Bringing Epigenetic Therapies From Bench to Bedside

OncologyLive, Vol. 17/No. 4, Volume 17, Issue 4

Partner | Cancer Centers | <b>Sylvester Comprehensive Cancer Center</b>

Epigenetic therapy has emerged as a novel approach, not necessarily by killing cancer cells, but perhaps by altering the network of chemical changes that affect the DNA/chromatin within cancer cells.

Ronan T. Swords, MD, PhD

Pap Corps Endowed Professor in Leukemia

Sylvester Comprehensive Cancer Center

University of Miami Miller School of Medicine

Miami, FL

Although there have been advances in therapeutics and supportive care, the majority of patients with acute myeloid leukemia (AML) die from the disease. As a result, efforts to find the most effective treatments for AML remain a key focus of research. Epigenetic therapy has emerged as a novel approach, not necessarily by killing cancer cells, but perhaps by altering the network of chemical changes that affect the DNA/chromatin within cancer cells.

The study of epigenetics deals primarily with cellular variations caused by aging, disease, or other external or environmental factors that switch genes on and off, independent of DNA sequence chances. Epigenetic factors are crucial in most of the myeloid diseases, the exception being chronic myelogenous leukemia, which is largely driven by abnormal signal transduction. In AML and other hematopoietic cancers, epigenetic mutations lock stem cells into a state of perpetual self-renewal, impeding differentiation to cause bone marrow failure with varying severity. At the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, research efforts are focused on how to restore or further inhibit the function of those genes, so that the stem cells will either die or differentiate themselves to a more normal growth state. This discovery has generated tremendous excitement about the promise of epigenetic therapies in myeloid diseases and other types of cancer.

Epigenetics in the Laboratory Arthur Zelent, PhD, research professor of Medicine at Sylvester, has had a long-standing interest in the mechanisms of transcriptional regulation of gene expression and the role that its deregulation contributes to cancer pathogenesis. In particular, the Zelent laboratory studies the regulation of gene expression by retinoic acid receptors (RARs) and epigenetic cellular mutations in AML. He has been interested in RARs as a therapeutic target for this type of leukemia, and researchers in the Zelent laboratory are working to find the right combination of agents to achieve long-term remissions for more patients.

Drawing on published and unpublished results, the Zelent laboratory has found that inhibition of LSD1 or EZH2 could unlock the therapeutic potential of retinoids in AML. Researchers have also discovered novel combination therapies with relevance beyond myeloid neoplasia to tackle lymphomas, prostate cancer, sarcomas, and brain tumors.

Drivers for epigenetic alterations in acute myeloid leukemia

Source: Mehdipour P, Santoro F, Minucci S. Epigenetic alterations in acute myeloid leukemias. FEBS Journal. 2015;282:1786—1800.

Launching Clinical Trials

Currently, the Zelent laboratory is playing an important role in moving these key epigenetic findings from the bench to the bedside. Through the use of sequencing to pinpoint exact epigenetic mutations, the laboratory is actively translating these findings to develop new drugs for patients or repurposing currently approved drugs for new indications.The standard “3+7” chemotherapy regimen, representing the standard of care for those patients with AML fit enough to tolerate it, has been the same in many of its particulars for the last 40 years. With 25,000 new cases of AML reported annually in the United States, there is a huge unmet medical need for better treatment, fueling researchers’ efforts to define epigenetic targets in AML and other cancers.

Our combined efforts have identified ways to make ATRA, the nonchemotherapy drug all-trans-retinoic acid, a more broadly effective drug in this disease. We hypothesized that epigenetic mutations make this drug less effective and that targeting these mutations to remove resistance mechanisms is an exciting opportunity.

The Zelent laboratory is leading a new clinical trial (NCT02273102) that combines ATRA and TCP (an anti-depressant drug which blocks LSD1, a key mediator of ATRA resistance) at Sylvester. Acute promyelocytic leukemia (APL), a subtype of AML accounting for 5% of all cases, is very curable. APL cells are highly sensitive to ATRA, which effectively differentiates the leukemic clone. It is estimated that over 80% of APL patients can be cured with ATRA-based therapies. For patients with non-APL AML, ATRA has little effect.

The investigators’ preliminary data suggest that non-APL AML cells can be resensitized to ATRA when combined with lysine-specific demethylase 1 (LSD 1) inhibitors. This combination has demonstrated safety, tolerability and clinical efficacy. Our group has made both seminal and subsequent discoveries validating LSD-1 as a new target for therapeutics in AML and consequently, highly selective inhibitors of this target are already in clinical trials.

Justin M. Watts, MD, assistant professor of Clinical Medicine at Sylvester, also part of our group, is working on two other clinical trials exploring AG-120 and AG-221, two oral drug candidates from Agios Pharmaceuticals that target mutated IDH1 and IDH2, two epigenetic- based mutations that have huge promise with impressive safety and activity profiles in heavily pretreated patients.

Finally, Stephen D. Nimer, MD, director of the Sylvester Comprehensive Cancer Center, is studying protein arginine methyltransferases (PRMTs) in the laboratory, seeking to develop potential inhibitors that may be effective in clinical trials.

Epigenetic-based therapies are effective options for many patients with myeloid neoplasms and represent a new frontier for therapeutics in this space. Epigenetic factors may account for chemotherapy resistance in patients diagnosed with these diseases, and hold promise for highly precise and personalized treatment strategies. At Sylvester, we are working to build a world-class Epigenetics Group to make a significant impact in cancer therapeutics.