhibited state.”

Dr Kalodimos said that treatment strategy could also be applied to other forms of leukemia that have uncontrolled Bcr-Abl activity. And this new basic understanding of Abl regulation will yield insight into similar enzymes in which allosteric regulation controls a kinase domain.

Photo from St. Jude Children’s Research Hospital

Researchers say they have determined how the structure of Abl kinase regulates its activity, enabling the enzyme to switch itself on and off.

The team believes these findings will pave the way to new treatment strategies that can overcome drug resistance in chronic myeloid leukemia (CML) and other malignancies.

Charalampos Kalodimos, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described this research in Nature Structural & Molecular Biology.

The researchers sought to understand how Abl manages to switch itself on and off by altering its shape. Abl controls this switching through allosteric regulation, in which a part of the molecule distant from its kinase domain somehow inhibits or activates Abl.

“We knew we had these 2 functional states, but we had no idea about the conditions under which Abl switched from one to another,” Dr Kalodimos said.

“We also didn’t understand how external molecules that regulate Abl acted on these 2 states. Nor did we understand how mutations that confer drug resistance affected the states.”

To investigate, the researchers used NMR spectroscopy to view Abl’s structure and watch the kinase change. The team explored how the region of Abl called the allosteric regulatory module interacted with the kinase domain to control it.

The research revealed that, in its shape-shifting, Abl was precisely balanced between its inhibition and activation states.

“We saw this very fast ‘breathing’ motion of several thousand times a second, in which the molecule goes on and off, on and off,” Dr Kalodimos said. “This motion is important because it allows other molecules that regulate Abl to adjust its activity one way or the other in a graded manner—like turning a rheostat up or down.”

Such regulation would involve pushing the Abl molecule toward either the inhibited or activated state, Dr Kalodimos said.

Newfound activator region

The researchers also discovered new details about how Abl’s structure affects its activation state. For example, the team’s experiments revealed a previously unknown activator region within Abl.

The researchers noted that the Abl regulatory module consists of 5 regions:

• An unstructured N-terminal region called the cap (residues 1–80)
• The SH3 domain (residues 85–138)
• A short linker called the connector^SH3/2 (residues 139–152), which links the SH3 and SH2 domains
• The SH2 domain (residues 153–237)
• A linker (linker^SH2–KD; residues 238–250) that connects SH2 to the kinase domain (residues 255–534).

The previously unknown activator region the researchers identified is part of the cap region comprising residues 14 to 20 (cap^PxxP), which carries a PxxP sequence motif, a preferred binding site of the SH3 domain.

The team found that cap^PxxP is an SH3-binding site that can compete with and displace the linker^SH2–KD from the SH3 domain, thereby destabilizing the inhibiting state.

The researchers said they believe the recently reported A19V drug-resistance mutation exerts its function by promoting the activated state of Abl by means of cap^PxxP.

Implications for treatment

The researchers also analyzed mutations in Bcr-Abl that allow it to become resistant to imatinib. The drug has proven effective in treating CML by plugging into the kinase domain of the over-activated Abl enzyme and shutting it down. However, in many patients, a mutation in the gene that produces Abl renders it drug-resistant.

While many of the mutations block imatinib from plugging into the kinase domain, others appear to interfere with the allosteric regulation. In effect, they may “warp” the enzyme to keep it activated.

In analyzing the structure of these allosteric mutants, Dr Kalodimos and his colleagues discovered the mutants altered Abl’s shape to activate it and did not interfere with how imatinib plugs into the kinase domain.

This finding points the way to new treatments to overcome such resistance, according to Dr Kalodimos.

“There is now a new generation of drugs that bind to the allosteric pocket to inhibit its activity,” he said. “These could be combined with [imatinib] to overcome allosteric mutations to shift Abl into an inhibited state.”

Dr Kalodimos said that treatment strategy could also be applied to other forms of leukemia that have uncontrolled Bcr-Abl activity. And this new basic understanding of Abl regulation will yield insight into similar enzymes in which allosteric regulation controls a kinase domain.

Photo from St. Jude Children’s Research Hospital

Researchers say they have determined how the structure of Abl kinase regulates its activity, enabling the enzyme to switch itself on and off.

The team believes these findings will pave the way to new treatment strategies that can overcome drug resistance in chronic myeloid leukemia (CML) and other malignancies.

Charalampos Kalodimos, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described this research in Nature Structural & Molecular Biology.

The researchers sought to understand how Abl manages to switch itself on and off by altering its shape. Abl controls this switching through allosteric regulation, in which a part of the molecule distant from its kinase domain somehow inhibits or activates Abl.

“We knew we had these 2 functional states, but we had no idea about the conditions under which Abl switched from one to another,” Dr Kalodimos said.

“We also didn’t understand how external molecules that regulate Abl acted on these 2 states. Nor did we understand how mutations that confer drug resistance affected the states.”

To investigate, the researchers used NMR spectroscopy to view Abl’s structure and watch the kinase change. The team explored how the region of Abl called the allosteric regulatory module interacted with the kinase domain to control it.

The research revealed that, in its shape-shifting, Abl was precisely balanced between its inhibition and activation states.

“We saw this very fast ‘breathing’ motion of several thousand times a second, in which the molecule goes on and off, on and off,” Dr Kalodimos said. “This motion is important because it allows other molecules that regulate Abl to adjust its activity one way or the other in a graded manner—like turning a rheostat up or down.”

Such regulation would involve pushing the Abl molecule toward either the inhibited or activated state, Dr Kalodimos said.

Newfound activator region

The researchers also discovered new details about how Abl’s structure affects its activation state. For example, the team’s experiments revealed a previously unknown activator region within Abl.

The researchers noted that the Abl regulatory module consists of 5 regions:

• An unstructured N-terminal region called the cap (residues 1–80)
• The SH3 domain (residues 85–138)
• A short linker called the connector^SH3/2 (residues 139–152), which links the SH3 and SH2 domains
• The SH2 domain (residues 153–237)
• A linker (linker^SH2–KD; residues 238–250) that connects SH2 to the kinase domain (residues 255–534).

The previously unknown activator region the researchers identified is part of the cap region comprising residues 14 to 20 (cap^PxxP), which carries a PxxP sequence motif, a preferred binding site of the SH3 domain.

The team found that cap^PxxP is an SH3-binding site that can compete with and displace the linker^SH2–KD from the SH3 domain, thereby destabilizing the inhibiting state.

The researchers said they believe the recently reported A19V drug-resistance mutation exerts its function by promoting the activated state of Abl by means of cap^PxxP.

Implications for treatment

The researchers also analyzed mutations in Bcr-Abl that allow it to become resistant to imatinib. The drug has proven effective in treating CML by plugging into the kinase domain of the over-activated Abl enzyme and shutting it down. However, in many patients, a mutation in the gene that produces Abl renders it drug-resistant.

While many of the mutations block imatinib from plugging into the kinase domain, others appear to interfere with the allosteric regulation. In effect, they may “warp” the enzyme to keep it activated.

In analyzing the structure of these allosteric mutants, Dr Kalodimos and his colleagues discovered the mutants altered Abl’s shape to activate it and did not interfere with how imatinib plugs into the kinase domain.

This finding points the way to new treatments to overcome such resistance, according to Dr Kalodimos.

“There is now a new generation of drugs that bind to the allosteric pocket to inhibit its activity,” he said. “These could be combined with [imatinib] to overcome allosteric mutations to shift Abl into an inhibited state.”

Dr Kalodimos said that treatment strategy could also be applied to other forms of leukemia that have uncontrolled Bcr-Abl activity. And this new basic understanding of Abl regulation will yield insight into similar enzymes in which allosteric regulation controls a kinase domain.

Lab mouse

Preclinical research suggests 2 drugs already approved for use in the US may improve upon tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML).

The drugs are prostaglandin E1 (PGE1), which is used to treat erectile dysfunction, and misoprostol, which is used to prevent stomach ulcers.

Researchers found that each of these drugs could suppress leukemic stem cells (LSCs) and enhance the activity of imatinib in mice with CML.

Hai-Hui (Howard) Xue, MD, PhD, of University of Iowa in Iowa City, and his colleagues reported these findings in Cell Stem Cell.

“A successful treatment [for CML] is expected to kill the bulk leukemia cells and, at the same time, get rid of the leukemic stem cells,” Dr Xue said. “Potentially, that could lead to a cure.”

Therefore, Dr Xue and his colleagues set out to find drugs that could eradicate LSCs.

The researchers had previously shown that CML LSCs are “strongly dependent” on 2 transcription factors—Tcf1 and Lef1—for self-renewal, whereas normal hematopoietic stem and progenitor cells are not.

With their current research, the team found that Tcf1/Lef1 deficiency “at least partly impairs the transcriptional program” that maintains LSCs in mice and humans with CML.

So the researchers used connectivity maps to identify molecules that could replicate Tcf1/Lef1 deficiency. This screen revealed PGE1.

The team found that PGE1 inhibited the activity and self-renewal of CML LSCs. And the combination of PGE1 and imatinib could reduce leukemia growth in mouse models of CML.

When the mice received no treatment or imatinib alone, LSCs persisted. However, PGE1 enhanced the efficacy of imatinib, and mice that received this combination saw their LSCs “greatly diminished.”

The researchers then transplanted LSCs from these mice into secondary hosts and monitored their survival without administering additional treatment.

Mice that received PGE1-pretreated LSCs lived significantly longer (P<0.001) than mice that received imatinib-pretreated LSCs. And mice that received LSCs pretreated with PGE1 and imatinib lived significantly longer than mice that received PGE1-pretreated LSCs (P=0.039).

Investigating how PGE1 works to suppress LSCs, the researchers found the effect relies on a critical interaction between PGE1 and its receptor, EP4.

So the team tested misoprostol, which also interacts with EP4, in mice with CML.

The researchers found that misoprostol alone diminished LSCs, and the combination of misoprostol and imatinib “exhibited stronger effects.”

In addition, mice that received LSCs from animals previously treated with misoprostol survived longer and had a reduction in leukemia burden compared to mice that received untreated LSCs.

“We would like to be able to test these compounds in a clinical trial,” Dr Xue said. “If we could show that the combination of TKI with PGE1 or misoprostol can eliminate both the bulk tumor cells and the stem cells that keep the tumor going, that could potentially eliminate the cancer to the point where a patient would no longer need to depend on TKI.”

Lab mouse

Preclinical research suggests 2 drugs already approved for use in the US may improve upon tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML).

The drugs are prostaglandin E1 (PGE1), which is used to treat erectile dysfunction, and misoprostol, which is used to prevent stomach ulcers.

Researchers found that each of these drugs could suppress leukemic stem cells (LSCs) and enhance the activity of imatinib in mice with CML.

Hai-Hui (Howard) Xue, MD, PhD, of University of Iowa in Iowa City, and his colleagues reported these findings in Cell Stem Cell.

“A successful treatment [for CML] is expected to kill the bulk leukemia cells and, at the same time, get rid of the leukemic stem cells,” Dr Xue said. “Potentially, that could lead to a cure.”

Therefore, Dr Xue and his colleagues set out to find drugs that could eradicate LSCs.

The researchers had previously shown that CML LSCs are “strongly dependent” on 2 transcription factors—Tcf1 and Lef1—for self-renewal, whereas normal hematopoietic stem and progenitor cells are not.

With their current research, the team found that Tcf1/Lef1 deficiency “at least partly impairs the transcriptional program” that maintains LSCs in mice and humans with CML.

So the researchers used connectivity maps to identify molecules that could replicate Tcf1/Lef1 deficiency. This screen revealed PGE1.

The team found that PGE1 inhibited the activity and self-renewal of CML LSCs. And the combination of PGE1 and imatinib could reduce leukemia growth in mouse models of CML.

When the mice received no treatment or imatinib alone, LSCs persisted. However, PGE1 enhanced the efficacy of imatinib, and mice that received this combination saw their LSCs “greatly diminished.”

The researchers then transplanted LSCs from these mice into secondary hosts and monitored their survival without administering additional treatment.

Mice that received PGE1-pretreated LSCs lived significantly longer (P<0.001) than mice that received imatinib-pretreated LSCs. And mice that received LSCs pretreated with PGE1 and imatinib lived significantly longer than mice that received PGE1-pretreated LSCs (P=0.039).

Investigating how PGE1 works to suppress LSCs, the researchers found the effect relies on a critical interaction between PGE1 and its receptor, EP4.

So the team tested misoprostol, which also interacts with EP4, in mice with CML.

The researchers found that misoprostol alone diminished LSCs, and the combination of misoprostol and imatinib “exhibited stronger effects.”

In addition, mice that received LSCs from animals previously treated with misoprostol survived longer and had a reduction in leukemia burden compared to mice that received untreated LSCs.

“We would like to be able to test these compounds in a clinical trial,” Dr Xue said. “If we could show that the combination of TKI with PGE1 or misoprostol can eliminate both the bulk tumor cells and the stem cells that keep the tumor going, that could potentially eliminate the cancer to the point where a patient would no longer need to depend on TKI.”

Lab mouse

Preclinical research suggests 2 drugs already approved for use in the US may improve upon tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML).

The drugs are prostaglandin E1 (PGE1), which is used to treat erectile dysfunction, and misoprostol, which is used to prevent stomach ulcers.

Researchers found that each of these drugs could suppress leukemic stem cells (LSCs) and enhance the activity of imatinib in mice with CML.

Hai-Hui (Howard) Xue, MD, PhD, of University of Iowa in Iowa City, and his colleagues reported these findings in Cell Stem Cell.

“A successful treatment [for CML] is expected to kill the bulk leukemia cells and, at the same time, get rid of the leukemic stem cells,” Dr Xue said. “Potentially, that could lead to a cure.”

Therefore, Dr Xue and his colleagues set out to find drugs that could eradicate LSCs.

The researchers had previously shown that CML LSCs are “strongly dependent” on 2 transcription factors—Tcf1 and Lef1—for self-renewal, whereas normal hematopoietic stem and progenitor cells are not.

With their current research, the team found that Tcf1/Lef1 deficiency “at least partly impairs the transcriptional program” that maintains LSCs in mice and humans with CML.

So the researchers used connectivity maps to identify molecules that could replicate Tcf1/Lef1 deficiency. This screen revealed PGE1.

The team found that PGE1 inhibited the activity and self-renewal of CML LSCs. And the combination of PGE1 and imatinib could reduce leukemia growth in mouse models of CML.

When the mice received no treatment or imatinib alone, LSCs persisted. However, PGE1 enhanced the efficacy of imatinib, and mice that received this combination saw their LSCs “greatly diminished.”

The researchers then transplanted LSCs from these mice into secondary hosts and monitored their survival without administering additional treatment.

Mice that received PGE1-pretreated LSCs lived significantly longer (P<0.001) than mice that received imatinib-pretreated LSCs. And mice that received LSCs pretreated with PGE1 and imatinib lived significantly longer than mice that received PGE1-pretreated LSCs (P=0.039).

Investigating how PGE1 works to suppress LSCs, the researchers found the effect relies on a critical interaction between PGE1 and its receptor, EP4.

So the team tested misoprostol, which also interacts with EP4, in mice with CML.

The researchers found that misoprostol alone diminished LSCs, and the combination of misoprostol and imatinib “exhibited stronger effects.”

In addition, mice that received LSCs from animals previously treated with misoprostol survived longer and had a reduction in leukemia burden compared to mice that received untreated LSCs.

“We would like to be able to test these compounds in a clinical trial,” Dr Xue said. “If we could show that the combination of TKI with PGE1 or misoprostol can eliminate both the bulk tumor cells and the stem cells that keep the tumor going, that could potentially eliminate the cancer to the point where a patient would no longer need to depend on TKI.”

Image by Difu Wu

The antibiotic tigecycline may enhance the treatment of chronic myeloid leukemia (CML), according to research published in Nature Medicine. ‌

Using cells isolated from CML patients, researchers showed that treatment with tigecycline, an antibiotic used to treat bacterial infection, is effective in killing CML stem cells when used in combination with the tyrosine kinase inhibitor (TKI) imatinib.

The study also suggested the combination can stave off relapse in animal models of CML.

“We were very excited to find that, when we treated CML cells with both the antibiotic tigecycline and the TKI drug imatinib, CML stem cells were selectively killed,” said study author Vignir Helgason, PhD, of the University of Glasgow in Scotland.

“We believe that our findings provide a strong basis for testing this novel therapeutic strategy in clinical trials in order to eliminate CML stem cells and provide cure for CML patients.”

The researchers said they found that, in primitive CML stem and progenitor cells, mitochondrial oxidative metabolism is crucial for the production of energy and anabolic precursors. This suggested that restraining mitochondrial functions might have a therapeutic benefit in CML.

The team knew that, in addition to inhibiting bacterial protein synthesis, tigecycline inhibits the synthesis of mitochondrion-encoded proteins, which are required for the oxidative phosphorylation machinery.

So the researchers tested tigecycline, alone or in combination with imatinib, in CML cells. Both treatments (tigecycline monotherapy and the combination) “strongly impaired” the proliferation of primary CD34+ CML cells.

However, imatinib alone had “a moderate effect.” The researchers said this is in line with the preferential effect of imatinib on differentiated CD34− cells.

Each drug alone decreased the number of short-term CML colony-forming cells (CFCs), and the combination eliminated colony formation entirely. This correlated with an increase in cell death.

Neither monotherapy nor the combination had a significant effect on non-leukemic CFCs.

The researchers then turned to a xenotransplantation model of human CML. Starting 6 weeks after transplant, mice received daily doses of vehicle, tigecycline (escalating doses of 25–100 mg per kg body weight), imatinib (100 mg per kg body weight), or both drugs. All treatment was given for 4 weeks.

The team said there were no signs of toxicity in any of the mice.

Compared to controls, tigecycline-treated mice had a marginal decrease in the total number of CML-derived CD45+ cells in the bone marrow, and imatinib-treated mice had a significant decrease in these cells. But the CML burden decreased even further with combination treatment.

The researchers noted that imatinib alone marginally decreased the number of CD45+CD34+CD38− CML cells, but combination treatment eliminated 95% of these cells.

Finally, the team tested each drug alone and in combination (as well as vehicle control) in additional cohorts of mice with CML. After receiving treatment for 4 weeks, mice were left untreated for either 2 weeks or 3 weeks.

Mice that received imatinib alone showed signs of relapse at 2 and 3 weeks, as they had similar numbers of leukemic cells as vehicle-treated mice. However, most of the mice treated with the combination had low numbers of leukemic stem cells in the bone marrow.

“Our work in this study demonstrates, for the first time, that CML stem cells are metabolically distinct from normal blood stem cells, and this, in turn, provides opportunities to selectively target them,” said study author Eyal Gottlieb, PhD, of the Cancer Research UK Beatson Institute in Glasgow.

“It’s exciting to see that using an antibiotic alongside an existing treatment could be a way to keep this type of leukemia at bay and potentially even cure it,” added Karen Vousden, PhD, Cancer Research UK’s chief scientist.

“If this approach is shown to be safe and effective in humans too, it could offer a new option for patients who, at the moment, face long-term treatment with the possibility of relapse.”

This research was funded by AstraZeneca, Cancer Research UK, The Medical Research Council, Scottish Government Chief Scientist Office, The Howat Foundation, Friends of the Paul O’Gorman Leukaemia Research Centre, Bloodwise, The Kay Kendall Leukaemia Fund, Lady Tata International Award, and Leuka.

Image by Difu Wu

The antibiotic tigecycline may enhance the treatment of chronic myeloid leukemia (CML), according to research published in Nature Medicine. ‌

Using cells isolated from CML patients, researchers showed that treatment with tigecycline, an antibiotic used to treat bacterial infection, is effective in killing CML stem cells when used in combination with the tyrosine kinase inhibitor (TKI) imatinib.

The study also suggested the combination can stave off relapse in animal models of CML.

“We were very excited to find that, when we treated CML cells with both the antibiotic tigecycline and the TKI drug imatinib, CML stem cells were selectively killed,” said study author Vignir Helgason, PhD, of the University of Glasgow in Scotland.

“We believe that our findings provide a strong basis for testing this novel therapeutic strategy in clinical trials in order to eliminate CML stem cells and provide cure for CML patients.”

The researchers said they found that, in primitive CML stem and progenitor cells, mitochondrial oxidative metabolism is crucial for the production of energy and anabolic precursors. This suggested that restraining mitochondrial functions might have a therapeutic benefit in CML.

The team knew that, in addition to inhibiting bacterial protein synthesis, tigecycline inhibits the synthesis of mitochondrion-encoded proteins, which are required for the oxidative phosphorylation machinery.

So the researchers tested tigecycline, alone or in combination with imatinib, in CML cells. Both treatments (tigecycline monotherapy and the combination) “strongly impaired” the proliferation of primary CD34+ CML cells.

However, imatinib alone had “a moderate effect.” The researchers said this is in line with the preferential effect of imatinib on differentiated CD34− cells.

Each drug alone decreased the number of short-term CML colony-forming cells (CFCs), and the combination eliminated colony formation entirely. This correlated with an increase in cell death.

Neither monotherapy nor the combination had a significant effect on non-leukemic CFCs.

The researchers then turned to a xenotransplantation model of human CML. Starting 6 weeks after transplant, mice received daily doses of vehicle, tigecycline (escalating doses of 25–100 mg per kg body weight), imatinib (100 mg per kg body weight), or both drugs. All treatment was given for 4 weeks.

The team said there were no signs of toxicity in any of the mice.

Compared to controls, tigecycline-treated mice had a marginal decrease in the total number of CML-derived CD45+ cells in the bone marrow, and imatinib-treated mice had a significant decrease in these cells. But the CML burden decreased even further with combination treatment.

The researchers noted that imatinib alone marginally decreased the number of CD45+CD34+CD38− CML cells, but combination treatment eliminated 95% of these cells.

Finally, the team tested each drug alone and in combination (as well as vehicle control) in additional cohorts of mice with CML. After receiving treatment for 4 weeks, mice were left untreated for either 2 weeks or 3 weeks.

Mice that received imatinib alone showed signs of relapse at 2 and 3 weeks, as they had similar numbers of leukemic cells as vehicle-treated mice. However, most of the mice treated with the combination had low numbers of leukemic stem cells in the bone marrow.

“Our work in this study demonstrates, for the first time, that CML stem cells are metabolically distinct from normal blood stem cells, and this, in turn, provides opportunities to selectively target them,” said study author Eyal Gottlieb, PhD, of the Cancer Research UK Beatson Institute in Glasgow.

“It’s exciting to see that using an antibiotic alongside an existing treatment could be a way to keep this type of leukemia at bay and potentially even cure it,” added Karen Vousden, PhD, Cancer Research UK’s chief scientist.

“If this approach is shown to be safe and effective in humans too, it could offer a new option for patients who, at the moment, face long-term treatment with the possibility of relapse.”

This research was funded by AstraZeneca, Cancer Research UK, The Medical Research Council, Scottish Government Chief Scientist Office, The Howat Foundation, Friends of the Paul O’Gorman Leukaemia Research Centre, Bloodwise, The Kay Kendall Leukaemia Fund, Lady Tata International Award, and Leuka.

Image by Difu Wu

The antibiotic tigecycline may enhance the treatment of chronic myeloid leukemia (CML), according to research published in Nature Medicine. ‌

Using cells isolated from CML patients, researchers showed that treatment with tigecycline, an antibiotic used to treat bacterial infection, is effective in killing CML stem cells when used in combination with the tyrosine kinase inhibitor (TKI) imatinib.

The study also suggested the combination can stave off relapse in animal models of CML.

“We were very excited to find that, when we treated CML cells with both the antibiotic tigecycline and the TKI drug imatinib, CML stem cells were selectively killed,” said study author Vignir Helgason, PhD, of the University of Glasgow in Scotland.

“We believe that our findings provide a strong basis for testing this novel therapeutic strategy in clinical trials in order to eliminate CML stem cells and provide cure for CML patients.”

The researchers said they found that, in primitive CML stem and progenitor cells, mitochondrial oxidative metabolism is crucial for the production of energy and anabolic precursors. This suggested that restraining mitochondrial functions might have a therapeutic benefit in CML.

The team knew that, in addition to inhibiting bacterial protein synthesis, tigecycline inhibits the synthesis of mitochondrion-encoded proteins, which are required for the oxidative phosphorylation machinery.

So the researchers tested tigecycline, alone or in combination with imatinib, in CML cells. Both treatments (tigecycline monotherapy and the combination) “strongly impaired” the proliferation of primary CD34+ CML cells.

However, imatinib alone had “a moderate effect.” The researchers said this is in line with the preferential effect of imatinib on differentiated CD34− cells.

Each drug alone decreased the number of short-term CML colony-forming cells (CFCs), and the combination eliminated colony formation entirely. This correlated with an increase in cell death.

Neither monotherapy nor the combination had a significant effect on non-leukemic CFCs.

The researchers then turned to a xenotransplantation model of human CML. Starting 6 weeks after transplant, mice received daily doses of vehicle, tigecycline (escalating doses of 25–100 mg per kg body weight), imatinib (100 mg per kg body weight), or both drugs. All treatment was given for 4 weeks.

The team said there were no signs of toxicity in any of the mice.

Compared to controls, tigecycline-treated mice had a marginal decrease in the total number of CML-derived CD45+ cells in the bone marrow, and imatinib-treated mice had a significant decrease in these cells. But the CML burden decreased even further with combination treatment.

The researchers noted that imatinib alone marginally decreased the number of CD45+CD34+CD38− CML cells, but combination treatment eliminated 95% of these cells.

Finally, the team tested each drug alone and in combination (as well as vehicle control) in additional cohorts of mice with CML. After receiving treatment for 4 weeks, mice were left untreated for either 2 weeks or 3 weeks.

Mice that received imatinib alone showed signs of relapse at 2 and 3 weeks, as they had similar numbers of leukemic cells as vehicle-treated mice. However, most of the mice treated with the combination had low numbers of leukemic stem cells in the bone marrow.

“Our work in this study demonstrates, for the first time, that CML stem cells are metabolically distinct from normal blood stem cells, and this, in turn, provides opportunities to selectively target them,” said study author Eyal Gottlieb, PhD, of the Cancer Research UK Beatson Institute in Glasgow.

“It’s exciting to see that using an antibiotic alongside an existing treatment could be a way to keep this type of leukemia at bay and potentially even cure it,” added Karen Vousden, PhD, Cancer Research UK’s chief scientist.

“If this approach is shown to be safe and effective in humans too, it could offer a new option for patients who, at the moment, face long-term treatment with the possibility of relapse.”

This research was funded by AstraZeneca, Cancer Research UK, The Medical Research Council, Scottish Government Chief Scientist Office, The Howat Foundation, Friends of the Paul O’Gorman Leukaemia Research Centre, Bloodwise, The Kay Kendall Leukaemia Fund, Lady Tata International Award, and Leuka.

Photo by Patrick Pelletier

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.

The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:

• As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
• As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
• As monotherapy for adults with Ph+ CML in blast crisis.
• Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
• As monotherapy for adults with relapsed or refractory Ph+ ALL.
• As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
• As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
• As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
• For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.

The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.

In adult and pediatric patients, the effectiveness of imatinib is based on:

• Overall hematologic and cytogenetic response rates and progression-free survival in CML
• Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
• Hematologic response rates in HES/CEL
• Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
• Recurrence-free survival in adjuvant GIST.

The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Photo by Patrick Pelletier

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.

The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:

• As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
• As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
• As monotherapy for adults with Ph+ CML in blast crisis.
• Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
• As monotherapy for adults with relapsed or refractory Ph+ ALL.
• As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
• As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
• As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
• For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.

The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.

In adult and pediatric patients, the effectiveness of imatinib is based on:

• Overall hematologic and cytogenetic response rates and progression-free survival in CML
• Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
• Hematologic response rates in HES/CEL
• Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
• Recurrence-free survival in adjuvant GIST.

The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Photo by Patrick Pelletier

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.

The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:

• As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
• As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
• As monotherapy for adults with Ph+ CML in blast crisis.
• Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
• As monotherapy for adults with relapsed or refractory Ph+ ALL.
• As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
• As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
• As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
• For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.

The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.

In adult and pediatric patients, the effectiveness of imatinib is based on:

• Overall hematologic and cytogenetic response rates and progression-free survival in CML
• Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
• Hematologic response rates in HES/CEL
• Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
• Recurrence-free survival in adjuvant GIST.

The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Photo from Novartis

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the authorized use for nilotinib (Tasigna) to include pediatric patients.

At present, nilotinib is approved for use in the European Economic Area to treat adults with chronic myeloid leukemia (CML).

The drug is used to treat adults with newly diagnosed, Philadelphia-chromosome-positive (Ph+), chronic phase CML and adults with chronic or accelerated phase, Ph+ CML with resistance or intolerance to prior therapy, including imatinib.

The CHMP has recommended expanding the marketing authorization of nilotinib to include pediatric patients with newly diagnosed, Ph+, chronic phase CML and pediatric patients with chronic phase, Ph+ CML with resistance or intolerance to prior therapy, including imatinib.

Detailed recommendations for the use of nilotinib will be described in the updated summary of product characteristics, which will be published in the revised European public assessment report. It will be available in all official European Union languages after a decision on this change to the marketing authorization has been granted by the European Commission (EC).

The EC typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The EC’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

Photo from Novartis

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the authorized use for nilotinib (Tasigna) to include pediatric patients.

At present, nilotinib is approved for use in the European Economic Area to treat adults with chronic myeloid leukemia (CML).

The drug is used to treat adults with newly diagnosed, Philadelphia-chromosome-positive (Ph+), chronic phase CML and adults with chronic or accelerated phase, Ph+ CML with resistance or intolerance to prior therapy, including imatinib.

The CHMP has recommended expanding the marketing authorization of nilotinib to include pediatric patients with newly diagnosed, Ph+, chronic phase CML and pediatric patients with chronic phase, Ph+ CML with resistance or intolerance to prior therapy, including imatinib.

Detailed recommendations for the use of nilotinib will be described in the updated summary of product characteristics, which will be published in the revised European public assessment report. It will be available in all official European Union languages after a decision on this change to the marketing authorization has been granted by the European Commission (EC).

The EC typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The EC’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

Photo from Novartis

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the authorized use for nilotinib (Tasigna) to include pediatric patients.

At present, nilotinib is approved for use in the European Economic Area to treat adults with chronic myeloid leukemia (CML).

The drug is used to treat adults with newly diagnosed, Philadelphia-chromosome-positive (Ph+), chronic phase CML and adults with chronic or accelerated phase, Ph+ CML with resistance or intolerance to prior therapy, including imatinib.

The CHMP has recommended expanding the marketing authorization of nilotinib to include pediatric patients with newly diagnosed, Ph+, chronic phase CML and pediatric patients with chronic phase, Ph+ CML with resistance or intolerance to prior therapy, including imatinib.

Detailed recommendations for the use of nilotinib will be described in the updated summary of product characteristics, which will be published in the revised European public assessment report. It will be available in all official European Union languages after a decision on this change to the marketing authorization has been granted by the European Commission (EC).

The EC typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The EC’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Image by Difu Wu

The US Food and Drug Administration (FDA) has granted priority review to a supplemental new drug application (sNDA) for the tyrosine kinase inhibitor (TKI) bosutinib (Bosulif®).

If approved, the sNDA would expand the use of bosutinib to include patients with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML).

Bosutinib is currently FDA-approved to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the sNDA for bosutinib by the end of this year.

Meanwhile, the European Medicines Agency (EMA) has validated for review a type II variation application for bosutinib in patients with newly diagnosed, chronic phase Ph+ CML.

Bosutinib already has conditional marketing authorization in the European Economic Area for the treatment of adults with Ph+ CML who previously received at least 1 TKI and adults with Ph+ CML for whom imatinib, nilotinib, and dasatinib are not considered appropriate.

Phase 3 trial

The applications submitted to the EMA and FDA are both supported by early results from the phase 3 BFORE trial. Results from this trial were presented at the ASCO Annual Meeting in May.

In this ongoing study, researchers are comparing bosutinib and imatinib as first-line treatment of chronic phase CML.

As of the ASCO presentation, the trial had enrolled 536 patients who were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).

The presentation included results in a modified intent-to-treat population of Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.

Most of the patients were still on therapy at the 12-month mark or beyond—78% in the bosutinib arm and 73.2% in the imatinib arm. The median treatment duration was 14.1 months and 13.8 months, respectively.

At 12 months, the rate of major molecular response was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P= 0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).

One patient in the bosutinib arm and 4 in the imatinib arm discontinued treatment due to disease progression, while 12.7% and 8.7%, respectively, discontinued treatment due to drug-related toxicity.

Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%). Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).

Image by Difu Wu

The US Food and Drug Administration (FDA) has granted priority review to a supplemental new drug application (sNDA) for the tyrosine kinase inhibitor (TKI) bosutinib (Bosulif®).

If approved, the sNDA would expand the use of bosutinib to include patients with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML).

Bosutinib is currently FDA-approved to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the sNDA for bosutinib by the end of this year.

Meanwhile, the European Medicines Agency (EMA) has validated for review a type II variation application for bosutinib in patients with newly diagnosed, chronic phase Ph+ CML.

Bosutinib already has conditional marketing authorization in the European Economic Area for the treatment of adults with Ph+ CML who previously received at least 1 TKI and adults with Ph+ CML for whom imatinib, nilotinib, and dasatinib are not considered appropriate.

Phase 3 trial

The applications submitted to the EMA and FDA are both supported by early results from the phase 3 BFORE trial. Results from this trial were presented at the ASCO Annual Meeting in May.

In this ongoing study, researchers are comparing bosutinib and imatinib as first-line treatment of chronic phase CML.

As of the ASCO presentation, the trial had enrolled 536 patients who were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).

The presentation included results in a modified intent-to-treat population of Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.

Most of the patients were still on therapy at the 12-month mark or beyond—78% in the bosutinib arm and 73.2% in the imatinib arm. The median treatment duration was 14.1 months and 13.8 months, respectively.

At 12 months, the rate of major molecular response was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P= 0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).

One patient in the bosutinib arm and 4 in the imatinib arm discontinued treatment due to disease progression, while 12.7% and 8.7%, respectively, discontinued treatment due to drug-related toxicity.

Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%). Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).

Image by Difu Wu

The US Food and Drug Administration (FDA) has granted priority review to a supplemental new drug application (sNDA) for the tyrosine kinase inhibitor (TKI) bosutinib (Bosulif®).

If approved, the sNDA would expand the use of bosutinib to include patients with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML).

Bosutinib is currently FDA-approved to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA plans to make a decision on the sNDA for bosutinib by the end of this year.

Meanwhile, the European Medicines Agency (EMA) has validated for review a type II variation application for bosutinib in patients with newly diagnosed, chronic phase Ph+ CML.

Bosutinib already has conditional marketing authorization in the European Economic Area for the treatment of adults with Ph+ CML who previously received at least 1 TKI and adults with Ph+ CML for whom imatinib, nilotinib, and dasatinib are not considered appropriate.

Phase 3 trial

The applications submitted to the EMA and FDA are both supported by early results from the phase 3 BFORE trial. Results from this trial were presented at the ASCO Annual Meeting in May.

In this ongoing study, researchers are comparing bosutinib and imatinib as first-line treatment of chronic phase CML.

As of the ASCO presentation, the trial had enrolled 536 patients who were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).

The presentation included results in a modified intent-to-treat population of Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.

Most of the patients were still on therapy at the 12-month mark or beyond—78% in the bosutinib arm and 73.2% in the imatinib arm. The median treatment duration was 14.1 months and 13.8 months, respectively.

At 12 months, the rate of major molecular response was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P= 0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).

One patient in the bosutinib arm and 4 in the imatinib arm discontinued treatment due to disease progression, while 12.7% and 8.7%, respectively, discontinued treatment due to drug-related toxicity.

Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%). Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).

Mast cells

Stem cell factor (SCF) and KIT signaling are not necessary for early mast cell development, according to research published in Blood.

It has been assumed that the differentiation of hematopoietic progenitors to mast cells requires SCF and KIT signaling.

However, researchers found that mast cell progenitors can survive, mature, and proliferate in the absence of SCF and KIT signaling.

The researchers began this work by analyzing mast cell progenitor populations in samples from healthy subjects, patients with chronic myeloid leukemia (CML) or gastrointestinal stromal tumors (GIST) who were treated with imatinib, and patients with systemic mastocytosis carrying the D816V KIT mutation.

Imatinib inhibits KIT signaling, and the D816V KIT mutation causes KIT signaling to be constitutively active.

The researchers found the imatinib-treated CML and GIST patients and the patients with systemic mastocytosis all had mast cell progenitor populations similar to those observed in healthy subjects.

The team therefore concluded that dysfunctional KIT signaling does not affect the frequency of circulating mast cell progenitors in vivo.

On the other hand, the researchers also found that circulating mast cells were sensitive to imatinib in patients with CML. The patients had higher numbers of peripheral blood mast cells at diagnosis than they did after treatment with imatinib.

“When the patients were treated with the drug imatinib, which blocks the effect of stem cell factor, the number of mature mast cells dropped, while the number of progenitor cells did not change,” said study author Gunnar Nilsson, PhD, of Karolinska Institutet in Stockholm, Sweden.

Subsequent experiments showed that mast cell progenitors can survive in vitro without KIT signaling and without SCF. In addition, mast cell progenitors were able to mature and proliferate in vitro without SCF.

In fact, the researchers said they found that interleukin 3 was sufficient to promote the survival of mast cell progenitors in vitro.

“The study increases our understanding of how mast cells are formed and could be important in the development of new therapies, for example, for mastocytosis . . . ,” said study author Joakim Dahlin, PhD, of the University of Cambridge in the UK.

“One hypothesis that we will now test is whether interleukin 3 can be a new target in the treatment of mast cell-driven diseases.”

Mast cells

Stem cell factor (SCF) and KIT signaling are not necessary for early mast cell development, according to research published in Blood.

It has been assumed that the differentiation of hematopoietic progenitors to mast cells requires SCF and KIT signaling.

However, researchers found that mast cell progenitors can survive, mature, and proliferate in the absence of SCF and KIT signaling.

The researchers began this work by analyzing mast cell progenitor populations in samples from healthy subjects, patients with chronic myeloid leukemia (CML) or gastrointestinal stromal tumors (GIST) who were treated with imatinib, and patients with systemic mastocytosis carrying the D816V KIT mutation.

Imatinib inhibits KIT signaling, and the D816V KIT mutation causes KIT signaling to be constitutively active.

The researchers found the imatinib-treated CML and GIST patients and the patients with systemic mastocytosis all had mast cell progenitor populations similar to those observed in healthy subjects.

The team therefore concluded that dysfunctional KIT signaling does not affect the frequency of circulating mast cell progenitors in vivo.

On the other hand, the researchers also found that circulating mast cells were sensitive to imatinib in patients with CML. The patients had higher numbers of peripheral blood mast cells at diagnosis than they did after treatment with imatinib.

“When the patients were treated with the drug imatinib, which blocks the effect of stem cell factor, the number of mature mast cells dropped, while the number of progenitor cells did not change,” said study author Gunnar Nilsson, PhD, of Karolinska Institutet in Stockholm, Sweden.

Subsequent experiments showed that mast cell progenitors can survive in vitro without KIT signaling and without SCF. In addition, mast cell progenitors were able to mature and proliferate in vitro without SCF.

In fact, the researchers said they found that interleukin 3 was sufficient to promote the survival of mast cell progenitors in vitro.

“The study increases our understanding of how mast cells are formed and could be important in the development of new therapies, for example, for mastocytosis . . . ,” said study author Joakim Dahlin, PhD, of the University of Cambridge in the UK.

“One hypothesis that we will now test is whether interleukin 3 can be a new target in the treatment of mast cell-driven diseases.”

Mast cells

Stem cell factor (SCF) and KIT signaling are not necessary for early mast cell development, according to research published in Blood.

It has been assumed that the differentiation of hematopoietic progenitors to mast cells requires SCF and KIT signaling.

However, researchers found that mast cell progenitors can survive, mature, and proliferate in the absence of SCF and KIT signaling.

The researchers began this work by analyzing mast cell progenitor populations in samples from healthy subjects, patients with chronic myeloid leukemia (CML) or gastrointestinal stromal tumors (GIST) who were treated with imatinib, and patients with systemic mastocytosis carrying the D816V KIT mutation.

Imatinib inhibits KIT signaling, and the D816V KIT mutation causes KIT signaling to be constitutively active.

The researchers found the imatinib-treated CML and GIST patients and the patients with systemic mastocytosis all had mast cell progenitor populations similar to those observed in healthy subjects.

The team therefore concluded that dysfunctional KIT signaling does not affect the frequency of circulating mast cell progenitors in vivo.

On the other hand, the researchers also found that circulating mast cells were sensitive to imatinib in patients with CML. The patients had higher numbers of peripheral blood mast cells at diagnosis than they did after treatment with imatinib.

“When the patients were treated with the drug imatinib, which blocks the effect of stem cell factor, the number of mature mast cells dropped, while the number of progenitor cells did not change,” said study author Gunnar Nilsson, PhD, of Karolinska Institutet in Stockholm, Sweden.

Subsequent experiments showed that mast cell progenitors can survive in vitro without KIT signaling and without SCF. In addition, mast cell progenitors were able to mature and proliferate in vitro without SCF.

In fact, the researchers said they found that interleukin 3 was sufficient to promote the survival of mast cell progenitors in vitro.

“The study increases our understanding of how mast cells are formed and could be important in the development of new therapies, for example, for mastocytosis . . . ,” said study author Joakim Dahlin, PhD, of the University of Cambridge in the UK.

“One hypothesis that we will now test is whether interleukin 3 can be a new target in the treatment of mast cell-driven diseases.”