M. Swamynathan, Manojit, Mathew, Grinu, Aziz, Andrei, Gordon, Chris, Hillowe, Andrew, Wang, Hehe, Jhaveri, Aashna, Kendall, Jude, Cox, Hilary, Giarrizzo, Michael, Azabdaftari, Gissou, Rizzo, Robert C, Diermeier, Sarah D, Ojima, Iwao, Bialkowska, Agnieszka B, Kaczocha, Martin, Trotman, Lloyd C (2024) FABP5 Inhibition against PTEN-Mutant Therapy Resistant Prostate Cancer. Cancers, 16 (1). p. 60. ISSN 2072-6694
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Abstract
Resistance to standard of care taxane and androgen deprivation therapy (ADT) causes the vast majority of prostate cancer (PC) deaths worldwide. We have developed RapidCaP, an autochthonous genetically engineered mouse model of PC. It is driven by the loss of PTEN and p53, the most common driver events in PC patients with life-threatening diseases. As in human ADT, surgical castration of RapidCaP animals invariably results in disease relapse and death from the metastatic disease burden. Fatty Acid Binding Proteins (FABPs) are a large family of signaling lipid carriers. They have been suggested as drivers of multiple cancer types. Here we combine analysis of primary cancer cells from RapidCaP (RCaP cells) with large-scale patient datasets to show that among the 10 FABP paralogs, FABP5 is the PC-relevant target. Next, we show that RCaP cells are uniquely insensitive to both ADT and taxane treatment compared to a panel of human PC cell lines. Yet, they share an exquisite sensitivity to the small-molecule FABP5 inhibitor SBFI-103. We show that SBFI-103 is well tolerated and can strongly eliminate RCaP tumor cells in vivo. This provides a pre-clinical platform to fight incurable PC and suggests an important role for FABP5 in PTEN-deficient PC.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > prostate cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Trotman lab CSHL labs > Wigler lab CSHL Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > Microscopy Service |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2024 |
| Date Deposited: | 10 Jan 2024 16:33 |
| Last Modified: | 11 Apr 2024 14:42 |
| PMCID: | PMC10871093 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41396 |
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