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Full Research Project: Epigenetic variations associated with aggressiveness in prostate cancer among Puerto Rican menJong Park, PhD (MCC) and Carmen Ortiz, PhD (PHSU)

Full Research Project: The impact of biobehavioral factors and aspirin on ovarian cancer biology – Lauren Peres, PhD (MCC) and Guillermo Armaiz-Peña, PhD (PHSU)

Pilot Research Project: Testing the effectiveness of an intervention to foster cervical cancer screening promotion for Latinx trans me among medical students – Matthew Schabath, PhD (MCC) and Alixida Ramos-Piberus, PhD (PHSU)

Full Research Project: Epigenetic variations associated with aggressiveness in prostate cancer among Puerto Rican men – Jong Park, PhD (MCC) and Carmen Ortiz, PhD (PHSU)

Puerto Rican (PR) Hispanic/Latino (H/L) men have the highest prostate cancer (PCa) mortality among Hispanic populations. According to the recent PR Cancer Registry data, PCa is the leading cancer type in terms of incidence (35% of all cancer cases) and mortality (17% of all cancer deaths) in PR H/L men. They have significantly higher PCa-specific mortality than non-Hispanic white (NHW) and non-Hispanic Black (NHB) men; addressing this gap constitutes our central efforts. While socioeconomic status and access to healthcare are contributors, manifest differences in molecular features between racial groups highlight the role of tumor biology in racially disparate outcomes in PCa. Our long-term goal is to identify DNA methylation biomarkers driving gene expression changes that underly PCa therapy resistance and aggressiveness in at-risk populations, particularly PR H/L men. The central hypothesis is that differences in tumor DNA methylation patterns and population admixture are associated with drug response and aggressiveness in PCa in PR H/L men. The rationale is that identifying the molecular basis of PCa disparities will serve to reduce the burden of lethal PCa disparities affecting PR H/L men. Our goals will be accomplished through two Specific Aims: Aim 1) Investigate associations between aggressiveness and methylated genes in PCa among the PR H/L population and the impact of methylation on their expression. (1a) Investigate differentially methylated genes associated with drug resistance and aggressiveness among PR H/L PCa patients and compare with methylation data from NHB from the Florida PCa biobank, NHW PCa patients from MCC, and TCGA. (1b) Evaluate differential DNA methylation on gene expression patterns. We will establish comparisons with previous data obtained from NHW men from MCC and TCGA. (1c) Evaluate whether population admixture will modify the methylation level of PR-specific methylated genes. Further, we will investigate whether genes that contain ancestry determinants are associated with the aggressiveness of PCa and disparity. Aim 2. Assess the contribution of DNA methylation to PCa resistance to standard therapies using drug-resistant PCa sublines and liquid biopsies from PCa patients progressing after treatment. (2a) Identify differentially methylated genes associated with drug-resistant phenotypes using cellbased models of drug resistance including castration resistance, enzalutamide resistance, and docetaxel resistance. (2b) Evaluate the expression of differentially methylated genes in resistant sublines compared to sensitive cell lines. (2c) Assess the effect of DNA methylation inhibition on drug sensitivity in resistant phenotypes. (2d) As an exploratory aim, we will evaluate resistance-associated methylation profiles in blood samples from PR and MCC patients previously treated with androgen deprivation therapy, androgen receptortargeting agents, or taxane-based chemotherapy. The identification and validation of novel DNA methylation signatures associated with aggressive and drug-resistant PCa in PR men have the potential to improve risk stratification and treatment selection in this high-risk, understudied population.

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Full Research Project: The impact of biobehavioral factors and aspirin on ovarian cancer biology – Lauren Peres, PhD (MCC) and Guillermo Armaiz-Peña, PhD (PHSU)

Growing evidence indicates that the biological response to chronic stress and subsequent distress can promote the progression of epithelial ovarian cancer via prolonged activation of the sympathetic nervous system and sustained norepinephrine release. Downstream consequences of norepinephrine exposure include increased prostaglandin-related inflammation and an immunosuppressive landscape. Conversely, increasing evidence supports the role of aspirin use in ovarian cancer prevention and survival. Yet, key questions remain about the underlying biological mechanism of action of chronic stress/distress and aspirin use (considering low and standard doses separately) and their interrelationship with ovarian cancer biology. Specifically, we propose to evaluate the hypothesis that distress enhances ovarian cancer progression by promoting inflammatory and immune processes and that aspirin abrogates these effects. Our innovative study uses unique population-based and experimental resources. Aim 1 will use data from four long-term prospective cohorts in diverse populations, a population-based case-control study, a hospital case series that collected self-reported measures of chronic stress and distress (e.g., depression), and ovarian tumor tissue. Aim 1 will measure gene expression in bulk high grade serous tumor samples (to capture the full tumor microenvironment) using whole exome RNASeq. We hypothesize that distress is associated with the upregulation of inflammation-related and immune suppression gene expression pathways that is normalized among aspirin users. We will also assess if the association of distress with ovarian cancer risk is attenuated among aspirin users. Notably, we are leveraging racially and ethnically diverse studies that have highly characterized ovarian cancer cases, allowing assessment of differences in association by race (Black, White) and ethnicity (Hispanic, non-Hispanic), as well as the examination of associations between distress related gene expression profiles and clinical outcomes. Using an orthogonal and interactive approach, Aim 2 will use experimental ovarian cancer mouse models to characterize the progressive effect over time of daily restraint stress on tumor inflammation and immunity as well as ovarian tumor growth, using RNASeq and stress hormones measured via ELISA assays. We also will examine if aspirin (recapitulating equivalents of low and standard dose aspirin in humans) counteracts the effects of chronic stress on tumor progression and inflammatory and immune gene expression networks. This project will leverage the scientific services of several cores, including the Puerto Rico BioBank (PRBB) and the Quantitative Science Core (QSC), with substantial interaction with the Outreach Core, the Planning and Evaluation Core, and working with trainees in the Research Education Core. This innovative application will inform future work to develop novel immunopreventive strategies, pharmacotherapies, and psychosocial interventions to prevent and treat invasive ovarian cancer in women who experience chronic stress and distress.

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Pilot Research Project: Testing the effectiveness of an intervention to foster cervical cancer screening promotion for Latinx trans me among medical students – Matthew Schabath, PhD (MCC) and Alixida Ramos-Piberus, PhD (PHSU)

Transmen (TM) and non-binary individuals (NB; individuals assigned female sex at birth who identify as a man, male, or another diverse non-binary gender identity on the masculine spectrum) are at higher risk of screening detectable cancers. The incidence of cervical cancer among Latinx (a gender-neutral term designating Hispanics/Latinos (H/L)) is the highest among all ethnic groups in the US. Thus, Latinx TM and NB (LTM-NB) are at a higher risk for cervical cancer as they lie at the intersection (i.e., gender and ethnic minorities) of two populations that experience health disparities for this disease. Individual and interpersonal level factors in interactions with health care providers such as the gendered nature of testing, “misgendering” or use of incorrect pronouns, and avoidance to discuss issues about body parts associated with their assigned at birth gender have been identified as some of the key aspects driving cervical cancer disparities among LTM-NB. In addition, healthcare providers’ negative attitudes and insensitivity can contribute to emotional discomfort for testing, adding another screening barrier. Our previous studies among LTM-NB in Puerto Rico and Florida show that providers lack knowledge about specific healthcare needs, have negative stigmatizing attitudes, and manifest discriminatory behaviors in clinical interactions with LTM-NB. However, although there are existing guidelines to foster cancer early detection and prevention among TM, no guidelines or interventions address the increased disparities encountered by ethnic minority LTM-NB. We developed a brief online intervention to improve medical students’ competencies for cervical cancer education and screening promotion among LTM- NB. The efficacy of this intervention has already been tested and exhibited medium to large effect sizes. The Aims of this proposed study are: Aim 1) Test the effectiveness of the intervention in increasing medical students’ knowledge, attitudes, and skills for providing healthcare to LTM-NB. This will be achieved by conducting a randomized controlled trial with participants from Ponce Health Science University and from Moffitt Cancer Center-University of South Florida. Quantitative measures (knowledge and attitudes) and SPS direct observations (behaviors) will be collected to examine the intervention’s effectiveness. The rationale for this aim is to determine the additional effect of the measure. Aim 2) Determine the acceptability, appropriateness, and feasibility of implementing the interventions in real-world medical educational settings. We will implement quantitative self-report measures and individual interviews with a sub-sample of participants from the experimental condition (n=10) to examine implementation outcomes (acceptability, appropriateness, and feasibility). The impact of this study will reveal new effective interventions and implementation strategies. The translational implications of this work will result in providing medical schools with a cross-cultural tool to train students on cervical cancer prevention for LTMNB.

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