The mechanisms that tumors use to shield themselves from chemotherapy and hormonal therapy often are targets for the development of new treatment strategies. Finding ways to dismantle the armor of drug resistance can restore cancer cells’ vulnerability and extend patients’ lives.
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However, as has become apparent from studies of advanced prostate cancer, tumors can adopt a drug-resistance mechanism that is essential for the life of their human host. This entanglement tactic makes it “particularly challenging” to devise treatment approaches aimed at deactivating the tumor’s drug resistance while not compromising the patient, Cleveland Clinic oncologist and researcher Nima Sharifi, MD, writes in a recent analysis and commentary in The New England Journal of Medicine (NEJM).
The key to disentanglement is a deeper understanding of how these conjoined drug-resistance/life-essential mechanisms work to combat newer hormonal therapies, said Dr. Sharifi, who holds the Kendrick Family Endowed Chair for Prostate Cancer Research in Lerner Research Institute’s Department of Cancer Biology. He is an associate staff member of the Taussig Cancer Institute’s Department of Solid Tumor Oncology, and of the Glickman Urological & Kidney Institute’s Department of Urology.
Prostate cancer provides an illustration of the complexities of drug resistance, and of the important role of steroid receptors.
Development of Castration-resistant Tumors
Standard treatment for metastatic prostate cancer is androgen deprivation therapy via medical or surgical castration. However, tumors eventually become castration-resistant. This resistance stems from tumors’ increased expression of the androgen receptor, and from the acquired ability to manufacture their own supply of 5α-dihydrotestosterone (DHT), the most potent androgen, from precursor steroids. Dr. Sharifi’s own recent research identified the first mutation responsible for increasing DHT synthesis.
Patients treated with the androgen-synthesis inhibitor abiraterone and the powerful androgenreceptor antagonist enzalutamide have shown increased survival. But even this new generation of hormonal therapies targeting the androgen receptor has fleeting success. Within days of exposure to enzalutamide, according to research by Vivek Arora, MD, PhD, Charles Sawyers, MD, and colleagues at Memorial Sloan-Kettering Cancer Center, a subset of prostate cancer cells is triggered to begin glucocorticoid receptor expression. This rapidly progresses to massive receptor upregulation and the development of enzalutamide resistance.
In essence, Dr. Sharifi writes in NEJM, when the next-generation hormonal therapies double down on the androgen receptor, the tumor apparently responds by producing an alternative steroid receptor that takes on at least part of the androgen receptor’s job.
While the androgen receptor is not essential for life, the glucocorticoid receptor is. That poses challenges for testing pharmacologic interventions involving the glucocorticoid receptor, and also requires a rethinking of current clinical practice, which relies on glucocorticoids as an important prostate cancer treatment.
If tumor expression of the glucocorticoid receptor spurs clinical resistance to enzalutamide, might there be other impacts? Dr. Sharifi asks in the NEJM article. “Is it possible that glucocorticoid administration has direct effects on the tumor that may be detrimental to the patient in other clinical settings?”
Future Investigative Approaches
Answers to these questions will depend in part on the collection of tumor tissue from patients who have castration-resistant prostate cancer, Dr. Sharifi says. This will permit researchers to identify and dissect the molecular signaling mechanisms that drive resistance, including the possibility that this might involve the glucocorticoid receptor.
“The androgen receptor and glucocorticoid receptor are both steroid receptors,” Dr. Sharifi says. “Much is already known about how androgens and the androgen receptor are central drivers of tumor growth and enable resistance to various standard hormonal therapies. Two investigative approaches may help bring these findings closer to clinical practice. The first is to identify how clinical tumors modulate glucocorticoid receptor signaling through various standard therapies. The second is to ask whether modulating glucocorticoid receptor signaling alters tumor progression in clinical settings where this receptor is thought to be important.”