Treatment patterns for metastatic castration-resistant prostate cancer (mCRPC) at the US Veterans Health Administration (VHA) have changed substantially in the past few years. VHA patients with mCRPC are still treated with androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonists initially. Nevertheless, a recent publication demonstrated that currently, 77% VHA mCRPC patients who progress on ADT are being further treated with 2nd generation anti-androgens: the CYP17A1 inhibitor abiraterone (ABI) with prednisone or the androgen receptor (AR) inhibitor enzalutamide (ENZA), while 23% are treated with the chemotherapy agent docetaxel. A post hoc analysis reported that docetaxel was the most common and effective first subsequent therapy (FST) among patients who progressed following protocol- specified treatment with ABI. However, the median docetaxel treatment duration among these patients was 4.2 months; hence, our goal is to find ways to prolong the efficacy of docetaxel in post-ABI VHA mCRPC patients. Multiple studies have pointed to a role for Galectin-1 (Gal-1) in tumor formation and aggressiveness in docetaxel resistant CRPC. We demonstrate that Gal-1 was elevated in CRPC, while inhibition of Gal-1 inhibited cell growth, invasion and migration. Based on these observations, we have now developed a novel Gal-1 inhibitor, LLS30, which is benzimidazole-based, and is therefore less toxic and of superior efficacy compared to conventional and existing Gal-1 inhibitors. LLS30 demonstrated significant cytotoxic effects in Gal-1 expressing, but not Gal-1 low, CRPC cell lines, and disrupted cell adhesion in high Gal1 cells. LLS30 also sensitized ABI-resistant cell lines to docetaxel in models of mCRPC that expressed high Gal-1. Based on these observations, we hypothesize that ABI/ENZA treatment promotes Gal-1 expression, and Gal-1 nuclear translocation, where it induces the formation of AR splice variants that induce resistance to ABI/ENZA. We propose that Gal-1 targeting to the nuclear envelope is mediated by microtubule dynamics, which is prevented by subsequent treatment with docetaxel; and by nuclear pore entry, which may be prevented by LLS30. Docetaxel resistance is often traced to the expression and activation of p-glycoprotein (p-gp), which promotes multi-drug resistance. Studies have shown that Gal-1 induces p-gp expression; hence LLS30 will prevent docetaxel resistance by suppressing p-gp expression and also inhibit Gal-1 nuclear localization.
Aim 1 : To determine the mechanism of Gal-1 involvement in docetaxel resistance and a potential role for LLS30 in overcoming that resistance will test the hypothesis that AR activity suppresses Gal-1 expression and/or subcellular localization, and whether nuclear Gal-1 induces resistance to ABI/ENZA by promoting expression of AR splice variants that lack the AR-LBD. Further, we will determine whether LLS30 prevents Gal- 1 nuclear localization by inhibiting its binding to the nuclear pore complex. Cooperation between docetaxel and LLS30 to impede progression in ABI/ENZA-resistant CRPC models by inhibiting Gal-1 nuclear translocation will also be investigated, especially in view of a role of p-gp.
Aim 2 : Test the role of Gal-1 in mediating the effects of the novel inhibitor LLS30 on the response of patient derived xenograft (PDX) models of ABI- resistant CRPC to docetaxel. PDX tumors derived from biopsy material of patients with post-ABI CRPC to docetaxel will be used to evaluate the effects of LLS30 on the response of CRPC to docetaxel. We will examine whether castration, LLS30 and/or docetaxel affect Gal-1 localization in the tumor, and whether translocation of Gal-1 by LLS30 or docetaxel correlate with the expression of AR and its splice variants.
Aim 3. To investigate the relationship between serum Gal-1 levels and docetaxel treatment in patients who progress on ABI/ENZA treatment for mCRPC at the VANCHCS. Here we will test the hypothesis that serum levels of Gal- 1 in patients with post-ABI/ENZA CRPC correlate with their subsequent response to docetaxel. Patient Criteria and Plan. Also, we will determine whether docetaxel or treatments with ABI or ENZA affects serum gal-1 levels.
OF THE PROPOSED RESEARCH TO VETERANS? HEALTH: VA patients with recurrent prostate cancer (CaP), who have developed resistance to androgen deprivation therapy (ADT), are further treated with chemotherapy (docetaxel) but mostly with 2nd generation anti-androgens: abiraterone acetate+prednisone or enzalutamide, then switched to the opposite treatment when patients develop resistance to one. Recent publications indicate that post-ABI castration-resistant prostate cancer (CRPC) patients significantly benefit from docetaxel, though for a limited time. Our goal is to find ways to prolong the efficacy of docetaxel in post-ABI CRPC patients being treated at the VA. We propose the use of a drug candidate that specifically targets galectin-1, which plays important roles in tumor transformation, tumor cell proliferation, migration, survival and drug resistance. This compound represents a novel class of anti-cancer drug, and its successful development will greatly impact future therapies against CRPC at the VA.
