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Sequencing aids management of young cancer patients
patient and her father
Photo by Rhoda Baer
Exome and transcriptome sequencing results can inform the management of young patients with relapsed, refractory, and rare malignancies, a new study suggests.
In a consecutive case series, sequencing data revealed potentially actionable findings for 46% of patients.
As a result, 15% of patients changed treatment, and 10% underwent genetic counseling.
Investigators described this research in JAMA.
“We found that, for some children with rare, difficult-to-treat, and aggressive cancers, this technology can dramatically change the course of their treatment,” said study author Rajen Mody, MBBS, of the University of Michigan in Ann Arbor.
Dr Mody and his colleagues evaluated 102 patients with relapsed, refractory, or rare cancers. Their median age was 11.5 (range, 0-22).
The patients underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing. Ninety-one patients (89%) had adequate tumor tissue to complete sequencing, including 28 patients (31%) with hematologic malignancies and 63 (69%) with solid tumors.
All sequencing results were discussed at a precision medicine tumor board, which included pediatric and adult oncologists, pathologists, genetics specialists, and other professionals. This group discussed the results and assessed the feasibility of pursuing treatment options based on the findings.
Actionable findings
Forty-two patients (46%) had potentially actionable findings, 15 (54%) with hematologic malignancies and 27 (43%) with solid tumors.
Actionable findings included a change in diagnosis (n=2), the presence of a genetic anomaly that could be targeted by an approved or experimental drug (n=31), and the need for genetic counseling for inherited cancer risk that could affect the patient or the whole family (n=9).
“We were excited to see an actionable finding in such a substantial percentage of patients, and we think it could potentially be higher over time,” said study author Arul Chinnaiyan, MD, PhD, also of the University of Michigan.
“These are patients who had exhausted all proven therapeutic options or who had an extremely rare diagnosis. If we can find a clinically actionable event and have a chance to act upon it, we show in this study that it can have a big impact on that patient.”
Actions were taken in 23 of the 42 patients. Fourteen patients (15%) had their treatment changed, and 9 of these patients (10%) had durable partial or complete remissions (CRs) as a result.
Nine patients (10%) underwent genetic counseling because of sequencing results. The researchers noted that 4 of these patients had no notable family history to suggest an inherited risk, and they would not otherwise have been referred for genetic counseling.
Hematologic malignancies
Fifteen patients with hematologic malignancies had potentially actionable findings, and 4 underwent treatment changes as a result. (None of the patients required genetic counseling.)
For a patient with pre-B acute lymphoblastic leukemia (ALL), sequencing revealed a homozygous CDKN2A deletion and an ETV6-ABL1 fusion. So the patient was placed on imatinib and had a sustained CR for 21 months.
A patient with early T-cell precursor ALL had a FLT3-ITD mutation, Chr16p gain, Chr16q loss, and FLT3 overexpression. The patient achieved a CR after transplant, was placed on the FLT3 inhibitor sorafenib, and remained in CR for 15 months.
Another patient with pre-B ALL had a FLT3 nonframeshift deletion and BLK and FLT3 overexpression. The patient was in CR for 9 months after a transplant and received sorafenib for 6 months.
A patient with biphenotypic leukemia had mutations in NRAS and PHF6; SPI1, ASXL1, and CBLC frameshift insertions; a JAK3-activating mutation; and JAK3 overexpression. The patient received the JAK3 inhibitor tofacitinib but could not tolerate the full dose and died of progressive disease.
Cost and turn-around time
The cost for sequencing was approximately $6000 per patient and was covered under the research protocol.
It took the researchers about 7 to 8 weeks to report the sequencing results back to treating physicians and families.
“These are early days, and the full promise of precision medicine is yet to be fully realized,” Dr Mody said. “We need better targeted therapies designed for children, and turnaround time for sequencing needs to be less than 2 weeks for it to be a regular part of a patient’s treatment plan.” 
patient and her father
Photo by Rhoda Baer
Exome and transcriptome sequencing results can inform the management of young patients with relapsed, refractory, and rare malignancies, a new study suggests.
In a consecutive case series, sequencing data revealed potentially actionable findings for 46% of patients.
As a result, 15% of patients changed treatment, and 10% underwent genetic counseling.
Investigators described this research in JAMA.
“We found that, for some children with rare, difficult-to-treat, and aggressive cancers, this technology can dramatically change the course of their treatment,” said study author Rajen Mody, MBBS, of the University of Michigan in Ann Arbor.
Dr Mody and his colleagues evaluated 102 patients with relapsed, refractory, or rare cancers. Their median age was 11.5 (range, 0-22).
The patients underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing. Ninety-one patients (89%) had adequate tumor tissue to complete sequencing, including 28 patients (31%) with hematologic malignancies and 63 (69%) with solid tumors.
All sequencing results were discussed at a precision medicine tumor board, which included pediatric and adult oncologists, pathologists, genetics specialists, and other professionals. This group discussed the results and assessed the feasibility of pursuing treatment options based on the findings.
Actionable findings
Forty-two patients (46%) had potentially actionable findings, 15 (54%) with hematologic malignancies and 27 (43%) with solid tumors.
Actionable findings included a change in diagnosis (n=2), the presence of a genetic anomaly that could be targeted by an approved or experimental drug (n=31), and the need for genetic counseling for inherited cancer risk that could affect the patient or the whole family (n=9).
“We were excited to see an actionable finding in such a substantial percentage of patients, and we think it could potentially be higher over time,” said study author Arul Chinnaiyan, MD, PhD, also of the University of Michigan.
“These are patients who had exhausted all proven therapeutic options or who had an extremely rare diagnosis. If we can find a clinically actionable event and have a chance to act upon it, we show in this study that it can have a big impact on that patient.”
Actions were taken in 23 of the 42 patients. Fourteen patients (15%) had their treatment changed, and 9 of these patients (10%) had durable partial or complete remissions (CRs) as a result.
Nine patients (10%) underwent genetic counseling because of sequencing results. The researchers noted that 4 of these patients had no notable family history to suggest an inherited risk, and they would not otherwise have been referred for genetic counseling.
Hematologic malignancies
Fifteen patients with hematologic malignancies had potentially actionable findings, and 4 underwent treatment changes as a result. (None of the patients required genetic counseling.)
For a patient with pre-B acute lymphoblastic leukemia (ALL), sequencing revealed a homozygous CDKN2A deletion and an ETV6-ABL1 fusion. So the patient was placed on imatinib and had a sustained CR for 21 months.
A patient with early T-cell precursor ALL had a FLT3-ITD mutation, Chr16p gain, Chr16q loss, and FLT3 overexpression. The patient achieved a CR after transplant, was placed on the FLT3 inhibitor sorafenib, and remained in CR for 15 months.
Another patient with pre-B ALL had a FLT3 nonframeshift deletion and BLK and FLT3 overexpression. The patient was in CR for 9 months after a transplant and received sorafenib for 6 months.
A patient with biphenotypic leukemia had mutations in NRAS and PHF6; SPI1, ASXL1, and CBLC frameshift insertions; a JAK3-activating mutation; and JAK3 overexpression. The patient received the JAK3 inhibitor tofacitinib but could not tolerate the full dose and died of progressive disease.
Cost and turn-around time
The cost for sequencing was approximately $6000 per patient and was covered under the research protocol.
It took the researchers about 7 to 8 weeks to report the sequencing results back to treating physicians and families.
“These are early days, and the full promise of precision medicine is yet to be fully realized,” Dr Mody said. “We need better targeted therapies designed for children, and turnaround time for sequencing needs to be less than 2 weeks for it to be a regular part of a patient’s treatment plan.”
patient and her father
Photo by Rhoda Baer
Exome and transcriptome sequencing results can inform the management of young patients with relapsed, refractory, and rare malignancies, a new study suggests.
In a consecutive case series, sequencing data revealed potentially actionable findings for 46% of patients.
As a result, 15% of patients changed treatment, and 10% underwent genetic counseling.
Investigators described this research in JAMA.
“We found that, for some children with rare, difficult-to-treat, and aggressive cancers, this technology can dramatically change the course of their treatment,” said study author Rajen Mody, MBBS, of the University of Michigan in Ann Arbor.
Dr Mody and his colleagues evaluated 102 patients with relapsed, refractory, or rare cancers. Their median age was 11.5 (range, 0-22).
The patients underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing. Ninety-one patients (89%) had adequate tumor tissue to complete sequencing, including 28 patients (31%) with hematologic malignancies and 63 (69%) with solid tumors.
All sequencing results were discussed at a precision medicine tumor board, which included pediatric and adult oncologists, pathologists, genetics specialists, and other professionals. This group discussed the results and assessed the feasibility of pursuing treatment options based on the findings.
Actionable findings
Forty-two patients (46%) had potentially actionable findings, 15 (54%) with hematologic malignancies and 27 (43%) with solid tumors.
Actionable findings included a change in diagnosis (n=2), the presence of a genetic anomaly that could be targeted by an approved or experimental drug (n=31), and the need for genetic counseling for inherited cancer risk that could affect the patient or the whole family (n=9).
“We were excited to see an actionable finding in such a substantial percentage of patients, and we think it could potentially be higher over time,” said study author Arul Chinnaiyan, MD, PhD, also of the University of Michigan.
“These are patients who had exhausted all proven therapeutic options or who had an extremely rare diagnosis. If we can find a clinically actionable event and have a chance to act upon it, we show in this study that it can have a big impact on that patient.”
Actions were taken in 23 of the 42 patients. Fourteen patients (15%) had their treatment changed, and 9 of these patients (10%) had durable partial or complete remissions (CRs) as a result.
Nine patients (10%) underwent genetic counseling because of sequencing results. The researchers noted that 4 of these patients had no notable family history to suggest an inherited risk, and they would not otherwise have been referred for genetic counseling.
Hematologic malignancies
Fifteen patients with hematologic malignancies had potentially actionable findings, and 4 underwent treatment changes as a result. (None of the patients required genetic counseling.)
For a patient with pre-B acute lymphoblastic leukemia (ALL), sequencing revealed a homozygous CDKN2A deletion and an ETV6-ABL1 fusion. So the patient was placed on imatinib and had a sustained CR for 21 months.
A patient with early T-cell precursor ALL had a FLT3-ITD mutation, Chr16p gain, Chr16q loss, and FLT3 overexpression. The patient achieved a CR after transplant, was placed on the FLT3 inhibitor sorafenib, and remained in CR for 15 months.
Another patient with pre-B ALL had a FLT3 nonframeshift deletion and BLK and FLT3 overexpression. The patient was in CR for 9 months after a transplant and received sorafenib for 6 months.
A patient with biphenotypic leukemia had mutations in NRAS and PHF6; SPI1, ASXL1, and CBLC frameshift insertions; a JAK3-activating mutation; and JAK3 overexpression. The patient received the JAK3 inhibitor tofacitinib but could not tolerate the full dose and died of progressive disease.
Cost and turn-around time
The cost for sequencing was approximately $6000 per patient and was covered under the research protocol.
It took the researchers about 7 to 8 weeks to report the sequencing results back to treating physicians and families.
“These are early days, and the full promise of precision medicine is yet to be fully realized,” Dr Mody said. “We need better targeted therapies designed for children, and turnaround time for sequencing needs to be less than 2 weeks for it to be a regular part of a patient’s treatment plan.”
A new, improved treatment approach for lymphoma?
Researchers believe they have discovered how therapy targeting CD47 harnesses the immune system to fight lymphoma and other cancers.
Conducting experiments in immune-competent mice, the team found that anti-CD47 therapy drives T-cell mediated elimination of lymphoma, colon cancer, and breast cancer.
The group’s research also revealed how the timing of chemotherapy administration affects anti-CD47 therapy.
Yang-Xin Fu, MD, PhD, of the University of Chicago in Illinois, and his colleagues described this research in Nature Medicine.
Previous research had shown that many cancer cells have CD47 on their surface. The protein instructs circulating macrophages not to devour the cells, but anti-CD47 therapy can negate this effect. This research relied on human tumors transplanted in immunocompromised mice.
With the current study, Dr Fu and his colleagues transplanted tumors from mice into genetically identical hosts with intact immune systems.
The team’s experiments revealed that anti-CD47-mediated tumor rejection requires both innate and adaptive immune responses. And the bulk of the therapeutic effect from CD47 blockade relies not on macrophages but on dendritic cells.
Dendritic cells proved more potent than macrophages at priming CD8+ T cells. Dendritic cells also caused type-1 interferon to boost adaptive immunity and activated the STING pathway, which was “absolutely essential for the antitumor effect of anti-CD47 therapy.”
The researchers also found evidence to suggest that chemotherapy should be administered before, rather than after, anti-CD47 therapy.
The team tested the anti-CD47 monoclonal antibody (mAb) MIAP301 in combination with clinically equivalent doses of cyclophosphamide or paclitaxel in mouse models of lymphoma (established A20 tumors).
When the chemotherapy was administered after the mAb, tumor regression was no faster than when the mAb was given alone.
In fact, the chemotherapy appeared to hinder antitumor memory responses generated by the mAb. When the researchers removed all tumors and rechallenged the mice with A20 cells, all of the mice that had received the mAb alone rejected the tumor rechallenge.
But mice that had received the mAb followed by chemotherapy were susceptible to tumor outgrowth—50% of cyclophosphamide-treated mice and 80% of paclitaxel-treated mice.
When chemotherapy was given before the mAb, however, it conferred benefits. A single dose of either chemotherapy drug synergized with the mAb to fight lymphoma.
And the treatment preserved the host memory response against relapsing tumors. All of the cyclophosphamide-treated mice and 80% of the paclitaxel-treated mice were resistant to tumor rechallenge.
The researchers said this suggests the order of treatment administration could have a major impact on primary and memory immune responses to tumors and alter outcomes of anti-CD47 therapy.
“Our results point to a new and more personalized strategy to modulate the tumor microenvironment,” Dr Fu said. “We think our approach, along with further investigation of scheduling and dosing, could improve survival and quality of life for patients battling advanced cancer.”
Researchers believe they have discovered how therapy targeting CD47 harnesses the immune system to fight lymphoma and other cancers.
Conducting experiments in immune-competent mice, the team found that anti-CD47 therapy drives T-cell mediated elimination of lymphoma, colon cancer, and breast cancer.
The group’s research also revealed how the timing of chemotherapy administration affects anti-CD47 therapy.
Yang-Xin Fu, MD, PhD, of the University of Chicago in Illinois, and his colleagues described this research in Nature Medicine.
Previous research had shown that many cancer cells have CD47 on their surface. The protein instructs circulating macrophages not to devour the cells, but anti-CD47 therapy can negate this effect. This research relied on human tumors transplanted in immunocompromised mice.
With the current study, Dr Fu and his colleagues transplanted tumors from mice into genetically identical hosts with intact immune systems.
The team’s experiments revealed that anti-CD47-mediated tumor rejection requires both innate and adaptive immune responses. And the bulk of the therapeutic effect from CD47 blockade relies not on macrophages but on dendritic cells.
Dendritic cells proved more potent than macrophages at priming CD8+ T cells. Dendritic cells also caused type-1 interferon to boost adaptive immunity and activated the STING pathway, which was “absolutely essential for the antitumor effect of anti-CD47 therapy.”
The researchers also found evidence to suggest that chemotherapy should be administered before, rather than after, anti-CD47 therapy.
The team tested the anti-CD47 monoclonal antibody (mAb) MIAP301 in combination with clinically equivalent doses of cyclophosphamide or paclitaxel in mouse models of lymphoma (established A20 tumors).
When the chemotherapy was administered after the mAb, tumor regression was no faster than when the mAb was given alone.
In fact, the chemotherapy appeared to hinder antitumor memory responses generated by the mAb. When the researchers removed all tumors and rechallenged the mice with A20 cells, all of the mice that had received the mAb alone rejected the tumor rechallenge.
But mice that had received the mAb followed by chemotherapy were susceptible to tumor outgrowth—50% of cyclophosphamide-treated mice and 80% of paclitaxel-treated mice.
When chemotherapy was given before the mAb, however, it conferred benefits. A single dose of either chemotherapy drug synergized with the mAb to fight lymphoma.
And the treatment preserved the host memory response against relapsing tumors. All of the cyclophosphamide-treated mice and 80% of the paclitaxel-treated mice were resistant to tumor rechallenge.
The researchers said this suggests the order of treatment administration could have a major impact on primary and memory immune responses to tumors and alter outcomes of anti-CD47 therapy.
“Our results point to a new and more personalized strategy to modulate the tumor microenvironment,” Dr Fu said. “We think our approach, along with further investigation of scheduling and dosing, could improve survival and quality of life for patients battling advanced cancer.”
Researchers believe they have discovered how therapy targeting CD47 harnesses the immune system to fight lymphoma and other cancers.
Conducting experiments in immune-competent mice, the team found that anti-CD47 therapy drives T-cell mediated elimination of lymphoma, colon cancer, and breast cancer.
The group’s research also revealed how the timing of chemotherapy administration affects anti-CD47 therapy.
Yang-Xin Fu, MD, PhD, of the University of Chicago in Illinois, and his colleagues described this research in Nature Medicine.
Previous research had shown that many cancer cells have CD47 on their surface. The protein instructs circulating macrophages not to devour the cells, but anti-CD47 therapy can negate this effect. This research relied on human tumors transplanted in immunocompromised mice.
With the current study, Dr Fu and his colleagues transplanted tumors from mice into genetically identical hosts with intact immune systems.
The team’s experiments revealed that anti-CD47-mediated tumor rejection requires both innate and adaptive immune responses. And the bulk of the therapeutic effect from CD47 blockade relies not on macrophages but on dendritic cells.
Dendritic cells proved more potent than macrophages at priming CD8+ T cells. Dendritic cells also caused type-1 interferon to boost adaptive immunity and activated the STING pathway, which was “absolutely essential for the antitumor effect of anti-CD47 therapy.”
The researchers also found evidence to suggest that chemotherapy should be administered before, rather than after, anti-CD47 therapy.
The team tested the anti-CD47 monoclonal antibody (mAb) MIAP301 in combination with clinically equivalent doses of cyclophosphamide or paclitaxel in mouse models of lymphoma (established A20 tumors).
When the chemotherapy was administered after the mAb, tumor regression was no faster than when the mAb was given alone.
In fact, the chemotherapy appeared to hinder antitumor memory responses generated by the mAb. When the researchers removed all tumors and rechallenged the mice with A20 cells, all of the mice that had received the mAb alone rejected the tumor rechallenge.
But mice that had received the mAb followed by chemotherapy were susceptible to tumor outgrowth—50% of cyclophosphamide-treated mice and 80% of paclitaxel-treated mice.
When chemotherapy was given before the mAb, however, it conferred benefits. A single dose of either chemotherapy drug synergized with the mAb to fight lymphoma.
And the treatment preserved the host memory response against relapsing tumors. All of the cyclophosphamide-treated mice and 80% of the paclitaxel-treated mice were resistant to tumor rechallenge.
The researchers said this suggests the order of treatment administration could have a major impact on primary and memory immune responses to tumors and alter outcomes of anti-CD47 therapy.
“Our results point to a new and more personalized strategy to modulate the tumor microenvironment,” Dr Fu said. “We think our approach, along with further investigation of scheduling and dosing, could improve survival and quality of life for patients battling advanced cancer.”
Daratumumab monotherapy impresses in hard-to-treat multiple myeloma
Daratumumab monotherapy yielded impressive results in patients with heavily pretreated and refractory multiple myeloma, according to the full results of a phase I/II study published online by the New England Journal of Medicine.
Among 42 patients receiving 16 mg/kg of daratumumab in part 2 of the study, the overall response rate was 36%, including 2 complete responses, 2 very good partial responses, and 11 partial responses.
Median progression-free survival was 5.6 months. Responses deepened over time, with 65% of responders remaining progression-free at 12 months, study author Dr. Henk M. Lokhorst, of University Medical Center Utrecht, and the VU University Medical Center, Amsterdam, both in the Netherlands, and his associates reported (N Engl J Med. 2015 Aug. 26 [doi:10.1056/NEJMoa1506348]).
In 30 patients given daratumumab 8 mg/kg, the response rate was 10%, including three partial responses.
Patients in part 2 of the study were heavily pretreated with a median of four prior lines of therapy (range 2-12) and 64% were refractory to the current standard treatment of protease inhibitors (PIs) and immunomodulatory agents (IMiDs). Such patients have a poor prognosis, with an estimated median overall survival of 9 months and estimated event-free survival of 5 months at best, Dr. Lokhorst and his associates noted.
“Daratumumab showed single-agent antitumor activity in a population of patients with highly difficult-to-treat myeloma who had very few effective treatment options,” the investigators concluded. “Its target and mechanisms of action differentiate it from existing therapies.”
Daratumumab is a human monoclonal antibody that targets CD38, which is uniformly overexpressed in multiple myeloma cells.
In part 1, the dose-escalation phase of the study, no maximum-tolerated dose was identified at doses up to 24 mg/kg in 32 patients. Two dose-limiting toxicities – grade 3 anemia and grade 3 elevated aspartate aminotransferase levels – occurred at 0.1 mg/kg and 1 mg/kg, but no further events were seen with dose escalation, Dr. Lokhorst and associates reported.
The most-common adverse events in part 2 of the study – occurring in at least 25% of patients – were fatigue, allergic rhinitis, and pyrexia. Infusion-related reactions were mild and were seen in 71% of patients, typically during the first infusion.
The most-common grade 3/4 events were pneumonia (five patients) and thrombocytopenia (four patients). Neutropenia, leukopenia, anemia, and hyperglycemia occurred in two patients each. There was one grade 5 pneumonia, but investigators did not think it was related to the study drug, they wrote.
Exploratory subgroup analyses revealed that response rates were similar in patients with disease refractory to both bortezomib (Velcade) and lenalidomide (Revlimid) and the total population, but were higher in patients with two or three prior lines of therapy vs. more heavily pretreated patients (56% vs. 23%).
Data from the study were included in a Biologics License Application submitted in July 2015 to the U.S. Food and Drug Administration for daratumumab as a treatment for patients with multiple myeloma who have received at least three prior lines of therapy including both a PI and an IMiD or who are double refractory to a PI and an IMiD, according to Genmab.
Daratumumab, which has already been granted breakthrough therapy status by the FDA, is being develop by Janssen Biotech, under an exclusive license from Genmab.
On Twitter @pwendl
The single-agent activity of daratumumab, including complete responses, in this patient population is surprising and very encouraging. These results are probably due to its pleiotropic mechanisms of action against myeloma.
The introduction of monoclonal antibodies into the arsenal against myeloma is game-changing in multiple myeloma treatment. These agents have the advantage of an immune-based approach without the need for patient-specific cell manipulation. Their limited toxicity allows for easy combining with existing therapies.
Even with this enthusiasm, unanswered questions remain. How do tumors escape the effects of daratumumab? Can daratumumab, like rituximab in the treatment of lymphoma, be active in many phases of treatment, such as in induction, consolidation, and maintenance therapies? Can daratumumab resistance be predicted? As we begin to tackle the complexity of these questions, it is reassuring to know that we have yet one more treatment option that will contribute in an important way to improvement in outcomes in patients with myeloma.
These comments were excerpted from an editorial accompanying the report by Lokhorst et al. (N Engl J Med. 2015 Aug 26 [doi: 10.1056/NEJMe1509419]).
Dr. Noopur Raje is director of the multiple myeloma program at Massachusetts General Hospital, Boston. Dr. Dan L. Longo is a professor of medicine at Harvard Medical School, Boston.
The single-agent activity of daratumumab, including complete responses, in this patient population is surprising and very encouraging. These results are probably due to its pleiotropic mechanisms of action against myeloma.
The introduction of monoclonal antibodies into the arsenal against myeloma is game-changing in multiple myeloma treatment. These agents have the advantage of an immune-based approach without the need for patient-specific cell manipulation. Their limited toxicity allows for easy combining with existing therapies.
Even with this enthusiasm, unanswered questions remain. How do tumors escape the effects of daratumumab? Can daratumumab, like rituximab in the treatment of lymphoma, be active in many phases of treatment, such as in induction, consolidation, and maintenance therapies? Can daratumumab resistance be predicted? As we begin to tackle the complexity of these questions, it is reassuring to know that we have yet one more treatment option that will contribute in an important way to improvement in outcomes in patients with myeloma.
These comments were excerpted from an editorial accompanying the report by Lokhorst et al. (N Engl J Med. 2015 Aug 26 [doi: 10.1056/NEJMe1509419]).
Dr. Noopur Raje is director of the multiple myeloma program at Massachusetts General Hospital, Boston. Dr. Dan L. Longo is a professor of medicine at Harvard Medical School, Boston.
The single-agent activity of daratumumab, including complete responses, in this patient population is surprising and very encouraging. These results are probably due to its pleiotropic mechanisms of action against myeloma.
The introduction of monoclonal antibodies into the arsenal against myeloma is game-changing in multiple myeloma treatment. These agents have the advantage of an immune-based approach without the need for patient-specific cell manipulation. Their limited toxicity allows for easy combining with existing therapies.
Even with this enthusiasm, unanswered questions remain. How do tumors escape the effects of daratumumab? Can daratumumab, like rituximab in the treatment of lymphoma, be active in many phases of treatment, such as in induction, consolidation, and maintenance therapies? Can daratumumab resistance be predicted? As we begin to tackle the complexity of these questions, it is reassuring to know that we have yet one more treatment option that will contribute in an important way to improvement in outcomes in patients with myeloma.
These comments were excerpted from an editorial accompanying the report by Lokhorst et al. (N Engl J Med. 2015 Aug 26 [doi: 10.1056/NEJMe1509419]).
Dr. Noopur Raje is director of the multiple myeloma program at Massachusetts General Hospital, Boston. Dr. Dan L. Longo is a professor of medicine at Harvard Medical School, Boston.
Daratumumab monotherapy yielded impressive results in patients with heavily pretreated and refractory multiple myeloma, according to the full results of a phase I/II study published online by the New England Journal of Medicine.
Among 42 patients receiving 16 mg/kg of daratumumab in part 2 of the study, the overall response rate was 36%, including 2 complete responses, 2 very good partial responses, and 11 partial responses.
Median progression-free survival was 5.6 months. Responses deepened over time, with 65% of responders remaining progression-free at 12 months, study author Dr. Henk M. Lokhorst, of University Medical Center Utrecht, and the VU University Medical Center, Amsterdam, both in the Netherlands, and his associates reported (N Engl J Med. 2015 Aug. 26 [doi:10.1056/NEJMoa1506348]).
In 30 patients given daratumumab 8 mg/kg, the response rate was 10%, including three partial responses.
Patients in part 2 of the study were heavily pretreated with a median of four prior lines of therapy (range 2-12) and 64% were refractory to the current standard treatment of protease inhibitors (PIs) and immunomodulatory agents (IMiDs). Such patients have a poor prognosis, with an estimated median overall survival of 9 months and estimated event-free survival of 5 months at best, Dr. Lokhorst and his associates noted.
“Daratumumab showed single-agent antitumor activity in a population of patients with highly difficult-to-treat myeloma who had very few effective treatment options,” the investigators concluded. “Its target and mechanisms of action differentiate it from existing therapies.”
Daratumumab is a human monoclonal antibody that targets CD38, which is uniformly overexpressed in multiple myeloma cells.
In part 1, the dose-escalation phase of the study, no maximum-tolerated dose was identified at doses up to 24 mg/kg in 32 patients. Two dose-limiting toxicities – grade 3 anemia and grade 3 elevated aspartate aminotransferase levels – occurred at 0.1 mg/kg and 1 mg/kg, but no further events were seen with dose escalation, Dr. Lokhorst and associates reported.
The most-common adverse events in part 2 of the study – occurring in at least 25% of patients – were fatigue, allergic rhinitis, and pyrexia. Infusion-related reactions were mild and were seen in 71% of patients, typically during the first infusion.
The most-common grade 3/4 events were pneumonia (five patients) and thrombocytopenia (four patients). Neutropenia, leukopenia, anemia, and hyperglycemia occurred in two patients each. There was one grade 5 pneumonia, but investigators did not think it was related to the study drug, they wrote.
Exploratory subgroup analyses revealed that response rates were similar in patients with disease refractory to both bortezomib (Velcade) and lenalidomide (Revlimid) and the total population, but were higher in patients with two or three prior lines of therapy vs. more heavily pretreated patients (56% vs. 23%).
Data from the study were included in a Biologics License Application submitted in July 2015 to the U.S. Food and Drug Administration for daratumumab as a treatment for patients with multiple myeloma who have received at least three prior lines of therapy including both a PI and an IMiD or who are double refractory to a PI and an IMiD, according to Genmab.
Daratumumab, which has already been granted breakthrough therapy status by the FDA, is being develop by Janssen Biotech, under an exclusive license from Genmab.
On Twitter @pwendl
Daratumumab monotherapy yielded impressive results in patients with heavily pretreated and refractory multiple myeloma, according to the full results of a phase I/II study published online by the New England Journal of Medicine.
Among 42 patients receiving 16 mg/kg of daratumumab in part 2 of the study, the overall response rate was 36%, including 2 complete responses, 2 very good partial responses, and 11 partial responses.
Median progression-free survival was 5.6 months. Responses deepened over time, with 65% of responders remaining progression-free at 12 months, study author Dr. Henk M. Lokhorst, of University Medical Center Utrecht, and the VU University Medical Center, Amsterdam, both in the Netherlands, and his associates reported (N Engl J Med. 2015 Aug. 26 [doi:10.1056/NEJMoa1506348]).
In 30 patients given daratumumab 8 mg/kg, the response rate was 10%, including three partial responses.
Patients in part 2 of the study were heavily pretreated with a median of four prior lines of therapy (range 2-12) and 64% were refractory to the current standard treatment of protease inhibitors (PIs) and immunomodulatory agents (IMiDs). Such patients have a poor prognosis, with an estimated median overall survival of 9 months and estimated event-free survival of 5 months at best, Dr. Lokhorst and his associates noted.
“Daratumumab showed single-agent antitumor activity in a population of patients with highly difficult-to-treat myeloma who had very few effective treatment options,” the investigators concluded. “Its target and mechanisms of action differentiate it from existing therapies.”
Daratumumab is a human monoclonal antibody that targets CD38, which is uniformly overexpressed in multiple myeloma cells.
In part 1, the dose-escalation phase of the study, no maximum-tolerated dose was identified at doses up to 24 mg/kg in 32 patients. Two dose-limiting toxicities – grade 3 anemia and grade 3 elevated aspartate aminotransferase levels – occurred at 0.1 mg/kg and 1 mg/kg, but no further events were seen with dose escalation, Dr. Lokhorst and associates reported.
The most-common adverse events in part 2 of the study – occurring in at least 25% of patients – were fatigue, allergic rhinitis, and pyrexia. Infusion-related reactions were mild and were seen in 71% of patients, typically during the first infusion.
The most-common grade 3/4 events were pneumonia (five patients) and thrombocytopenia (four patients). Neutropenia, leukopenia, anemia, and hyperglycemia occurred in two patients each. There was one grade 5 pneumonia, but investigators did not think it was related to the study drug, they wrote.
Exploratory subgroup analyses revealed that response rates were similar in patients with disease refractory to both bortezomib (Velcade) and lenalidomide (Revlimid) and the total population, but were higher in patients with two or three prior lines of therapy vs. more heavily pretreated patients (56% vs. 23%).
Data from the study were included in a Biologics License Application submitted in July 2015 to the U.S. Food and Drug Administration for daratumumab as a treatment for patients with multiple myeloma who have received at least three prior lines of therapy including both a PI and an IMiD or who are double refractory to a PI and an IMiD, according to Genmab.
Daratumumab, which has already been granted breakthrough therapy status by the FDA, is being develop by Janssen Biotech, under an exclusive license from Genmab.
On Twitter @pwendl
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Daratumumab monotherapy has encouraging efficacy and a favorable safety profile in heavily pretreated and refractory multiple myeloma.
Major finding: The overall response rate was 36% with daratumumab 16 mg/kg.
Data source: Open-label phase I/II study in 104 patients with relapsed or refractory multiple myeloma.
Disclosures: The study was funded by Janssen Biotech and Genmab. Dr. Lokhorst reported grant support and personal fees from Genmab and Janssen and personal fees from Amgen. Several coauthors also reported fees from Janssen and/or Genmab. Dr. Raje reported personal fees from Celgene and Millennium/Takeda and grant support from Eli Lilly and AstraZeneca. Dr. Longo disclosed being employed as deputy editor at the New England Journal of Medicine.
Public uninformed about cancer therapies, survey suggests
receiving chemotherapy
Photo by Rhoda Baer
Results of a new survey suggest many adults in the UK may be uninformed about cancer treatment options, despite broad media coverage of these therapies.
Personalized drug treatment, immunotherapy, and proton beam therapy have all been covered by the lay media and featured in news stories across the globe.
But a survey of more than 2000 UK adults showed that most respondents were not aware of these treatment types.
Only 19% of respondents said they had heard about immunotherapy, 29% had heard of personalized drug treatment, and 30% had heard of proton beam therapy.
The survey, which included 2081 adults, was conducted online by YouGov in June. It was commissioned by Cancer Research UK and other members of the Radiotherapy Awareness Programme.
The primary goal of the survey was to examine public awareness of radiotherapy. And the results showed that many respondents were unaware of newer, more targeted radiotherapy options.
Respondents were largely uninformed about other types of cancer treatment as well. However, of the respondents who elected to give their opinion (n=1877), most said the National Health Service (NHS) should fund chemotherapy and other drug treatments over radiotherapy.
Survey questions and responses were as follows.
Radiotherapy
Before taking this survey, which, if any, of the following types of radiotherapy had you heard of?
| Intensity-modulated radiotherapy | 4% |
| Stereotactic radiotherapy/
stereotactic ablative radiotherapy |
3% |
| Image-guided radiotherapy | 9% |
| Proton beam therapy | 30% |
| Brachytherapy | 5% |
| Radiofrequency ablation | 7% |
| Cyberknife | 4% |
| Gammaknife | 6% |
| Higgs-boson radiotherapy
(red herring option) |
6% |
| Carbon ion radiotherapy
(red herring option) |
3% |
| None of these | 50% |
| Prefer not to say | 11% |
Other cancer treatments
Which, if any, of the following specific types of cancer treatments/tests had you heard of before taking this survey?
| Immunotherapy | 19% |
| Personalized drugs | 29% |
| Monoclonal antibodies | 5% |
| High-dose chemotherapy
with stem cell transplant |
26% |
| Tablet chemotherapy | 28% |
| Molecular diagnostic tests | 6% |
| Robotically assisted surgery/Da Vinci robot | 12% |
| Laparoscopic (keyhole) surgery | 39% |
| None of these | 32% |
| Prefer not to say | 11% |
NHS funding
What level of priority do you think the NHS should give to funding each of the following 4 types of cancer treatments?
| Treatment | 1st priority | 2nd priority | 3rd priority | Lowest priority |
| Chemotherapy &
other drug treatments |
57% | 29% | 10% | 4% |
| Surgery | 29% | 35% | 31% | 5% |
| Radiotherapy | 9% | 32% | 53% | 5% |
| Alternative treatments | 5% | 4% | 6% | 86% |
receiving chemotherapy
Photo by Rhoda Baer
Results of a new survey suggest many adults in the UK may be uninformed about cancer treatment options, despite broad media coverage of these therapies.
Personalized drug treatment, immunotherapy, and proton beam therapy have all been covered by the lay media and featured in news stories across the globe.
But a survey of more than 2000 UK adults showed that most respondents were not aware of these treatment types.
Only 19% of respondents said they had heard about immunotherapy, 29% had heard of personalized drug treatment, and 30% had heard of proton beam therapy.
The survey, which included 2081 adults, was conducted online by YouGov in June. It was commissioned by Cancer Research UK and other members of the Radiotherapy Awareness Programme.
The primary goal of the survey was to examine public awareness of radiotherapy. And the results showed that many respondents were unaware of newer, more targeted radiotherapy options.
Respondents were largely uninformed about other types of cancer treatment as well. However, of the respondents who elected to give their opinion (n=1877), most said the National Health Service (NHS) should fund chemotherapy and other drug treatments over radiotherapy.
Survey questions and responses were as follows.
Radiotherapy
Before taking this survey, which, if any, of the following types of radiotherapy had you heard of?
| Intensity-modulated radiotherapy | 4% |
| Stereotactic radiotherapy/
stereotactic ablative radiotherapy |
3% |
| Image-guided radiotherapy | 9% |
| Proton beam therapy | 30% |
| Brachytherapy | 5% |
| Radiofrequency ablation | 7% |
| Cyberknife | 4% |
| Gammaknife | 6% |
| Higgs-boson radiotherapy
(red herring option) |
6% |
| Carbon ion radiotherapy
(red herring option) |
3% |
| None of these | 50% |
| Prefer not to say | 11% |
Other cancer treatments
Which, if any, of the following specific types of cancer treatments/tests had you heard of before taking this survey?
| Immunotherapy | 19% |
| Personalized drugs | 29% |
| Monoclonal antibodies | 5% |
| High-dose chemotherapy
with stem cell transplant |
26% |
| Tablet chemotherapy | 28% |
| Molecular diagnostic tests | 6% |
| Robotically assisted surgery/Da Vinci robot | 12% |
| Laparoscopic (keyhole) surgery | 39% |
| None of these | 32% |
| Prefer not to say | 11% |
NHS funding
What level of priority do you think the NHS should give to funding each of the following 4 types of cancer treatments?
| Treatment | 1st priority | 2nd priority | 3rd priority | Lowest priority |
| Chemotherapy &
other drug treatments |
57% | 29% | 10% | 4% |
| Surgery | 29% | 35% | 31% | 5% |
| Radiotherapy | 9% | 32% | 53% | 5% |
| Alternative treatments | 5% | 4% | 6% | 86% |
receiving chemotherapy
Photo by Rhoda Baer
Results of a new survey suggest many adults in the UK may be uninformed about cancer treatment options, despite broad media coverage of these therapies.
Personalized drug treatment, immunotherapy, and proton beam therapy have all been covered by the lay media and featured in news stories across the globe.
But a survey of more than 2000 UK adults showed that most respondents were not aware of these treatment types.
Only 19% of respondents said they had heard about immunotherapy, 29% had heard of personalized drug treatment, and 30% had heard of proton beam therapy.
The survey, which included 2081 adults, was conducted online by YouGov in June. It was commissioned by Cancer Research UK and other members of the Radiotherapy Awareness Programme.
The primary goal of the survey was to examine public awareness of radiotherapy. And the results showed that many respondents were unaware of newer, more targeted radiotherapy options.
Respondents were largely uninformed about other types of cancer treatment as well. However, of the respondents who elected to give their opinion (n=1877), most said the National Health Service (NHS) should fund chemotherapy and other drug treatments over radiotherapy.
Survey questions and responses were as follows.
Radiotherapy
Before taking this survey, which, if any, of the following types of radiotherapy had you heard of?
| Intensity-modulated radiotherapy | 4% |
| Stereotactic radiotherapy/
stereotactic ablative radiotherapy |
3% |
| Image-guided radiotherapy | 9% |
| Proton beam therapy | 30% |
| Brachytherapy | 5% |
| Radiofrequency ablation | 7% |
| Cyberknife | 4% |
| Gammaknife | 6% |
| Higgs-boson radiotherapy
(red herring option) |
6% |
| Carbon ion radiotherapy
(red herring option) |
3% |
| None of these | 50% |
| Prefer not to say | 11% |
Other cancer treatments
Which, if any, of the following specific types of cancer treatments/tests had you heard of before taking this survey?
| Immunotherapy | 19% |
| Personalized drugs | 29% |
| Monoclonal antibodies | 5% |
| High-dose chemotherapy
with stem cell transplant |
26% |
| Tablet chemotherapy | 28% |
| Molecular diagnostic tests | 6% |
| Robotically assisted surgery/Da Vinci robot | 12% |
| Laparoscopic (keyhole) surgery | 39% |
| None of these | 32% |
| Prefer not to say | 11% |
NHS funding
What level of priority do you think the NHS should give to funding each of the following 4 types of cancer treatments?
| Treatment | 1st priority | 2nd priority | 3rd priority | Lowest priority |
| Chemotherapy &
other drug treatments |
57% | 29% | 10% | 4% |
| Surgery | 29% | 35% | 31% | 5% |
| Radiotherapy | 9% | 32% | 53% | 5% |
| Alternative treatments | 5% | 4% | 6% | 86% |
Protein may be key in virus, cancer research
Image courtesy of the
University of North Carolina
Researchers say they have uncovered a viral protein that inhibits cGAS, the principal cytosolic DNA sensor that detects invading viral DNA and triggers antiviral responses.
The protein, Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF52, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity.
The team believes this finding could have a range of therapeutic implications.
“We can manipulate the protein and/or the sensor to boost or tune down the immune response in order to fight infectious and autoimmune diseases, as well as cancers,” said Fanxiu Zhu, PhD, of Florida State University in Tallahassee.
Dr Zhu and his colleagues described this research in Cell Host and Microbe.
The authors noted that, although cGAS senses several DNA viruses, viral strategies targeting cGAS are “virtually unknown.”
To uncover a cGAS inhibitor, the researchers screened every protein in a KSHV cell—90 in total. This revealed KSHV ORF52, which the team renamed “KicGas,” an abbreviation for “KSHV inhibitor of cGAS.”
Further investigation revealed how KicGas inhibits cGAS activity: it must bind to both DNA and cGAS.
The researchers then found that ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA.
Finally, the team infected human cell lines with KSHV to mimic natural infection. They found that KSHV triggers a cGAS-dependent immune response that can be partially mitigated by KicGas.
When the researchers eliminated KicGas from infected cells, the cells produced a much stronger immune response.
For the next phase of research, the team is building a 3-dimensional model to help them better understand how KicGas functions. They hope this will help them utilize KicGas to fight disease.
Image courtesy of the
University of North Carolina
Researchers say they have uncovered a viral protein that inhibits cGAS, the principal cytosolic DNA sensor that detects invading viral DNA and triggers antiviral responses.
The protein, Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF52, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity.
The team believes this finding could have a range of therapeutic implications.
“We can manipulate the protein and/or the sensor to boost or tune down the immune response in order to fight infectious and autoimmune diseases, as well as cancers,” said Fanxiu Zhu, PhD, of Florida State University in Tallahassee.
Dr Zhu and his colleagues described this research in Cell Host and Microbe.
The authors noted that, although cGAS senses several DNA viruses, viral strategies targeting cGAS are “virtually unknown.”
To uncover a cGAS inhibitor, the researchers screened every protein in a KSHV cell—90 in total. This revealed KSHV ORF52, which the team renamed “KicGas,” an abbreviation for “KSHV inhibitor of cGAS.”
Further investigation revealed how KicGas inhibits cGAS activity: it must bind to both DNA and cGAS.
The researchers then found that ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA.
Finally, the team infected human cell lines with KSHV to mimic natural infection. They found that KSHV triggers a cGAS-dependent immune response that can be partially mitigated by KicGas.
When the researchers eliminated KicGas from infected cells, the cells produced a much stronger immune response.
For the next phase of research, the team is building a 3-dimensional model to help them better understand how KicGas functions. They hope this will help them utilize KicGas to fight disease.
Image courtesy of the
University of North Carolina
Researchers say they have uncovered a viral protein that inhibits cGAS, the principal cytosolic DNA sensor that detects invading viral DNA and triggers antiviral responses.
The protein, Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF52, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity.
The team believes this finding could have a range of therapeutic implications.
“We can manipulate the protein and/or the sensor to boost or tune down the immune response in order to fight infectious and autoimmune diseases, as well as cancers,” said Fanxiu Zhu, PhD, of Florida State University in Tallahassee.
Dr Zhu and his colleagues described this research in Cell Host and Microbe.
The authors noted that, although cGAS senses several DNA viruses, viral strategies targeting cGAS are “virtually unknown.”
To uncover a cGAS inhibitor, the researchers screened every protein in a KSHV cell—90 in total. This revealed KSHV ORF52, which the team renamed “KicGas,” an abbreviation for “KSHV inhibitor of cGAS.”
Further investigation revealed how KicGas inhibits cGAS activity: it must bind to both DNA and cGAS.
The researchers then found that ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA.
Finally, the team infected human cell lines with KSHV to mimic natural infection. They found that KSHV triggers a cGAS-dependent immune response that can be partially mitigated by KicGas.
When the researchers eliminated KicGas from infected cells, the cells produced a much stronger immune response.
For the next phase of research, the team is building a 3-dimensional model to help them better understand how KicGas functions. They hope this will help them utilize KicGas to fight disease.
Discovery reveals potential for viral cancer treatment
Image by Eric Smith
Researchers say they have discovered critical details that explain how a cellular response system tells the difference between damage to the body’s own DNA and the foreign DNA of an invading virus.
The team believes this discovery could aid the development of new cancer-selective viral therapies, and it may help explain why aging, cancers, and other diseases
seem to open the door to viral infections.
“Our study reveals fundamental mechanisms that distinguish DNA breaks at cellular and viral genomes to trigger different responses that protect the host,” said Clodagh O’Shea, of the Salk Institute for Biological Studies in La Jolla, California.
“The findings may also explain why certain conditions like aging, cancer chemotherapy, and inflammation make us more susceptible to viral infection.”
Dr O’Shea and Govind Shah, PhD, also of the Salk Institute, reported these findings in Cell.
The pair described how a cluster of proteins known as the MRN complex detects DNA breaks and amplifies its response through histones.
MRN starts a domino effect, activating histones on surrounding chromosomes, which summons a cascade of additional proteins and results in a cell-wide, all-hands-on-deck alarm to help mend the DNA.
If the cell can’t fix the DNA break, it will induce apoptosis—a self-destruct mechanism that helps to prevent mutated cells from replicating and therefore prevents tumor growth.
“What’s interesting is that even a single break transmits a global signal through the cell, halting cell division and growth,” Dr O’Shea said. “This response prevents replication so the cell doesn’t pass on a break.”
Drs O’Shea and Shah also found that, when it comes to defending against DNA viruses, the cell’s response system begins the same way—with MRN detecting breaks. But it never progresses to the global alarm signal in the case of the virus.
Typically, a common DNA virus enters the cell’s nucleus and turns on genes to replicate its own DNA. The cell detects the unauthorized replication, and the MRN complex grabs and selectively neutralizes viral DNA without triggering a global response that would arrest or kill the cell.
So the MRN response to the virus stays localized and only selectively prevents viral, but not cellular, replication.
When both threats to the genome are present, MRN will activate the massive response at the DNA break, and no MRN is left to respond to the virus. This means the virus is effectively ignored while the cell responds to the more massive alarm.
“The requirement of MRN for sensing both cellular and viral genome breaks has profound consequences,” Dr O’Shea said.
“When MRN is recruited to cellular DNA breaks, it can no longer sense and respond to incoming viral genomes. Thus, the act of responding to cellular genome breaks inactivates the host’s defenses to viral replication.”
Dr O’Shea said this may explain why people who have high levels of cellular DNA damage—such as cancer patients—are more susceptible to viral infections.
“Having damaged DNA compromises our cells’ ability to fight viral infection, while having healthy DNA boosts our cells’ ability to catch viral DNA,” Dr Shah said. “Our work implies that we may be able to engineer viruses that selectively kill cancer cells.”
The researchers aim to use this new knowledge to create viruses that are destroyed in normal cells but replicate specifically in cancer cells.
Unlike normal cells, cancer cells almost always have very high levels of DNA damage. In cancer cells, MRN is already so preoccupied with responding to DNA breaks that an engineered virus could sneak in undetected.
“Cancer cells, by definition, have high mutation rates and genomic instability even at the very earliest stages,” Dr O’Shea said. “So you could imagine building a virus that could destroy even the earliest lesions and be used as a prophylactic.”
Image by Eric Smith
Researchers say they have discovered critical details that explain how a cellular response system tells the difference between damage to the body’s own DNA and the foreign DNA of an invading virus.
The team believes this discovery could aid the development of new cancer-selective viral therapies, and it may help explain why aging, cancers, and other diseases
seem to open the door to viral infections.
“Our study reveals fundamental mechanisms that distinguish DNA breaks at cellular and viral genomes to trigger different responses that protect the host,” said Clodagh O’Shea, of the Salk Institute for Biological Studies in La Jolla, California.
“The findings may also explain why certain conditions like aging, cancer chemotherapy, and inflammation make us more susceptible to viral infection.”
Dr O’Shea and Govind Shah, PhD, also of the Salk Institute, reported these findings in Cell.
The pair described how a cluster of proteins known as the MRN complex detects DNA breaks and amplifies its response through histones.
MRN starts a domino effect, activating histones on surrounding chromosomes, which summons a cascade of additional proteins and results in a cell-wide, all-hands-on-deck alarm to help mend the DNA.
If the cell can’t fix the DNA break, it will induce apoptosis—a self-destruct mechanism that helps to prevent mutated cells from replicating and therefore prevents tumor growth.
“What’s interesting is that even a single break transmits a global signal through the cell, halting cell division and growth,” Dr O’Shea said. “This response prevents replication so the cell doesn’t pass on a break.”
Drs O’Shea and Shah also found that, when it comes to defending against DNA viruses, the cell’s response system begins the same way—with MRN detecting breaks. But it never progresses to the global alarm signal in the case of the virus.
Typically, a common DNA virus enters the cell’s nucleus and turns on genes to replicate its own DNA. The cell detects the unauthorized replication, and the MRN complex grabs and selectively neutralizes viral DNA without triggering a global response that would arrest or kill the cell.
So the MRN response to the virus stays localized and only selectively prevents viral, but not cellular, replication.
When both threats to the genome are present, MRN will activate the massive response at the DNA break, and no MRN is left to respond to the virus. This means the virus is effectively ignored while the cell responds to the more massive alarm.
“The requirement of MRN for sensing both cellular and viral genome breaks has profound consequences,” Dr O’Shea said.
“When MRN is recruited to cellular DNA breaks, it can no longer sense and respond to incoming viral genomes. Thus, the act of responding to cellular genome breaks inactivates the host’s defenses to viral replication.”
Dr O’Shea said this may explain why people who have high levels of cellular DNA damage—such as cancer patients—are more susceptible to viral infections.
“Having damaged DNA compromises our cells’ ability to fight viral infection, while having healthy DNA boosts our cells’ ability to catch viral DNA,” Dr Shah said. “Our work implies that we may be able to engineer viruses that selectively kill cancer cells.”
The researchers aim to use this new knowledge to create viruses that are destroyed in normal cells but replicate specifically in cancer cells.
Unlike normal cells, cancer cells almost always have very high levels of DNA damage. In cancer cells, MRN is already so preoccupied with responding to DNA breaks that an engineered virus could sneak in undetected.
“Cancer cells, by definition, have high mutation rates and genomic instability even at the very earliest stages,” Dr O’Shea said. “So you could imagine building a virus that could destroy even the earliest lesions and be used as a prophylactic.”
Image by Eric Smith
Researchers say they have discovered critical details that explain how a cellular response system tells the difference between damage to the body’s own DNA and the foreign DNA of an invading virus.
The team believes this discovery could aid the development of new cancer-selective viral therapies, and it may help explain why aging, cancers, and other diseases
seem to open the door to viral infections.
“Our study reveals fundamental mechanisms that distinguish DNA breaks at cellular and viral genomes to trigger different responses that protect the host,” said Clodagh O’Shea, of the Salk Institute for Biological Studies in La Jolla, California.
“The findings may also explain why certain conditions like aging, cancer chemotherapy, and inflammation make us more susceptible to viral infection.”
Dr O’Shea and Govind Shah, PhD, also of the Salk Institute, reported these findings in Cell.
The pair described how a cluster of proteins known as the MRN complex detects DNA breaks and amplifies its response through histones.
MRN starts a domino effect, activating histones on surrounding chromosomes, which summons a cascade of additional proteins and results in a cell-wide, all-hands-on-deck alarm to help mend the DNA.
If the cell can’t fix the DNA break, it will induce apoptosis—a self-destruct mechanism that helps to prevent mutated cells from replicating and therefore prevents tumor growth.
“What’s interesting is that even a single break transmits a global signal through the cell, halting cell division and growth,” Dr O’Shea said. “This response prevents replication so the cell doesn’t pass on a break.”
Drs O’Shea and Shah also found that, when it comes to defending against DNA viruses, the cell’s response system begins the same way—with MRN detecting breaks. But it never progresses to the global alarm signal in the case of the virus.
Typically, a common DNA virus enters the cell’s nucleus and turns on genes to replicate its own DNA. The cell detects the unauthorized replication, and the MRN complex grabs and selectively neutralizes viral DNA without triggering a global response that would arrest or kill the cell.
So the MRN response to the virus stays localized and only selectively prevents viral, but not cellular, replication.
When both threats to the genome are present, MRN will activate the massive response at the DNA break, and no MRN is left to respond to the virus. This means the virus is effectively ignored while the cell responds to the more massive alarm.
“The requirement of MRN for sensing both cellular and viral genome breaks has profound consequences,” Dr O’Shea said.
“When MRN is recruited to cellular DNA breaks, it can no longer sense and respond to incoming viral genomes. Thus, the act of responding to cellular genome breaks inactivates the host’s defenses to viral replication.”
Dr O’Shea said this may explain why people who have high levels of cellular DNA damage—such as cancer patients—are more susceptible to viral infections.
“Having damaged DNA compromises our cells’ ability to fight viral infection, while having healthy DNA boosts our cells’ ability to catch viral DNA,” Dr Shah said. “Our work implies that we may be able to engineer viruses that selectively kill cancer cells.”
The researchers aim to use this new knowledge to create viruses that are destroyed in normal cells but replicate specifically in cancer cells.
Unlike normal cells, cancer cells almost always have very high levels of DNA damage. In cancer cells, MRN is already so preoccupied with responding to DNA breaks that an engineered virus could sneak in undetected.
“Cancer cells, by definition, have high mutation rates and genomic instability even at the very earliest stages,” Dr O’Shea said. “So you could imagine building a virus that could destroy even the earliest lesions and be used as a prophylactic.”
Team quantifies CAM use among seniors with cancer
Photo by Rhoda Baer
A new study suggests that seniors with cancer may be taking complementary or alternative medicines (CAMs) without their oncologists’ knowledge.
In this single-center study, 27% of senior cancer patients took CAMs at some point during their cancer care.
CAM usage was highest among patients ages 80 to 89, women, Caucasians, and patients with solid tumor malignancies.
Polypharmacy and certain comorbidities were linked to CAM use as well.
Researchers reported these findings in the Journal of Geriatric Oncology.
“Currently, few oncologists are aware of the alternative medicines their patients take,” said study author Ginah Nightingale, PharmD, of Thomas Jefferson University in Philadelphia, Pennsylvania.
“Patients often fail to disclose the CAMs they take because they think they are safe, natural, nontoxic, and not relevant to their cancer care; because they think their doctor will disapprove; or because the doctor doesn’t specifically ask.”
To quantify CAM use in older cancer patients treated at their institution, Dr Nightingale and her colleagues surveyed patients who came to the Senior Adult Oncology Center at Thomas Jefferson University.
In a single visit, patients were seen by a medical oncologist, geriatrician, clinical pharmacist, social worker, and dietician. As part of this assessment, the patients brought in the contents of their medicine cabinets, and the medications they actively used were reviewed and recorded.
A total of 234 patients were included in the final analysis. Their mean age was 79.9 (range, 61–98). Most (87%) had solid tumor malignancies, were Caucasian (74%), and were female (64%).
In all, 26.5% of patients (n=62) had taken at least 1 CAM during their cancer care, with 19.2% taking 1 CAM, 6.4% taking 2, 0.4% taking 3, and 0.4% taking 4 or more CAMs. The highest number of CAMs taken was 10.
CAM usage was highest among patients ages 80 to 89, women, Caucasians, and patients with solid tumor malignancies.
Comorbidities significantly associated with CAM use were vision impairment (P=0.048) and urologic comorbidities (P=0.021). Polypharmacy (concurrent use of 5 or more medications) was significantly associated with CAM use as well (P=0.045).
Some of the commonly used CAMs were mega-dose vitamins or minerals, as well as treatments for macular degeneration, stomach probiotics, and joint health.
The researchers did not examine the potential adverse effects of these medications, but Dr Nightingale said some are known to have a biochemical effect on the body and other drugs.
“It is very important to do a comprehensive screen of all of the medications that older cancer patients take, including CAMs,” she added. “Clear and transparent documentation of CAM use should be recorded in the patient’s medical record. This documentation should indicate that patient-specific communication and/or education was provided so that shared and informed decisions by the patient can be made regarding the continued use of these medications.”
Photo by Rhoda Baer
A new study suggests that seniors with cancer may be taking complementary or alternative medicines (CAMs) without their oncologists’ knowledge.
In this single-center study, 27% of senior cancer patients took CAMs at some point during their cancer care.
CAM usage was highest among patients ages 80 to 89, women, Caucasians, and patients with solid tumor malignancies.
Polypharmacy and certain comorbidities were linked to CAM use as well.
Researchers reported these findings in the Journal of Geriatric Oncology.
“Currently, few oncologists are aware of the alternative medicines their patients take,” said study author Ginah Nightingale, PharmD, of Thomas Jefferson University in Philadelphia, Pennsylvania.
“Patients often fail to disclose the CAMs they take because they think they are safe, natural, nontoxic, and not relevant to their cancer care; because they think their doctor will disapprove; or because the doctor doesn’t specifically ask.”
To quantify CAM use in older cancer patients treated at their institution, Dr Nightingale and her colleagues surveyed patients who came to the Senior Adult Oncology Center at Thomas Jefferson University.
In a single visit, patients were seen by a medical oncologist, geriatrician, clinical pharmacist, social worker, and dietician. As part of this assessment, the patients brought in the contents of their medicine cabinets, and the medications they actively used were reviewed and recorded.
A total of 234 patients were included in the final analysis. Their mean age was 79.9 (range, 61–98). Most (87%) had solid tumor malignancies, were Caucasian (74%), and were female (64%).
In all, 26.5% of patients (n=62) had taken at least 1 CAM during their cancer care, with 19.2% taking 1 CAM, 6.4% taking 2, 0.4% taking 3, and 0.4% taking 4 or more CAMs. The highest number of CAMs taken was 10.
CAM usage was highest among patients ages 80 to 89, women, Caucasians, and patients with solid tumor malignancies.
Comorbidities significantly associated with CAM use were vision impairment (P=0.048) and urologic comorbidities (P=0.021). Polypharmacy (concurrent use of 5 or more medications) was significantly associated with CAM use as well (P=0.045).
Some of the commonly used CAMs were mega-dose vitamins or minerals, as well as treatments for macular degeneration, stomach probiotics, and joint health.
The researchers did not examine the potential adverse effects of these medications, but Dr Nightingale said some are known to have a biochemical effect on the body and other drugs.
“It is very important to do a comprehensive screen of all of the medications that older cancer patients take, including CAMs,” she added. “Clear and transparent documentation of CAM use should be recorded in the patient’s medical record. This documentation should indicate that patient-specific communication and/or education was provided so that shared and informed decisions by the patient can be made regarding the continued use of these medications.”
Photo by Rhoda Baer
A new study suggests that seniors with cancer may be taking complementary or alternative medicines (CAMs) without their oncologists’ knowledge.
In this single-center study, 27% of senior cancer patients took CAMs at some point during their cancer care.
CAM usage was highest among patients ages 80 to 89, women, Caucasians, and patients with solid tumor malignancies.
Polypharmacy and certain comorbidities were linked to CAM use as well.
Researchers reported these findings in the Journal of Geriatric Oncology.
“Currently, few oncologists are aware of the alternative medicines their patients take,” said study author Ginah Nightingale, PharmD, of Thomas Jefferson University in Philadelphia, Pennsylvania.
“Patients often fail to disclose the CAMs they take because they think they are safe, natural, nontoxic, and not relevant to their cancer care; because they think their doctor will disapprove; or because the doctor doesn’t specifically ask.”
To quantify CAM use in older cancer patients treated at their institution, Dr Nightingale and her colleagues surveyed patients who came to the Senior Adult Oncology Center at Thomas Jefferson University.
In a single visit, patients were seen by a medical oncologist, geriatrician, clinical pharmacist, social worker, and dietician. As part of this assessment, the patients brought in the contents of their medicine cabinets, and the medications they actively used were reviewed and recorded.
A total of 234 patients were included in the final analysis. Their mean age was 79.9 (range, 61–98). Most (87%) had solid tumor malignancies, were Caucasian (74%), and were female (64%).
In all, 26.5% of patients (n=62) had taken at least 1 CAM during their cancer care, with 19.2% taking 1 CAM, 6.4% taking 2, 0.4% taking 3, and 0.4% taking 4 or more CAMs. The highest number of CAMs taken was 10.
CAM usage was highest among patients ages 80 to 89, women, Caucasians, and patients with solid tumor malignancies.
Comorbidities significantly associated with CAM use were vision impairment (P=0.048) and urologic comorbidities (P=0.021). Polypharmacy (concurrent use of 5 or more medications) was significantly associated with CAM use as well (P=0.045).
Some of the commonly used CAMs were mega-dose vitamins or minerals, as well as treatments for macular degeneration, stomach probiotics, and joint health.
The researchers did not examine the potential adverse effects of these medications, but Dr Nightingale said some are known to have a biochemical effect on the body and other drugs.
“It is very important to do a comprehensive screen of all of the medications that older cancer patients take, including CAMs,” she added. “Clear and transparent documentation of CAM use should be recorded in the patient’s medical record. This documentation should indicate that patient-specific communication and/or education was provided so that shared and informed decisions by the patient can be made regarding the continued use of these medications.”
Genomic oncology: moving beyond the tip of the iceberg
In the 15 years since the first map of the human genome emerged, genetics has become an integral part of medical practice worldwide.1 Oncology is no exception; the genetic origins of cancer were suspected more than a century ago and it is now well understood that most cancers are driven by genetic alterations that disrupt key cellular pathways involved in tumor survival and progression.2
In the 15 years since the first map of the human genome emerged, genetics has become an integral part of medical practice worldwide.1 Oncology is no exception; the genetic origins of cancer were suspected more than a century ago and it is now well understood that most cancers are driven by genetic alterations that disrupt key cellular pathways involved in tumor survival and progression.2
In the 15 years since the first map of the human genome emerged, genetics has become an integral part of medical practice worldwide.1 Oncology is no exception; the genetic origins of cancer were suspected more than a century ago and it is now well understood that most cancers are driven by genetic alterations that disrupt key cellular pathways involved in tumor survival and progression.2
Panobinostat: a novel mechanism of action shows promise in multiple myeloma
Following an initial “no” vote from the Oncologic Drugs Advisory Committee (ODAC) in late 2014, the US Food and Drug Administration eventually awarded accelerated approval in February 2015 to the histone deacetylase (HDAC) inhibitor panobinostat for use in select patients with relapsed multiple myeloma. Panobinostat has a novel mechanism of action that demonstrates synergy with the proteasome inhibitor bortezomib and the immunomodulatory agent dexamethasone, which translated into improved progression-free survival (PFS) for patients with multiple myeloma who had received at least 2 prior therapies, according to data from a prespecified subgroup analysis from the Panorama-1 trial.
Click on the PDF icon at the top of this introduction to read the full article.
Following an initial “no” vote from the Oncologic Drugs Advisory Committee (ODAC) in late 2014, the US Food and Drug Administration eventually awarded accelerated approval in February 2015 to the histone deacetylase (HDAC) inhibitor panobinostat for use in select patients with relapsed multiple myeloma. Panobinostat has a novel mechanism of action that demonstrates synergy with the proteasome inhibitor bortezomib and the immunomodulatory agent dexamethasone, which translated into improved progression-free survival (PFS) for patients with multiple myeloma who had received at least 2 prior therapies, according to data from a prespecified subgroup analysis from the Panorama-1 trial.
Click on the PDF icon at the top of this introduction to read the full article.
Following an initial “no” vote from the Oncologic Drugs Advisory Committee (ODAC) in late 2014, the US Food and Drug Administration eventually awarded accelerated approval in February 2015 to the histone deacetylase (HDAC) inhibitor panobinostat for use in select patients with relapsed multiple myeloma. Panobinostat has a novel mechanism of action that demonstrates synergy with the proteasome inhibitor bortezomib and the immunomodulatory agent dexamethasone, which translated into improved progression-free survival (PFS) for patients with multiple myeloma who had received at least 2 prior therapies, according to data from a prespecified subgroup analysis from the Panorama-1 trial.
Click on the PDF icon at the top of this introduction to read the full article.
BET inhibitor appears to cause memory loss in mice
Photo by Aaron Logan
New research suggests the BET inhibitor JQ1 causes molecular changes in mouse neurons and can lead to memory loss in mice.
Investigators believe this discovery, published in Nature Neuroscience, will fuel more research into the neurological effects of BET inhibitors, which are currently under development as potential treatments for a range of hematologic and solid tumor malignancies.
The researchers noted that, although JQ1 has the ability to cross the blood-brain barrier, this may not be the case for other BET inhibitors.
Several companies are testing the inhibitors using unique formulations they’ve optimized in proprietary ways—for example, by adding chemical groups to make a compound more targeted or effective—which might make it more difficult for the drug to cross the blood-brain barrier.
Still, the investigators said their findings suggests more research is needed to determine whether other BET inhibitors can enter the brain, since that could potentially cause unwanted side effects.
“We found that if a drug blocks a BET protein throughout the body, and that drug can get into the brain, you could very well produce neurological side effects,” said study author Erica Korb, PhD, of The Rockefeller University in New York, New York.
Experiments with JQ1
To assess the effects of BET inhibitors on the brain, the researchers used a compound that was designed to thwart the activity of a specific BET protein, Brd4. They used the drug JQ1, which they knew could cross the blood-brain barrier.
The investigators added the drug to mouse neurons grown in the lab, then stimulated the cells in a way that mimicked the process of memory formation. Normally, when neurons receive this type of signal, they begin transcribing genes into proteins, resulting in the formation of new memories—a process that is partly regulated by Brd4.
“To turn a recent experience into a long-term memory, you need to have gene transcription in response to these extracellular signals,” Dr Korb said.
Indeed, when the researchers stimulated mouse neurons with signals that mimicked those they would normally receive in the brain, there were “massive changes” in gene transcription. But when the team performed this experiment after adding JQ1, they saw much less activity.
“After administering a Brd4 inhibitor, we no longer saw those changes in transcription after stimuli,” Dr Korb said.
To test how the drug affected the animals’ memories, the investigators placed the mice in a box with two objects they had never seen before, such as pieces of Lego or tiny figurines. Mice typically explore anything unfamiliar, climbing and sniffing around.
After a few minutes, the researchers took the mice out of the box. One day later, the team put the mice back in, this time with one of the objects from the day before and another, unfamiliar one.
Mice that received a placebo were much more interested in the new object, presumably because the one from the day before was familiar. But mice treated with JQ1 were equally interested in both objects, suggesting they didn’t remember the previous day’s experience.
Next, the investigators took their findings a step further. If JQ1 reduces molecular activity in the brain, they wondered if it could help in conditions marked by too much brain activity, such as epilepsy.
Brd4 regulates a receptor protein present at the synapse, a structure where two neurons connect and transmit signals. When the researchers administered the Brd4 inhibitor, they saw decreased levels of that receptor, and neurons fired much less frequently.
Next, the team gave the drug to mice for a week, then added a chemical that induces seizures. Mice that received JQ1 had a much lower rate of seizures than mice given a placebo.
“In the case of the epileptic brain, when there’s too much activity and neurons talking to each other, this drug could be potentially be beneficial,” Dr Korb concluded.
Photo by Aaron Logan
New research suggests the BET inhibitor JQ1 causes molecular changes in mouse neurons and can lead to memory loss in mice.
Investigators believe this discovery, published in Nature Neuroscience, will fuel more research into the neurological effects of BET inhibitors, which are currently under development as potential treatments for a range of hematologic and solid tumor malignancies.
The researchers noted that, although JQ1 has the ability to cross the blood-brain barrier, this may not be the case for other BET inhibitors.
Several companies are testing the inhibitors using unique formulations they’ve optimized in proprietary ways—for example, by adding chemical groups to make a compound more targeted or effective—which might make it more difficult for the drug to cross the blood-brain barrier.
Still, the investigators said their findings suggests more research is needed to determine whether other BET inhibitors can enter the brain, since that could potentially cause unwanted side effects.
“We found that if a drug blocks a BET protein throughout the body, and that drug can get into the brain, you could very well produce neurological side effects,” said study author Erica Korb, PhD, of The Rockefeller University in New York, New York.
Experiments with JQ1
To assess the effects of BET inhibitors on the brain, the researchers used a compound that was designed to thwart the activity of a specific BET protein, Brd4. They used the drug JQ1, which they knew could cross the blood-brain barrier.
The investigators added the drug to mouse neurons grown in the lab, then stimulated the cells in a way that mimicked the process of memory formation. Normally, when neurons receive this type of signal, they begin transcribing genes into proteins, resulting in the formation of new memories—a process that is partly regulated by Brd4.
“To turn a recent experience into a long-term memory, you need to have gene transcription in response to these extracellular signals,” Dr Korb said.
Indeed, when the researchers stimulated mouse neurons with signals that mimicked those they would normally receive in the brain, there were “massive changes” in gene transcription. But when the team performed this experiment after adding JQ1, they saw much less activity.
“After administering a Brd4 inhibitor, we no longer saw those changes in transcription after stimuli,” Dr Korb said.
To test how the drug affected the animals’ memories, the investigators placed the mice in a box with two objects they had never seen before, such as pieces of Lego or tiny figurines. Mice typically explore anything unfamiliar, climbing and sniffing around.
After a few minutes, the researchers took the mice out of the box. One day later, the team put the mice back in, this time with one of the objects from the day before and another, unfamiliar one.
Mice that received a placebo were much more interested in the new object, presumably because the one from the day before was familiar. But mice treated with JQ1 were equally interested in both objects, suggesting they didn’t remember the previous day’s experience.
Next, the investigators took their findings a step further. If JQ1 reduces molecular activity in the brain, they wondered if it could help in conditions marked by too much brain activity, such as epilepsy.
Brd4 regulates a receptor protein present at the synapse, a structure where two neurons connect and transmit signals. When the researchers administered the Brd4 inhibitor, they saw decreased levels of that receptor, and neurons fired much less frequently.
Next, the team gave the drug to mice for a week, then added a chemical that induces seizures. Mice that received JQ1 had a much lower rate of seizures than mice given a placebo.
“In the case of the epileptic brain, when there’s too much activity and neurons talking to each other, this drug could be potentially be beneficial,” Dr Korb concluded.
Photo by Aaron Logan
New research suggests the BET inhibitor JQ1 causes molecular changes in mouse neurons and can lead to memory loss in mice.
Investigators believe this discovery, published in Nature Neuroscience, will fuel more research into the neurological effects of BET inhibitors, which are currently under development as potential treatments for a range of hematologic and solid tumor malignancies.
The researchers noted that, although JQ1 has the ability to cross the blood-brain barrier, this may not be the case for other BET inhibitors.
Several companies are testing the inhibitors using unique formulations they’ve optimized in proprietary ways—for example, by adding chemical groups to make a compound more targeted or effective—which might make it more difficult for the drug to cross the blood-brain barrier.
Still, the investigators said their findings suggests more research is needed to determine whether other BET inhibitors can enter the brain, since that could potentially cause unwanted side effects.
“We found that if a drug blocks a BET protein throughout the body, and that drug can get into the brain, you could very well produce neurological side effects,” said study author Erica Korb, PhD, of The Rockefeller University in New York, New York.
Experiments with JQ1
To assess the effects of BET inhibitors on the brain, the researchers used a compound that was designed to thwart the activity of a specific BET protein, Brd4. They used the drug JQ1, which they knew could cross the blood-brain barrier.
The investigators added the drug to mouse neurons grown in the lab, then stimulated the cells in a way that mimicked the process of memory formation. Normally, when neurons receive this type of signal, they begin transcribing genes into proteins, resulting in the formation of new memories—a process that is partly regulated by Brd4.
“To turn a recent experience into a long-term memory, you need to have gene transcription in response to these extracellular signals,” Dr Korb said.
Indeed, when the researchers stimulated mouse neurons with signals that mimicked those they would normally receive in the brain, there were “massive changes” in gene transcription. But when the team performed this experiment after adding JQ1, they saw much less activity.
“After administering a Brd4 inhibitor, we no longer saw those changes in transcription after stimuli,” Dr Korb said.
To test how the drug affected the animals’ memories, the investigators placed the mice in a box with two objects they had never seen before, such as pieces of Lego or tiny figurines. Mice typically explore anything unfamiliar, climbing and sniffing around.
After a few minutes, the researchers took the mice out of the box. One day later, the team put the mice back in, this time with one of the objects from the day before and another, unfamiliar one.
Mice that received a placebo were much more interested in the new object, presumably because the one from the day before was familiar. But mice treated with JQ1 were equally interested in both objects, suggesting they didn’t remember the previous day’s experience.
Next, the investigators took their findings a step further. If JQ1 reduces molecular activity in the brain, they wondered if it could help in conditions marked by too much brain activity, such as epilepsy.
Brd4 regulates a receptor protein present at the synapse, a structure where two neurons connect and transmit signals. When the researchers administered the Brd4 inhibitor, they saw decreased levels of that receptor, and neurons fired much less frequently.
Next, the team gave the drug to mice for a week, then added a chemical that induces seizures. Mice that received JQ1 had a much lower rate of seizures than mice given a placebo.
“In the case of the epileptic brain, when there’s too much activity and neurons talking to each other, this drug could be potentially be beneficial,” Dr Korb concluded.