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Spatial and mechanistic assessment of the role of stromal fibroblasts in driving emergence of aggressive prostate and bladder cancer

Award Number: U54CA274370
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary: Epidemiological and pathological studies have implicated lifestyle, microbial, and environmental factors in prostate cancer etiology/risk. A potential link between these factors and prostate carcinogenesis is the presence of chronic inflammation associated with atrophy (PIA) in prostates of aging men. Yet, there is a paradox surrounding the role of the immune response in prostate cancer: “the inflammation paradox”. On one hand, inflammation may be a driver of carcinogenesis. On the other, the immune system is known to seek and destroy cancer cells. The majority prostate cancer lesions are “immune deserts”, and ICIs are ineffective in most cases. Why is there an evidently strong immune reaction in non- neoplastic regions in PIA, but a lack of a robust immune response in most prostate cancers? We hypothesize that chronic inflammation in PIA represents evidence of an innate immune response that drives carcinogenesis. However, in this inflammatory “proving ground”, only cells that can epigenetically switch off this response can emerge to become aggressive neoplastic precursors. We hypothesize that the paucity of immune infiltrates and lack of PD-L1, is evidence that prostate cancer cells develop a number of different mechanisms that evade anti-tumor adaptive immunity. We postulate that additional cell non- autonomous immune suppressive mechanisms enable disease progression. We propose 3 synergistic Research Projects (2 basic,1 translational) to mechanistically test key questions stemming from our “proving ground” hypothesis. In Proj 1 (Basic Science) we hypothesize that the STING induction in PIA drives acute and chronic inflammation, leading to cell injury/cell death and proliferation. Second, in a subset of PIA cells, epigenetic silencing of STING dampens of the immune response, allowing them to emerge as overt pre- neoplastic cells. We will test this in animal models and in translational studies employing annotated and molecularly characterized prostatectomies. The combination of PTEN loss and MYC copy number gain is an independent predictor of poor outcome in prostate cancer. We hypothesize that the combination of MYC and PTEN stimulates a cell non-autonomous immune evasion mechanism induced by the recruitment of immuno- suppressive myeloid cells, and fibroblast activation protein (FAP)-positive fibroblasts. Proj 2 (Basic Science) will test these hypotheses in animal models and in human tissues. Recently introduced imaging technologies have raised the hypothesis that PET/CT imaging results may be able to predict molecular and tumoral micro- environmental characteristics of aggressive prostate cancer. PET imaging for PSMA using PyL PET/CT has been FDA approved for imaging high risk men prior to prostatectomy. In Proj 3 (Translational) we employ PET/CT scanning for PSMA and combine this with mpMRI to address these hypotheses. Also in Proj 3 we will apply newly developed/developing PET imaging agents to non-invasively and longitudinally study the extent of M2 macrophages and cancer associated fibroblasts in our mouse prostate progression cancer models.


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: 2023 ( Subtotal = $1,658,337 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Centers Support Grants	003	2	9/18/2023	SUPPLEMENT FOR EXPANSION	$82,234
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Centers Support Grants	002	2	9/1/2023	NON-COMPETING CONTINUATION	$1,485,601
2023	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Centers Support Grants	001	1	8/18/2023	NEW	$0
2023	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Centers Support Grants	000	1	1/13/2023	NEW	$90,502
														Subtotal = $1,658,337

Issue Date FY: 2022 ( Subtotal = $1,468,402 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Centers Support Grants	000	1	9/6/2022	NEW	$1,468,402
														Subtotal = $1,468,402

Grand Total All Awards = $3,126,739

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Spatial and mechanistic assessment of the role of stromal fibroblasts in driving emergence of aggressive prostate and bladder cancer

Award Number: U54CA274370

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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