Clinical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, PIK3CD-S, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative and invasive capacity in vitro and confers resistance to selective PI3Kδ inhibitor, CAL-101 (idelalisib), in mouse xenograft models. High PIK3CD-S expression in PCa specimens associates with poor survival. These results highlight the potential of RNA splice variants to serve as novel biomarkers and molecular targets for developmental therapeutics in aggressive PCa.
LBA5009 Background: Pivotal trials of AAP for patients with mCRPC enrolled few B pts, a population with a higher mortality from prostate cancer. Retrospective data suggests B pts may have higher PSA response rates than W pts treated with AAP for mCRPC. Therefore, we prospectively investigated AAP in B vs. W pts with mCRPC. Methods: Abi Race (NCT01940276) is a prospective, multicenter, parallel group study of AP in 100 men (50 B, 50 W) with mCRPC, self-identified by race. All pts received AA 1000 mg/D and P 10 mg/D (AAP) until disease progression or unacceptable adverse events (AE). The primary objective was radiographic progression-free survival (rPFS); key secondary endpoints include PSA kinetics and safety. Exploratory analyses include SNP, metabolomics and hormonal differences by race. Results: Baseline characteristics among pts were similar. The median rPFS for B and W pts was 16.8 months (mo) in each. However, PSA PFS varied by race; median PSA PFS for B and W pts were 16.6 and 11.5 mo [Table]. B pts also had numerically higher rates of ≥30%, ≥50% and ≥90% PSA decline [Table]. AEs were similar in frequency and severity by race including hypertension (42 vs 40%); however, fatigue was higher in W pts (40 vs 26%), and hypokalemia was higher in B pts (36 vs 18%). SNP profiling revealed differences in key genes involved in androgen metabolism and transport. Conclusions: This is the first prospective multicenter study by race of secondary hormonal therapy in mCRPC. B pts may have greater and more durable PSA response to AAP than W pts. SNP patterns vary by race and will be evaluated for prognostic significance. Further prospective studies in B pts are possible and needed to understand the impact of racial determinants on outcome of new hormonal regimens. Clinical trial information: NCT01940276. [Table: see text]
Treatment with androgen-targeted therapies can induce upregulation of epithelial plasticity pathways. Epithelial plasticity is known to be important for metastatic dissemination and therapeutic resistance. The goal of this study is to elucidate the functional consequence of induced epithelial plasticity on AR regulation during disease progression to identify factors important for treatment-resistant and metastatic prostate cancer. We pinpoint the epithelial plasticity transcription factor, Snail, at the nexus of enzalutamide resistance and prostate cancer metastasis both in preclinical models of prostate cancer and in patients. In patients, Snail expression is associated with Gleason 9-10 high-risk disease and is strongly overexpressed in metastases as compared to localized prostate cancer. Snail expression is also elevated in enzalutamide-resistant prostate cancer cells compared to enzalutamide-sensitive cells, and downregulation of Snail re-sensitizes enzalutamide-resistant cells to enzalutamide. While activation of Snail increases migration and invasion, it is also capable of promoting enzalutamide resistance in enzalutamide-sensitive cells. This Snail-mediated enzalutamide resistance is a consequence of increased full-length AR and AR-V7 expression and nuclear localization. Downregulation of either full-length AR or AR-V7 re-sensitizes cells to enzalutamide in the presence of Snail, thus connecting Snail-induced enzalutamide resistance directly to AR biology. Finally, we demonstrate that Snail is capable of mediating-resistance through AR even in the absence of AR-V7. These findings imply that increased Snail expression during progression to metastatic disease may prime cells for resistance to AR-targeted therapies by promoting AR activity in prostate cancer.
Despite advances in contemporary chemotherapeutic strategies, long term survival still remains elusive for patients with metastatic colorectal cancer. A better understanding of the molecular markers of drug sensitivity to match therapy with patient is needed to improve clinical outcomes. In this study, we used in vitro drug sensitivity data from the NCI-60 cell lines together with their Affymetrix microarray data to develop a gene expression signature to predict sensitivity to oxaliplatin. In order to validate our oxaliplatin sensitivity signature, Patient-Derived Colorectal Cancer Explants (PDCCEs) were developed in NOD-SCID mice from resected human colorectal tumors. Analysis of gene expression profiles found similarities between the PDCCEs and their parental human tumors, suggesting their utility to study drug sensitivity in vivo. The oxaliplatin sensitivity signature was then validated in vivo with response data from 14 PDCCEs treated with oxaliplatin and was found to have an accuracy of 92.9% (Sensitivity=87.5%; Specificity=100%). Our findings suggest that PDCCEs can be a novel source to study drug sensitivity in colorectal cancer. Furthermore, genomic-based analysis has the potential to be incorporated into future strategies to optimize individual therapy for patients with metastatic colorectal cancer.
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