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A First-in-Class FAP-activated Protoxin to disrupt the Tumor-Stroma Parasitic Cycle fueling lethal Prostate Cancer Progression

Award Number: R01CA255259
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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A First-in-Class FAP-activated Protoxin to disrupt the Tumor-Stroma Parasitic Cycle fueling lethal Prostate Cancer Progression - Though initially responsive to hormonal therapy, prostate cancer (PCa) invariably progresses to an incurable metastatic castration-resistant state (mCRPC). Additionally, the proportion of patients with androgen receptor (AR)-indifferent mCRPCe has increased significantly in the post-supracastration (e.g. -enzalutamide/- abiraterone) era in men with late-stage lethal disease. Whether treatment-induced or otherwise, this emphasizes the urgent need to develop innovative non-AR targeted approaches if we want to do more than provide incremental increases in patient survival and combat this emerging highly-aggressive lethal phenotype. Tumor- infiltrating fibroblast activation protein (FAP)-positive cells (i.e. MSCs, CAFs, and TAMs) are recognized as key architects of the pro-tumorigenic and immunosuppressive microenvironment conducive to tumor progression. This is in part through their production of energy-rich nutrients and metabolic intermediates that the cancer cells “parasitize” from the extracellular fluid to fuel tumor growth and progression. These observations suggest that a FAP-targeted therapy could provide an AR-independent multi-faceted anti-tumor assault by simultaneously disrupting the parasitic dependence on the tumor stroma and eliminating multiple immunosuppressive cell types within the tumor microenvironment (TME). To accomplish this goal, we have synthesized an orally-available small molecule FAP-activated mitochondrial protoxin based on niclosamide, an FDA-approved anti-helminthic that uncouples mitochondrial oxidative phosphorylation with nanomolar potency in a cell cycle-independent manner, making it an ideal warhead for FAP+ stromal cells with a low proliferative index. This proposal is innovative from conceptual and technical perspectives: 1) multiple tumor-infiltrating FAP+ cells in the TME are selectively and simultaneously targeted to overcome the immune barrier and disrupt the “parasitic cycle” fueling tumor growth; 2) a first-in-class enzymatically-activated lipophilic mitochondrial protoxin designed to increase the therapeutic index of an FDA-approved drug while sparing toxicity to surrounding healthy tissue is synthesized and characterized; 3) FAP expression patterns in a unique series of human prostate tissues, lymph nodes, and metastases as a function of malignancy and treatment status are assessed to identify clinical states most likely to benefit from FAP-targeted therapy; and 4) efficacy, toxicity, and specificity are evaluated using a novel series of patient-derived xenograft (PDX) and syngeneic models that recapitulate key clinical features of human PCa in order to delineate biologically-relevant immune-independent and –dependent mechanisms underlying the anti-tumor response. Furthermore, this strategy combines agents that have been individually tested in patients, which significantly bolsters potential for near-term patient benefit. More immediately, the proposal will provide important insights into the role of FAP+ cells in PCa pathophysiology particularly with respect to their interaction with the immune system, while providing the necessary preclinical proof-of-principle data needed to translate this innovative therapeutic platform into the clinic.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $415,155 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	5	12/13/2024	NON-COMPETING CONTINUATION	$373,640
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	001	5	6/2/2025	NON-COMPETING CONTINUATION	$41,515
														Subtotal = $415,155

Issue Date FY: 2024 ( Subtotal = $394,398 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	4	1/25/2024	NON-COMPETING CONTINUATION	$373,640
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	001	4	4/18/2024	NON-COMPETING CONTINUATION	$20,758
														Subtotal = $394,398

Issue Date FY: 2023 ( Subtotal = $406,852 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	3	2/13/2023	NON-COMPETING CONTINUATION	$406,852
														Subtotal = $406,852

Issue Date FY: 2022 ( Subtotal = $415,155 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	001	2	4/27/2022	NON-COMPETING CONTINUATION	$41,516
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	2	11/30/2021	NON-COMPETING CONTINUATION	$373,639
														Subtotal = $415,155

Issue Date FY: 2021 ( Subtotal = $471,718 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	1	12/17/2020	NEW	$471,718
														Subtotal = $471,718

Grand Total All Awards = $2,103,278

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A First-in-Class FAP-activated Protoxin to disrupt the Tumor-Stroma Parasitic Cycle fueling lethal Prostate Cancer Progression

Award Number: R01CA255259

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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