Grant Details
Grant Number: |
5R01CA255349-04 Interpret this number |
Primary Investigator: |
Platz, Elizabeth |
Organization: |
Johns Hopkins University |
Project Title: |
Stromal Senescence in Lethal Prostate Cancer: a Novel Target for Prognosis and Therapy |
Fiscal Year: |
2024 |
Abstract
Our overarching hypothesis is that senescent stromal fibroblasts, especially if they elicit an inflammatory
response, promote progression to lethal disease in men with prostate cancer. Senescent stromal fibroblasts
may result from telomere attrition, but also other aging and non-aging mechanisms, and can elicit inflammation
that acts in cancer initiation and promotion to a lethal state. Our preliminary findings implicate prostate stromal
cell telomere shortening and intraprostatic inflammation, both are intimately linked to the biology of cellular
senescence, in prostate cancer. Thus, we expect that specifically senescent fibroblasts, which have been
shown to secrete cytokines and other growth promoting factors, will be present in prostate-cancer associated
stroma and be related to lethal disease in men with prostate cancer. To address our hypothesis, we developed
and documented a multi-marker tissue-based strategy to uniquely identify fibroblasts, one of two major cell
types in the prostate stroma, the subset of fibroblasts that are senescent, and the associated immune infiltrate.
We propose these aims: 1. Evaluate the association between senescent stromal fibroblasts, especially in the
presence of stromal inflammation, in prostatectomy tissue and risk of progression to metastatic prostate cancer
in men with intermediate and high-risk disease (Cohort 1). 2. Evaluate the association between senescent
stromal fibroblasts, especially in the presence of stromal inflammation, and risk of progression to metastasis or
rapidly rising PSA in a second, independent cohort of men with intermediate and high-risk disease (Cohort 2).
3. Determine whether senescent fibroblasts are present in prostate metastases, and if so, their heterogeneity
across metastatic sites in bone and in soft tissues, in men who died of castrate-resistant prostate cancer. We
will identify senescent stromal fibroblasts in fixed prostate tissues using multiplex in situ immunofluorescence
staining with quantification via image analysis. In Aims 1 and 2, we will calculate the density of specific
senescent stomal fibroblasts per stromal area, the proportion with associated inflammation, and estimate
adjusted relative risks of lethal disease progression. Given that Black men have substantially higher prostate
cancer mortality rates, we will estimate associations separately in Black men. If our hypothesis is confirmed,
we will determine prognostic performance of senescent stromal fibroblasts, and assess whether their addition
enhances performance of existing cancer cell-based genomic prognostic tests already measured in Cohorts 1
and 2. Goal 1 is to inform the pressing clinical need for identifying which men’s, including Black men’s prostate
cancers are very likely to kill and, equally important, which ones are very unlikely to kill. If our hypothesis is
confirmed, data from our work could be incorporated into a prognostic tool. Goal 2 is to inform novel
therapeutics (senolytics) that eliminate senescent stromal fibroblasts in men at risk for progression or harboring
metastases. A prognostic tool incorporating senescent stromal fibroblasts could also serve as a companion
diagnostic, in that it would identify men with these senescent cells for targeting.
Publications
Prognostic and therapeutic potential of senescent stromal fibroblasts in prostate cancer.
Authors: Mori J.O.
, Elhussin I.
, Brennen W.N.
, Graham M.K.
, Lotan T.L.
, Yates C.C.
, De Marzo A.M.
, Denmeade S.R.
, Yegnasubramanian S.
, Nelson W.G.
, et al.
.
Source: Nature Reviews. Urology, 2023-10-31 00:00:00.0; , .
EPub date: 2023-10-31 00:00:00.0.
PMID: 37907729
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