PP2A Activation as a Therapy for AR-Addicted Refractory Castration-Resistant Prostate Cancer
Abstract
Background: Prostate cancer is the second leading cause of cancer-related death in men in the USA. I t is estimated that about 1 in 7 men will be diagnosed with prostate cancer during his lifetime. While effective surgical, radiation, and androgen ablation therapy exists for the clinically localized prostate cancer, progression to metastatic castration-resistant prostate cancer (CRPC) remains virtually incurable. Despite the success of recently approved therapies targeting AR (androgen receptor) signaling, durable responses are limited due to acquired resistance. 20-40% of patients treated with the top-line anti-androgen therapies such as enzalutamide and abiraterone are initially resistant. The majority of the remaining population will develop resistance to these drugs, thereby progressing to refractory disease. In addition to enzalutamide, structurally similar second-generation antiandrogen drugs, namely apalutamide and darolutamide, have recently been approved by the FDA for non-metastatic castration-resistant prostate cancer (nmCRPC), which is also expected to lead to resistance disease. Therefore, there is a strong need to understand the mechanism of resistance to these drugs and develop treatments for this advanced refractory stage of prostate cancer. Discovering critical players responsible for the restoration of AR signaling in the refractory disease may also be useful to be measured as a diagnostic marker of prostate cancer progression. We have identified SMAP (small molecule activator of phosphatase) that stabilizes PP2A (Protein Phosphatase 2A) as a new therapeutic option in anti-androgen resistant CRPC. In this proposal, we are explicitly looking at enzalutamide (used as a model anti-androgen) resistant CRPC, for which current treatment options are not effective. By continuously growing the prostate cancer cells in the presence of enzalutamide, apalutamide, and darolutamide, we have made the cells resistant to these FDA-approved first-line therapies for advanced castration-resistant prostate cancer. These resistant cell line models will be used to assess the anti-cancer activity of SMAPs. Justification: Our preliminary data have shown that the AR, MED1, and BRD4 protein required for prostate cancer growth is modified (hyper-phosphorylated) when the cells become resistant to anti-androgens, accompanied by reduced amounts of PP2A protein – a known tumor suppressor. Additionally, lower PP2A protein amount was correlated with early death by prostate cancer. We have also observed that the hyper-phosphorylated form (a kind of modification that makes the protein more active/bad for cancer) of AR, MED1, and BRD4 in the enzalutamide-resistant cells could be reduced by treating them with SMAP – a drug that reactivates PP2A. Also, SMAP treatment led to the death of enzalutamide-, apalutamide-, and darolutamide-resistant prostate cancer cells in vitro. Research Questions and Clinical Applicability: Is AR signaling still required for anti-androgens such as enzalutamide-, darolutamide-, and apalutamide-resistant prostate cancer. Why and how PP2A is lost in the antiandrogen-resistant cells? What role the increased phosphorylated form of AR, MED1, and BRD4 play in the enzalutamide-resistant CRPC? Is this phosphorylation on AR, MED1, and BRD4 related to the reduced phosphatase enzyme PP2A activity? Can these phosphorylated forms of protein be measured as a novel prognostic marker of PCa? Suppose MED1 and BRD4 are as necessary as our preliminary studies indicate; then we will investigate whether the PP2A activator SMAP specifically impacts enzalutamide resistant prostate cancer cells that are still addicted to AR. Is the loss of PP2A drives the increased AR output in the enzalutamide resistant state? Are SMAPs effective in cancers that have refracted following standard of care enzalutamide therapy? To answer these questions, we will use naïve and enzalutamide resistant cell lines, for in vitro experimen
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110436
Entities
People
- Irfan Asangani
Organizations
- United States Army
- University of Pennsylvania