Drugs that Reprogram Tumor Cells Introduce New Options for Blood Cancer Patients

THE TOPLINE

  • Researchers are investigating the efficacy of epigenetic therapies in the treatment of myelodysplastic syndromes and acute myeloid leukemia
  • Various clinical trials have been conducted to test multiple epigenetic agents with the hope they will expand treatment options for patients

A growing body of evidence supports the idea that epigenetic changes, which affect gene expression without altering the DNA sequence, play an important role in the initiation and progression of cancer. Because epigenetic therapies restore normal gene activity rather than kill cancer cells, they could be an attractive alternative for patients who cannot tolerate traditional chemotherapy. The Fox Chase Cancer Center-Temple University Hospital Bone Marrow Transplant Program is currently conducting clinical studies to test the effectiveness of epigenetic therapies in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)—blood cancers associated with particularly high mortality rates.

ewc_TempleFC(2)0220150264-rev

Patricia Kropf, MD
Photo courtesy of Ed Cunicelli

“Because epigenetic changes on DNA are reversible, it is possible to reprogram cancerous cells to reactivate previously silenced genes, such as tumor suppressor genes, and restore normal function,” says Patricia Kropf, MD, assistant director of the Fox Chase-Temple Bone Marrow Transplant Program. “Epigenetic therapies are low intensity with decreased side effects as compared to traditional chemotherapy, so they provide a viable option for many MDS and AML patients who are not candidates for aggressive chemotherapy.”

Within a few years after diagnosis, many MDS patients develop AML. Survival is significantly decreased among these patients. At present, the only cure for MDS or AML is a bone marrow transplant, which is not a viable option for many older patients.

One major hallmark of these cancers is excessive DNA methylation—an epigenetic process that silences the activity of genes involved in tumor suppression, differentiation, and programmed cell death. Patients with advanced MDS are typically treated with demethylating drugs such as decitabine, and these drugs have also shown effectiveness at treating AML. However, individuals who do not initially respond to these drugs or relapse after treatment have a poor prognosis, so there is a strong need for new therapeutic approaches.

To address this need, researchers at Fox Chase-Temple Bone Marrow Transplant Program and MD Anderson Cancer Center are conducting a Phase II study of decitabine either alone or in combination with carboplatin or arsenic in patients with AML and MDS. Carboplatin is an approved chemotherapy drug that is used to treat many types of cancer and has recently been shown in laboratory studies to boost the epigenetic effects of decitabine. Early-stage clinical trials in patients with ovarian cancer showed an encouraging response rate for this combination.

Meanwhile, arsenic trioxide, which has a long history as an antileukemic agent for one specific subtype of AML, has now been identified as a demethylating agent that could potentially synergize with decitabine. A Phase I-II study showed that this combination was safe and well tolerated by patients with AML and MDS.

In addition, a multicenter trial called ASTEX-3 is testing the efficacy of a new hypomethylating agent called SGI-110 in patients with MDS and AML. Compared with decitabine, which deactivates rapidly in cancer cells, SGI-110 is significantly more stable and has a prolonged half-life, which increases the total drug exposure time. As Kropf reported in June at the 20th Congress of the European Hematology Association, SGI-110 produced a 57% remission rate in treatment-naïve elderly AML patients in a Phase II study.

“The success of demethylating agents in treating MDS and AML has validated an epigenetic approach to cancer care,” Kropf says. “As such, our trials at Fox Chase are aimed at enhancing epigenetic effects, either as single agents or in combination with other drugs. In the end, we are optimistic that our efforts will translate into expanded treatment options and dramatically better outcomes for patients.”