FABP5 Inhibition against <i>PTEN</i>-Mutant Therapy Resistant Prostate Cancer
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 even...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/16/1/60 |
| _version_ | 1797359052061147136 |
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| author | Manojit M. Swamynathan Grinu Mathew Andrei Aziz Chris Gordon Andrew Hillowe Hehe Wang Aashna Jhaveri Jude Kendall Hilary Cox Michael Giarrizzo Gissou Azabdaftari Robert C. Rizzo Sarah D. Diermeier Iwao Ojima Agnieszka B. Bialkowska Martin Kaczocha Lloyd C. Trotman |
| author_facet | Manojit M. Swamynathan Grinu Mathew Andrei Aziz Chris Gordon Andrew Hillowe Hehe Wang Aashna Jhaveri Jude Kendall Hilary Cox Michael Giarrizzo Gissou Azabdaftari Robert C. Rizzo Sarah D. Diermeier Iwao Ojima Agnieszka B. Bialkowska Martin Kaczocha Lloyd C. Trotman |
| author_sort | Manojit M. Swamynathan |
| collection | DOAJ |
| description | 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 <i>PTEN</i>-deficient PC. |
| first_indexed | 2024-03-08T15:10:07Z |
| format | Article |
| id | doaj.art-1d109320975d418cab3e6b18f038b834 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-08T15:10:07Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-1d109320975d418cab3e6b18f038b8342024-01-10T14:52:27ZengMDPI AGCancers2072-66942023-12-011616010.3390/cancers16010060FABP5 Inhibition against <i>PTEN</i>-Mutant Therapy Resistant Prostate CancerManojit M. Swamynathan0Grinu Mathew1Andrei Aziz2Chris Gordon3Andrew Hillowe4Hehe Wang5Aashna Jhaveri6Jude Kendall7Hilary Cox8Michael Giarrizzo9Gissou Azabdaftari10Robert C. Rizzo11Sarah D. Diermeier12Iwao Ojima13Agnieszka B. Bialkowska14Martin Kaczocha15Lloyd C. Trotman16Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USACold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USACold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USADepartment of Anesthesiology, Stony Brook University, Stony Brook, NY 11794, USADepartment of Anesthesiology, Stony Brook University, Stony Brook, NY 11794, USADepartment of Chemistry, Stony Brook University, Stony Brook, NY 11794, USACold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USACold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USACold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USADepartment of Medicine, Stony Brook University, Stony Brook, NY 11794, USADepartment of Anatomic Pathology, Stony Brook University, Stony Brook, NY 11794, USADepartment of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, USADepartment of Biochemistry, University of Otago, Dunedin 9016, New ZealandDepartment of Chemistry, Stony Brook University, Stony Brook, NY 11794, USADepartment of Medicine, Stony Brook University, Stony Brook, NY 11794, USADepartment of Anesthesiology, Stony Brook University, Stony Brook, NY 11794, USACold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USAResistance 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 <i>PTEN</i>-deficient PC.https://www.mdpi.com/2072-6694/16/1/60prostate cancer (PC)PTEN tumor suppressorlipid signalingfatty acid binding proteins (FABPs)FABP5SBFI-103 |
| spellingShingle | Manojit M. Swamynathan Grinu Mathew Andrei Aziz Chris Gordon Andrew Hillowe Hehe Wang Aashna Jhaveri Jude Kendall Hilary Cox Michael Giarrizzo Gissou Azabdaftari Robert C. Rizzo Sarah D. Diermeier Iwao Ojima Agnieszka B. Bialkowska Martin Kaczocha Lloyd C. Trotman FABP5 Inhibition against <i>PTEN</i>-Mutant Therapy Resistant Prostate Cancer Cancers prostate cancer (PC) PTEN tumor suppressor lipid signaling fatty acid binding proteins (FABPs) FABP5 SBFI-103 |
| title | FABP5 Inhibition against <i>PTEN</i>-Mutant Therapy Resistant Prostate Cancer |
| title_full | FABP5 Inhibition against <i>PTEN</i>-Mutant Therapy Resistant Prostate Cancer |
| title_fullStr | FABP5 Inhibition against <i>PTEN</i>-Mutant Therapy Resistant Prostate Cancer |
| title_full_unstemmed | FABP5 Inhibition against <i>PTEN</i>-Mutant Therapy Resistant Prostate Cancer |
| title_short | FABP5 Inhibition against <i>PTEN</i>-Mutant Therapy Resistant Prostate Cancer |
| title_sort | fabp5 inhibition against i pten i mutant therapy resistant prostate cancer |
| topic | prostate cancer (PC) PTEN tumor suppressor lipid signaling fatty acid binding proteins (FABPs) FABP5 SBFI-103 |
| url | https://www.mdpi.com/2072-6694/16/1/60 |
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