Leveraging SULT2B1b Oxysterol Sulfotransferase for Inhibition of Castration-Resistant Prostate Cancer
Abstract
The objective of our proposal is to explore a new avenue for overcoming resistance of prostate cancer to hormone therapy by leveraging our recently reported results and new unpublished findings. The National Cancer Institute estimates that, in 2020, treatment resistance of PC will cause more than 33,000 deaths of U.S. men, which is ~ 5.5% of all cancer deaths. This sobering statistic highlights the urgency to develop new avenues of medical intervention that can overcome treatment resistance, delay disease progression, and improve quality of life for patients. Finding a clinically actionable new plan for reaching this goal is an overarching challenge. Androgen receptor (AR), activated by the hormone androgen, promotes prostate cancer. Androgen deprivation (medical castration) suppresses the androgen-sensitive stage of the advanced disease when AR is inactive in the absence of androgen. Post-remission, AR is reactivated by the androgen produced by the cancer tissue, allowing the disease to advance as castration-resistant prostate cancer (CRPC). Enzalutamide, a drug that inhibits AR, is widely used to manage CRPC, although drug resistance develops invariably. The enzyme AKR1C3 promotes androgen synthesis in tumor tissue. Thus, AKR1C3 is a crucial regulator of AR reactivation. AKR1C3 is elevated in drug resistant CRPC and it is a major target for drug development. Targeting AKR1C3 from multiple angles is desirable, since it would avoid dependence on a single route for AKR1C3 inhibition. We have uncovered a new mechanism by which AKR1C3 is elevated in CRPC due to loss of the sulfating enzyme SULT2B1b (aka SULT2B). SULT2B, which is induced by vitamin D (calcitriol), is undetectable in clinical samples of CRPC. SULT2B reduces activity of the gene regulatory proteins LXRa (liver X receptor-alpha) by converting oxysterols to sulfated metabolites. Oxysterols, the oxidized metabolites of cholesterol, are activating ligands of LXR. Only non-sulfated oxysterols can bind and activate LXR. We found that LXR activation due to loss of SULT2B leads to increased levels of ERRa, which is another gene regulatory protein. Cholesterol is the activating ligand for ERRa. ERRa enhances AKR1C3 gene activity, thus causing elevation of the AKR1C3 protein in CRPC. This novel LXRaERRaAKR1C3 cascade, at least in part, contributes to AKR1C3 induction. The proposal is designed to explore whether this novel cascade can be targeted for CRPC inhibition. In Aim 1, we will concurrently inhibit LXRa by the drug UDCA, which is a clinically active bile acid against cholestasis and a known inhibitor of LXRa and ERRa by the drug simvastatin, which, being a cholesterol-lowering drug, curbs the ligand pool for ERRa and possibly also for LXRa by reducing the cholesterol-derived oxysterol pool. Along with LXRa and ERRa inhibition, we will induce SULT2B by calcitriol (hormonally active vitamin D), which can enhance the SULT2B protein level, as reported by us. Given the clinical availability of these inhibitors, as well as calcitriol, results will be translatable and may lead to clinical trial for a new intervention approach for enzalutamide resistant CRPC. In Aim 2, we will conduct basic mechanistic studies to identify other molecules and regulatory proteins that cooperate with ERRa to cause AKR1C3 induction. The basic mechanistic study may uncover new drug targets for AKR1C3 inhibition. Oxysterols secreted from tumor cells play an additional pro-tumorigenic role outside of cancer cells by promoting infiltration of neutrophils to tumor region. Neutrophils are a type of immune cells that help cancer cells evade immune surveillance by cancer killing T cells. In Aim 3, we hypothesize that, due to its activity for enzymatic sulfation of oxysterols, SULT2B may interfere with the pro-tumor role of oxysterol signaling in cancer immune cell dynamics. We will use archived clinical prostate cancer specimens and fresh explants from radical prost
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110307
Entities
People
- Bandana Chatterjee
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio