Kathy Miller, MD and Ken Nephew, PhD are among nearly 20 scientists at six institutions who will work to improve epigenetic therapies for cancer with the five-year, estimated $12.4 million grant.
The SPORE grant was awarded to The Coriell Institute for Medical Research (Camden, NJ) and Van Andel Institute (Grand Rapids, MI) and includes three research projects focusing on epigenetic therapy, which aims to treat cancer by correcting abnormal gene expression.
The project at Indiana University will investigate the impact of epigenetic therapy on cancers driven by BRCAness, a major cancer-related vulnerability. Nephew and Miller, both researchers at the Vera Bradley Foundation Center for Breast Cancer Research at the IU Simon Comprehensive Cancer Center, will collaborate with project co-investigator Feyruz Rassool, PhD, of the University of Maryland School of Medicine.
Patients who inherit mutations in the BRCA1 or BRCA2 genes are at higher risk for breast and ovarian cancers. While approved therapies exist for those patient populations, those therapies won’t work for women diagnosed with triple negative breast cancer or ovarian cancer with BRCAness—a defect in the DNA repair process that imitates BRCA mutations, even though the gene is intact. This research could offer a treatment approach for both BRCA mutant and intact cancers.
“We are pioneering an epigenetic therapy-PARP inhibitor combination that will generate a vulnerability in cancer cells. Our strategy represents a potentially important treatment advance and therapeutic option for women diagnosed with breast or ovarian cancer who lack BRCA mutations and address an urgent clinical need,” Nephew said.
Nephew is assistant director of research-Bloomington and co-leader of the Tumor Microenvironment and Metastasis research program at the cancer center and Jerry W. and Peggy S. Throgmartin Professor of Oncology at IU School of Medicine. Nephew traces his work testing the combination of epigenetic therapy and PARP inhibitors in mouse models with breast cancer metastasis to generous funding from 100 Voices of Hope.
“We are also pre-clinically testing whether the efficacy of this treatment strategy may be further enhanced by including immune checkpoint therapy,” Nephew said. “Cancer immunotherapy has yet to achieve meaningful survival benefit in breast and ovarian cancer patients. Epigenetic drug approaches for epigenetic immunosensitization could be a game-changer.”
Miller, Nephew and collaborators will explore possible benefits of epigenetic combination therapies for patients with triple negative breast cancer and ovarian cancer patients who are resistant to PARP inhibitor (PARPi) therapy. PARP is an enzyme in cells that help repair damaged DNA; the PARP inhibitors work by blocking cancer cells from repairing the damage. The research could bring the benefits of PARPi therapy to a larger group of patients, offering more treatment options.
“We began the first clinical trial combining epigenetic therapy with a PARP inhibitor last year, exploring different doses and learning how to use the combination safely. With support from the SPORE grant, we can expand that initial trial and study how this combination controls breast and ovarian cancers,” Miller said. Miller is associate director of clinical research at the cancer center and the Ballvé-Lantero Professor of Oncology at IU School of Medicine.
“Blood and tumor samples collected from patients in the trial will complement the work Dr. Nephew and Dr. Rassool are doing in the lab, helping us to better understand how the combination works and which patients are most likely to benefit,” Miller said.
Researchers on this SPORE grant have collaborated on epigenetic research for many years. In 2018, Miller and Nephew were named to the Van Andel Institute–Stand Up To Cancer (SU2C) Epigenetics Dream Team, a multi-institutional effort to identify new and more effective cancer therapies and test them in the clinic to improve patient care. The VAI-SU2C Epigenetics Dream Teamhas launched more than a dozen epigenetic therapy clinical trials in recent years and will support trials from this SPORE.
“SPORE grants are the highest level of research funding dedicated to moving science from the laboratory to cancer patients, and they have great impact in advancing new and innovative approaches in cancer care and treatment,” said Kelvin Lee, MD, director of the IU Simon Comprehensive Cancer Center. “The very impressive research project of Drs. Nephew, Rassool and Miller is at the heart of clinical research in this epigenetics SPORE; it has the real potential to be a groundbreaking approach for some of the hardest to treat breast and ovarian cancers.”
This SPORE grant is the first in NCI history to support a thematic focus on epigenetics and can be renewed indefinitely. Read more about the grant and additional projects on the NCI website.
IU School of Medicine is the largest medical school in the U.S. and is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability.