Document text
Principal Investigator: Paramita M. Ghosh
Organization: VA NORTHERN CALIFORNIA HEALTH CARE SYS
Fiscal Year: 2024
Funding agency: Veterans Affairs
SUMMARY: 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.
Terms: <1, 2-Dehydrocortisone><ABC20><ABCB1><ABCB1 gene><Acetates><Affect><Alternate Splicing><Alternative RNA Splicing><Alternative Splicing><Androgen Antagonists><Androgen Receptor><Anti-Androgen><Anti-Androgen Agents><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Binding><Binding Site Domain><Biopsy><Blood Serum><CPT7><CYP17><CYP17A1><CYP17A1 gene><Cancer Drug><Cancer Patient><Castration><Cell Adhesion><Cell Body><Cell Growth in Number><Cell Line><Cell Multiplication><Cell Nucleus><Cell Proliferation><CellLine><Cells><Cellular Adhesion><Cellular Expansion><Cellular Growth><Cellular Proliferation><Data><Dehydrocortisone><Delta(1)-Cortisone><Deltacortisone><Deltadehydrocortisone><Development><Drug resistance><Drugs><Future><GAL1><GP170><Galectin 1><Generations><Goals><Health><Invaded><LGALS1><Ligand Binding Domain><Luteinizing Hormone-releasing Hormone Agonist><MDR-1><MDR1><MDR1 Protein><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Medication><Metacortandracin><Micro-tubule><Microtubule Stabilization><Microtubules><Modeling><Molecular Interaction><Multi-Drug Resistance><Multidrug Resistance><Multidrug Resistance 1><Multidrug Resistance Gene-1><Multidrug Resistance Gene-1s><Multidrug Resistance Proteins><Multidrug Resistant Proteins><Multiple Drug Resistance><Multiple Drug Resistant><NPC><Neoplastic Disease Chemotherapeutic Agents><Nuclear><Nuclear Envelope><Nuclear Import><Nuclear Membrane><Nuclear Pore><Nuclear Pore Complex><Nuclear Translocation><Nucleus><P-GP><P-Glycoprotein><P-Glycoprotein 1 Gene><P450C17><PDX model><PGY-1 Protein><PGY1><Patient derived xenograft><Patients><Pharmaceutical Preparations><Play><Prednisone><Prednisonum><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><Protocol><Protocols documentation><Publications><RNA Splicing><Recommendation><Recurrence><Recurrent><Regulation><Reporting><Research><Resistance><Resistance development><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant development><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Role><S17AH><STAT3><STAT3 gene><Scientific Publication><Serum><Specific qualifier value><Specified><Splicing><Strains Cell Lines><Surgical Castration><Taxotere><Testing><Time><Treatment Period><Tumor Cell><Tumor-Derived><Tumor-Specific Treatment Agents><Variant><Variation><Veterans><Veterans Health Administration><Veterans Health Affairs><Xtandi><abiraterone><androgen ablation therapy><androgen blockade therapy><androgen deprivation therapy><androgen deprivation treatment><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen inhibitor><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><anti-cancer drug><benzimidazole><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><cell growth><chemotherapy><comparable efficacy><comparative efficacy><compare efficacy><cultured cell line><cytotoxic><delta-Cortisone><developing resistance><developmental><docetaxel><docetaxol><drug candidate><drug resistant><drug/agent><enzalutamide><hormone refractory prostate cancer><inhibitor><migration><multi-drug resistant><multidrug resistant><neoplastic cell><novel><patient derived xenograft model><patient response><patient specific response><prevent><preventing><prostate cancer cell line><prostate cancer model><prostate cancer resistant to androgen><prostate tumor model><resistance to Drug><resistant><resistant to Drug><response><responsive patient><social role><treatment days><treatment duration><treatment pattern><tumor>