Epigenetic Cancer Therapies Emerge out of the Lab into the Limelight

Abstract

“What is interesting about this model is that it does begin to break down barriers, to take big ideas, driven by pipeline science, to the bedside.” said Dr. Stephen Baylin, deputy director of oncology and medicine at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, who, with Peter Jones, Ph.D., D.Sc., director, University of Southern California/Norris Comprehensive Cancer Center, is heading up the Epigenetics Dream Team. SU2C awarded the dream team $9.1 million dollars over 3 years, which has been extended to a no-cost fourth year. The team is presenting trial results combining entinostat and azacitidine at the AACR April 2013 meeting, focusing on lung cancer as well as breast, colon, and MDS. So far, the lung cancer trials have furnished the most promising results, as a few patients have shown a surprisingly durable response to epigenetic therapy, living for years—one up to 4 years. The team is initiating two new clinical trials for patients with metastatic non-small cell lung cancer. Previous clinical trials showed that patients with advanced non-small cell lung carcinoma treated with low doses of azacitidine and entinostat underwent a “priming effect” in which they responded better to chemotherapy or a new form of immunotherapy called immune checkpoint blockade.DMNT inhibitors have been around since the late 1960s but were cytotoxic in the clinic. In the 1990s, they were revisited at lower doses that caused tolerable side effects for preleukemia. According to Baylin, the SU2C team found that azacitidine together with HDAC inhibitors has significant antitumor effects on cancer stem-like cells if used at nanomolar levels, suggesting that these very low doses can reprogram cells with specificity; however, it takes several cycles to show a hematological response. They also are better tolerated at lower doses. While trials were conducted on patients with advanced cancer and multiple tumors, there is evidence that this therapy would be effective earlier in treatment, even as a second line therapy for solid tumors. Baylin’s group will next investigate biomarkers. Patients have to be cautioned on expectations as well. “You have to be very careful and delicate,” says Baylin. “You don’t want to give false hope and promise. In no gratuitous sense, they are the heroes. They put their lives on the line.”Dream Team member Dr. Vered Stearns, codirector of the Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, is using azacitidine with entinostat to reverse epigenetic changes in the genome and wake up important genes that could make breast cancers more sensitive to treatment. About a third of breast cancer patients do not have estrogen receptors on their cells. Her group is investigating epigenetic agents that can sensitize cells to endocrine treatment among cancer subtypes. Stearns is recruiting hormone resistant patients whose tumors have estrogen receptors for a study and has just concluded a study of triple-negative patients, none of whom responded to treatment. Estrogen receptor-positive patients did, encouragingly, show a response in the first stage of the study. “Women are not losing their hair,” says Stearns. “Their quality of life, we feel, is better than on chemotherapy agents.”