Metastatic prostate cancer remains incurable, why?

Abstract

Metastatic prostate cancer patients present in two ways—with already disseminated disease at the time of presentation or with disease recurrence after definitive local therapy. Androgen deprivation therapy is given as the most effective initial treatment to patients. However, after the initial response, almost all patients will eventually progress despite the low levels of testosterone. Disease at this stage is termed castration resistant prostate cancer (CRPC). Before 2010, the taxane docetaxel was the first and only life prolonging agent for metastatic CRPC (mCRPC). The last decade has witnessed robust progress in CRPC therapeutics development. Abiraterone, enzalutamide, apalutamide and sipuleucel-T have been evaluated as first- and second-line agents in mCRPC patients, while cabazitaxel was approved as a second-line treatment. Radium-223 dichloride was approved in symptomatic patients with bone metastases and no known visceral metastases pre- and post-docetaxel. However, despite significant advances, mCRPC remains a lethal disease. Both primary and acquired resistance have been observed in CRPC patients treated by these new agents. It could be solely cell intrinsic or it is possible that the clonal heterogeneity in treated tumors may result from the adaptive responses to the selective pressures within the tumor microenvironment. The aim of this review is to list current treatment agents of CRPC and summarize recent findings in therapeutic resistance mechanisms.

The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy

“…This study highlighted the importance of androgen in driving disease state. Based on these observations, Dr. Huggins received a Nobel Prize in Physiology or Medicine in 1966 “ for his discoveries concerning hormonal treatment of prostatic cancer ” [ 17 , 60 , 61 , 62 ]. Today, ADT, a form of “ castration ”, remains key to the treatment of advanced and metastatic PCa.…”

“…GnRH antagonists reversibly inhibit GnRH receptors on the anterior pituitary gland, preventing LH secretion [ 62 ]. To ensure full blockade of T production, adrenal androgen inhibitors, including corticosteroids, ketoconazole, and aminoglutethimide, may also be used [ 61 ], though the toxicities of ketoconazole often outweigh its benefits [ 17 ]. Regardless of the form of ADT, however, within 2–3 years, most PCa patients develop resistance to ADT monotherapy and progress to CRPC [ 9 , 15 , 16 , 17 , 18 , 19 ].…”

“…For patients with BCR or with metastatic PCa, androgen deprivation therapy (ADT), a treatment aiming to reduce cancer growth and alleviate pain by reducing circulating androgens, becomes the standard of care treatment [ 9 , 12 , 13 , 14 ]. Within 2–3 years, patients often develop resistance to ADT monotherapy, resulting in castration-resistant PCa (CRPC) [ 9 , 15 , 16 , 17 , 18 , 19 ].…”

Glucosinolate-Degradation Products as Co-Adjuvant Therapy on Prostate Cancer in Vitro

“…Recently, there is no satisfactory treatment for PC when the cancer cells lose responsiveness to ADT [12]. DOCE is a therapeutic alternative but with important side effects and limited anti-cancer response, among other aspects due to the appearance of resistance [3,4].…”

In honor of Dr. Donald S. Coffey – Prostate cancer biology and therapy

“…ADT is the most effective initial treatment for patients, however, after the initial response, almost all patients will eventually progress to castration-resistant prostate cancer (CRPC). Dr. Kenneth Pienta and colleagues [4] provided an overview of current treatments for CRPC and summarized recent findings in therapeutic resistance mechanisms. Dr. Allen C. Gao and colleagues [5] provided an overview of the mechanisms of resistance associated with the most relevant AR variants, and discussed current AR variant targeting strategies including a phase II clinical trial testing niclosamide as an AR-V7 targeting agent for CRPC.…”