Prostate inflammatory lesions as a proving ground for development of aggressive prostate cancer

Active Cooperative Agreement Awarded Last action

Award ID
U54CA274370
Recipient
Awarding agency
Obligated
$15,308,880

Award facts

Assistance listing
93.397 Cancer Centers Support Grants
Completion date 83% complete
Place of performance
Baltimore, MD 21287, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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.

Transactions

Action Obligated Date
Amendment $0
Amendment $1,515,775
Amendment $1,516,118
Amendment $0
Amendment $0
Amendment $1,440,117
Amendment $1,440,117
Amendment $0
Amendment $0
Amendment $0
Amendment Spatial and mechanistic assessment of the role of stromal fibroblasts in driving emergence of aggressive prostate and bladder cancer $82,234
Amendment $1,485,601
Amendment $1,485,601
Amendment Spatial and mechanistic assessment of the role of stromal fibroblasts in driving emergence of aggressive prostate and bladder cancer $1,485,601
Amendment $0
Amendment $0
Amendment Spatial and mechanistic assessment of the role of stromal fibroblasts in driving emergence of aggressive prostate and bladder cancer $0
Amendment $90,502
Amendment $90,502
Amendment $90,502
Amendment $90,502
Amendment Spatial and mechanistic assessment of the role of stromal fibroblasts in driving emergence of aggressive prostate and bladder cancer $90,502
Amendment $1,468,402
Amendment $1,468,402
Original award $1,468,402
Show all 25

Subawards

Subrecipient Amount Awarded
University Of Maryland Baltimore County Prostate inflammatory lesions as a proving ground for development of aggressive prostate cancer $1,256,988
The University Of Texas Southwestern Medical Center Prostate inflammatory lesions as a proving ground for development of aggressive $514,103

Quick answers

Who received award U54CA274370?

U54CA274370 was awarded to The Johns Hopkins University by National Cancer Institute (National Institutes of Health) on September 15, 2022.

How much is award U54CA274370 worth?

$15,308,880 has been obligated on U54CA274370.

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