Grant to fund prostate cancer evolution

Dr. Ekta Khurana, associate professor of physiology and biophysics at Weill Cornell Medicine, has received a three-year, $1.2 million grant from the United States Department of Defense to investigate how prostate cancer cells evolve to become resistant to hormone-blocking therapy. This work will contribute to further understanding prostate cancer and the development of effective targeted therapies for the disease.

Prostate cancer growth is dependent on androgens – male hormones such as testosterone – binding to androgen receptors inside cancer cells. Because of this relationship, prostate cancer is commonly treated with castration or hormone therapy which disrupts this binding. In 2022, Khurana and colleagues from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center published a paper in Science that identified four subtypes of a lethal stage of prostate cancer called castration-resistant prostate cancer (CRPC). Three of these subtypes can grow independently of androgen receptors, rendering androgen-based therapies ineffective.

“Currently, patients who develop these subtypes of prostate cancer have no real targeted therapy,” said Khurana, who is also co-leader of the Cancer Genetics and Epigenetics Program at the Meyer Cancer Center and a WorldQuant Foundation Research Scholar. “This grant will enable us to identify the subtypes earlier in patients and identify new drugs that could be used to treat them to improve clinical outcomes.”

Patients with the stem cell-like subtype of CRPC (CRPC-SCL) are referred to as “double-negative” or “androgen-indifferent” and often suffer from worsening symptoms and lower likelihood of improvement from hormone-based treatment. Furthermore, it is difficult to distinguish between these tumors and tumors that are androgen dependent. This resemblance also poses a challenge to clinicians when deciding whether androgen-based therapies will be effective for patients.

Khurana and her lab team will investigate the biology of how prostate cancer evolves to be castration resistant. The overarching goals of this work will be to reduce death from prostate cancer and develop treatments that improve clinical outcomes for patients with this subtype of prostate cancer.

Specifically, the team will develop noninvasive methods to identify CRPC-SCL in a patient using tumor DNA in the blood, enabling clinicians to predict whether androgen receptor therapy will work for that patient. They will also further study the effects of drugs that might inhibit CRPC-SCL tumor growth. Finally, the group will analyze the genetics of CRPC-SCL to reveal any variants or alterations that drive its evolution.

“This work is really critical, and we are very happy we can continue to improve outcomes in patients that exhibit the prostate cancer subtype we identified,” Khurana said. “While this grant helps us research prostate cancer specifically, I am also excited that the innovative techniques we are developing can be generalized to other cancers like breast or lung cancers to identify new subtypes and the emergence of treatment resistance.”

Chloe Tenn is a freelance writer for Weill Cornell Medicine.

/Public Release. View in full here.