Drugs could improve treatment of CML

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.”