Exploring epigenetic therapy for aggressive prostate cancer
As tumors go, it’s a trickster: A subset of prostate cancer that eludes traditional androgen receptor (AR)- targeted therapies by losing its reliance on AR for growth and survival and adopting features characteristic of a much more difficult form of the disease, neuroendocrine prostate cancer.
Loredana Puca, Ph.D., a researcher working with Weill Cornell Medicine prostate cancer experts Himisha Beltran, M.D., and Mark Rubin, M.D., is hoping to identify new strategies to treat these tricky cases.
“This neuroendocrine phenotype is highly aggressive, for which new understandings and treatments are urgently needed,” Dr. Puca said.
With the help of a 2016 Lori Milken–PCF Young Investigator Award from the Prostate Cancer Foundation, Puca is studying the genomic characteristics of neuroendocrine prostate cancer and whether it might be possible to develop an epigenetic therapy to treat it.
In particular, she will be examining the EZH2 gene, which has been implicated in previous studies as a driver of the neuroendocrine phenotype. It is a critical regulator of the epigenetic program of cells -- the DNA structure that controls access to various genes for expression.
“To better understand the mechanisms by which EZH2 modulates AR signaling and the neuroendocrine phenotype, prostate tumors with neuroendocrine features will be profiled for EZH2-regulated genes and alterations in the epigenetic program, and compared with AR therapy-resistant prostate tumor without neuroendocrine features,” Dr. Puca said.
She is developing patient-derived tumor organoids and xenografts from metastatic biopsies to test the efficacy of targeting EZH2 through EZH2-inhibitors and in combination with other therapies.
“My goal is to elucidate the mechanisms that control development and maintenance of this phenotype, and to test a novel treatment strategy that has the potential to extend the lives of patients,” Dr. Puca added.