Abstract PO-100: Ancestry-related variation in Sphingosine Kinase Type 1-Interacting Protein (SKIP) and Sphingosine Kinase 1 (SPHK1) and response to secondary hormonal therapy in metastatic castration-resistant prostate cancer

Abstract

Abstract The number of cases and deaths from prostate cancer (PCa) is highest for African American (AA) men compared with men of other racial and ethnic groups, and AA men more frequently have more aggressive disease. However, recent studies have shown that AA PCa patients have a better response to certain therapeutic regimens than white PCa patients. We conducted a DoD Prostate Cancer Clinical Trials Consortium (PCCTC) prospective study of secondary hormonal therapy (HT) in metastatic castration-resistant PCa (mCRPC) patients stratified by race, Abi-Race. This study enrolled 50 AA and 50 white patients with mCRPC and received abiraterone and prednisone daily until disease progression or adverse event. AA men had higher rates of Prostate Specific Antigen (PSA) response and time to PSA progression. Herein we focus on correlative science in the context of Abi-Race to determine novel relationships between ancestry-related genetic variation and response and time to progression on secondary HT in mCRPC. An exploratory genome-wide analysis assessing the role of genotypic and local ancestry variation with respect to time to progression identified a missense variant in Sphingosine Kinase Type 1-Interacting Protein (SKIP) with predicted pathogenicity and potentially high ancestral variation. SKIP plays a role in modulating the conversion of sphingosine to sphingosine-1-phosphate (S1P) by regulating Sphingosine Kinase 1 (SPHK1) activity within the cytosol. S1P is a potent lipid mediator that plays a role in multiple cancer-promoting biofunctions. SKIP directly binds and inhibits SPHK1 activity, resulting in the decreased production of S1P and S1P-associated cell signaling. The relationship between SKIP and SPHK1 and response to secondary HT in mCRPC was investigated. We knocked down SKIP or SPHK1 in LN95 prostate cancer cells and assessed resulting alterations in proliferation with or without abiraterone. Knockdown of SKIP increased proliferation in untreated cells and knockdown cells were more resistant to treatment with abiraterone compared with the control group. Conversely, knockdown of SPHK1 decreased proliferation in untreated cells and knockdown cells were more sensitive to treatment with abiraterone compared with the control group. In addition, we are measuring changes in sphingosine and S1P in serum samples we collected from fasting Abi-Race patients at baseline and cycle 4 of treatment to investigate ancestry-related sphingosine and S1P variations and associated outcomes. Lastly, we are further investigating the potential function of the variant in SKIP associated with time to progression on secondary HT in mCRPC. These findings will further the understanding of ancestry-related biological factors that influence response to secondary HT in mCRPC and could have direct implications for the timing and selection of AA patients for secondary HT and those needing additional therapy. Ultimately, such strategies have the potential to mitigate prostate cancer disparities. Citation Format: Sean A. Piwarski, Tyler A. Allen, Dadong Zhang, Alexander B. Sibley, Patrick Healy, Brendon M. Patierno, Bonnie L. LaCroix, Rick A. Kittles, Kouros Owzar, Terry Hyslop, Steven R. Patierno, Daniel J. George, Jennifer A. Freedman. Ancestry-related variation in Sphingosine Kinase Type 1-Interacting Protein (SKIP) and Sphingosine Kinase 1 (SPHK1) and response to secondary hormonal therapy in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-100.