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Promise and Progress - Using Epigenetics to Get the Right Treatments to the Right Patients

Reprogramming Cancer Cells - The Story of Epigenetics
Issue No. 1

Using Epigenetics to Get the Right Treatments to the Right Patients

Date: July 16, 2014

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Roisin Connolly

Breaking Resistance in Breast Cancer

Epigenetic alterations are found frequently in breast cancer. Drugs that target and block the effects of these alterations are of great interest to breast cancer researchers and clinicians.  Of particular interest are changes that may aid breast cancers in becoming resistant to treatment.

Breast cancer clinician-scientist Roisin Connolly has recently completed a clinical trial of combined epigenetic therapy in patients with advanced breast cancer. This trial, a collaborative project of the SU2C Epigenetics Dream Team, will include analyses of blood and biopsy samples obtained from women before and after treatment with epigenetic therapy. “We are trying to better understand how these treatments work in breast cancer patients and identify markers which can predict benefit from treatment for an individual patient,” says Dr. Connolly.  “We want to understand what these drugs do to tumor cells, whether it is overcoming hormone resistance, sensitizing them to future treatments, working on the immune system, or a combination of all these things.”

Based on this work, Dr. Connolly was selected to chair a large, 600-patient study through the ECOG-ACRIN Cancer Research Group (Eastern Cooperative Oncology the American College of Radiology Imaging Network). “This international multi-institutional trial is designed to determine whether the addition of an epigenetic HDAC inhibitor to breast cancer endocrine therapy improves survival in patients with advanced breast cancer,” said Dr. Connolly.

The trial is based on earlier Kimmel Cancer Center studies of epigenetic therapy that found that silenced estrogen receptor genes were re-activated and caused resistant breast cancer cells to respond to hormonal treatment.  Another study, by the University of Maryland scientist and aromatase inhibitor pioneer Angela Brodie found that HDAC inhibitors sensitized breast tumors in mice to an aromatase inhibitor.  A clinical trial subsequently revealed that breast cancer patients who received combined treatment with an HDAC inhibitor and an aromatase inhibitor lived about 8 months longer than patients who received only an aromatase inhibitor.  As a result, the FDA gave this treatment combination “breakthrough therapy designation” to speed up the drug approval process.

Priming Childhood Leukemia for Treatment

Acute lymphocytic leukemia (ALL) is one of the most treatable forms of childhood leukemia.  However, about 15 percent of patients relapse, and when their leukemia comes back the once responsive cancer is now stubbornly treatment resistant. Pediatric cancer expert and researcher Dr. Patrick Brown compared leukemia cells at the time of diagnosis to leukemia cells at recurrence and found that the overwhelming change was an acquired pattern of hypermethylation of genes. “This change in the epigenetic signature seems to be causing the drug resistance,” says Dr. Brown.  He has begun an epigenetic priming patient study, in which he gives relapsed patients epigenetic drugs to reprogram the resistant cells followed by chemotherapy. The study is ongoing, but Dr. Brown says the addition of epigenetic drugs to treatment appears to be making the leukemia cells respond to subsequent treatment with anticancer drugs.

Personalized Epigenetic Medicine for Colon Cancer

Dr. Nilo Azad is testing the priming effect of epigenetic therapy in colon cancer.  Patients will first receive treatment  with an epigenetic-targeted drug followed by chemotherapy.  Based on earlier studies in lung cancer, as well as laboratory work by Dr. Nita Ahuja in colon cancer, Dr. Azad expects the epigenetic therapy to sensitize the colon cancers to anticancer drugs.  A similar approach is being explored in a study of surgically treated pancreatic cancer. In another study, she will be using a test developed by epigenetics researcher Jim Herman, to identify patients whose colon cancers have a specific epigenetic biomarker that should make their cancers vulnerable to a commonly used class of drugs known as taxanes, once deemed ineffective in colon cancer.   “Many drugs have been tested and looked inactive when they are given broadly to large groups of patients, but we believe there are specific subsets of patients who will benefit. We need to use epigenetic markers to identify these patients,” says Dr. Azad.  She is working with Dr. Herman to tease out other epigenetic alterations that could predict for drug sensitivity in colon cancer. Drug treatments for colon cancer are very limited. Dr. Azad believes this personalized epigenetic approach could significantly expand the drug treatment options for patients.

Paradoxical Treatment for Prostate Cancer

Researchers Theodore DeWeese, Vasan Yegnasubramanian, Michael Haffner, and Mohammad Hedayati found that testosterone, a hormone prostate cancer cells need to survive can also play a role in the cells’ demise. Dr. DeWeese says testosterone forms breaks in the DNA that would make cancer cells more vulnerable to treatment with radiation therapy.  The team is working with prostate cancer clinician Samuel Denmeade to see if short pulses of testosterone, enough to stimulate the breaks but not so much to stimulate the cancer, followed by radiation therapy to cause even more DNA breaks can overwhelm and kill prostate cancer cells. “It seems antithetical to what anyone would think for prostate cancer.  The standard of care has been to take testosterone away, and it works,” says Dr. DeWeese, the Director of Radiation Oncology and Molecular Radiation Sciences. “Maybe we can make the standard care, which is radiation therapy and testosterone-blocking hormone therapy, better by introducing short pulses of testosterone to sensitize prostate cancer cells just when we need to.”  The priming strategy is a targeted treatment that affects only prostate cancer cells and prostate tissue.  Dr. Yegnasubramanian is also developing a test to determine if the treatment is working, using blood and urine samples to determine the methylation pattern of patients’ prostate cancer genes. “After the patient receives radiation treatment, if cancer cells were killed, the amount of abnormally methylated cancer-specific DNA should go down,” he says. “This will tell us if cancer cells are dying off or if they are not. If the methylation pattern is still high, it tells us we need to try a different treatment.” 

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