PROJECT SUMMARY This application addresses targeted health issues through a Cooperative Research Agreement with the World Trade Center (WTC) Health Program (UO1). The presence of carcinogens and inducers of inflammation in WTC dust have raised the possibility that those exposed to WTC dust during the 9/11 attacks could have increased cancer incidence. To date, several cohort studies indicate that total cancer rates are 6-14% above background rates with significantly greater increases for thyroid and prostate cancer (Moir, 2016; Solan, 2013; Li, 2012; Jordan, 2011; Zeig-Owens, 2011). Increased exposure based on the time of arrival for workers, their proximity to early response to the WTC and duration of exposure have been associated with increased risk of tumor progression (de la Hoz, 2008; Lioy and Georgopoulos, 2006). Recent studies in small animal models indicate that WTC dust particles or metals are undetectable or present at exceedingly low levels in prostate tissues compared to lung following WTC dust exposure by inhalation or gavage (Wang, 2022; Gong, 2019), and long-term studies of rodents have not revealed evidence of a direct carcinogenic mechanism. Instead, there is evidence from both human RNA expression and DNA methylation analyses (Yu, 2022) and animal models (Wang, 2022; Gong, 2019) that inflammation induced by this dust may be implicated in promoting prostate cancer. In the mouse, WTC dust exposure promotes systemic as well as localized prostate inflammation, increased growth in PTEN deficient prostate epithelia and promotion of genetically initiated prostate tumors (Wang, 2022). Aim 1 will investigate whether WTC associated prostate cancer is more likely to recur independent of tumor grade at diagnosis and if there are molecular signatures of aggressiveness at diagnosis in those who recur. We will utilize increased biochemical (PSA) recurrence to define responders with adverse clinical response to WTC dust following surgery or radiation therapy. We will also apply recently identified signatures by RNA expression analysis and mass spec multiplex immunostaining of primary prostate cancer tissues to test whether these immune/inflammatory markers correlate with increased tumor recurrence in WTC responders. Aim 2 will focus on correlating our human findings with those in mouse genetically engineered mouse models bearing targeted lesions to prostate that model human PC. These experiments take advantage of our strong preliminary evidence that these models support a role of WTC dust exposure in PC progression. Experiments will include testing whether WTC dust exposure promotes recurrence of genetically initiated PCs following androgen deprivation therapy and/or experimental PC metastasis. We will also compare, and contrast WTC dust associated immune/inflammatory biomarkers in the mouse with those identified in human PCs. Our overarching goal is to translate understanding gained toward improved surveillance of WTC responders most at risk for prostate cancer.

Project Narrative. This project will investigate how exposure to World Trade Center (WTC) dust during the 9/11 attacks impacts prostate cancer recurrence in First Responders with correlative mechanistic studies in relevant mouse genetic models. The results should aid in assessing whether responders with high exposure levels require increased active surveillance for evidence of biochemical recurrence and the presence of more aggressive disease.