Investigators at Johns Hopkins Kimmel Cancer Center are among the world’s leaders in epigenetics and genetics research. The research below highlights just a few of the many projects ongoing at our East Baltimore campus.
Experimental Blood Test for Breast Cancer
Sara Sukumar, Ph.D.
A new blood test detects advanced breast cancer and could also be used to monitor the effectiveness of treatments.
Saraswati Sukumar, Ph.D., Co-Director of the Breast Cancer Program, her research associate Mary Jo Fackler, Ph.D., and team developed the test, called cMethDNA assay, to detect 10 genes altered in breast cancer. Specifically it finds increased methylation of any of these breast-cancer specific genes in circulating tumor DNA found in the blood.
In a study of 52 women, half with recurrent, late-stage breast cancer and half who did not have breast cancer, the test was 95 percent accurate in distinguishing the breast cancer patients from the healthy women. The findings were tested against 60 blood samples from the general population and confirmed.
Dr. Sukumar and team also examined the test’s ability to measure treatment response in an additional study of 58 blood samples. The test successfully detected a decrease in DNA methylation in the blood from patients with stable disease or who had responded to treatment. Conversely, it found no decreased methylation in patients whose breast cancers did not respond to treatment.
“Our assay shows great potential for development as a clinical laboratory test for monitoring therapy and disease progression and recurrence,” says Dr. Sukumar, the Barbara B. Rubenstein Professor of Oncology. “If it’s determined early that a treatment is not working, clinicians can save time and switch to a different therapy.” The team says the test may also detect recurrent lung and colorectal cancers.
Shutting Down Cancer Cells
Marikki Laiho, M.D., Ph.D.
Researchers have uncovered a potential way to stop cancer cells in their tracks. The studies are in a very early stage, but they have demonstrated the ability in laboratory and animal studies to completely shut down the cellular machinery cancers need to survive.
The research focuses on a pathway within RNA called POL I, which is necessary for mutant cancer genes to communicate with cells.
In studies using human cancer cell lines, directed by Marikki Laiho, M.D., Ph.D., the Willard and Lillian Hackerman Professor of Oncology and Director of Molecular Radiation Sciences, a new, never-described compound known as BMH-21 destroyed this critical communication pathway.
“Without this transcription machinery, cancer cells cannot recover,” says Dr. Laiho. “The cancer cells cannot function.”
Using Epigenetics To Get The Right Treatments To the Right Patients
Breaking Resistance in Breast Cancer
Roisin Connolly, M.B.B.S.
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, M.B.B.S., has recently completed a clinical trial of combined epigenetic therapy in patients with advanced breast cancer. This trial, a collaborative project of the Stand Up 2 Cancer 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). The international trial is designed to determine whether the addition of an epigenetic HDAC inhibitor drug to breast cancer endocrine therapy improves survival in patients with advanced breast cancer, Dr. Connolly said.
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 eight 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
Patrick Brown, M.D.
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 Patrick Brown, M.D., 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 adding epigenetic drugs to treatment appears to be making the leukemia cells respond to subsequent treatment with anti-cancer drugs.
Personalized Epigenetic Medicine for Colon Cancer
Nilo Azad, M.D.
Nilo Azad, M.D., 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, Dr. Azad expects the epigenetic therapy to sensitize the colon cancers to anti-cancer 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
Vasan Yegnasubramanian, M.D., Ph.D.
Researchers Theodore DeWeese, M.D.; Vasan Yegnasubramanian, M.D., Ph.D.; Michael Haffner, M.D.; and Mohammad Hedayati, Ph.D.; found that testosterone, a hormone that prostate cancer cells need to survive, also can 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, M.D., 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.”