Full Research Project: Epigenetic variations associated with aggressiveness in prostate cancer among American men – Jong 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 2: Understanding the biology of an ADCK4-NUMBL fusion in lung adenocarcinoma aggressiveness - Doug Cress, PhD (MCC) and Pedro Santiago, PhD (PHSU)
Full Research Project: Epigenetic variations associated with aggressiveness in prostate cancer among American men – Jong Park, PhD (MCC) and Carmen Ortiz, PhD (PHSU)
This project addresses health drivers that contribute to differences in prostate cancer (PCa) outcomes in our catchment area. While socioeconomic status and access to healthcare are contributors, manifest differences in molecular features between groups within our catchment area highlight the role of tumor biology in disparate outcomes in PCa. Our long-term goal is to identify DNA methylation biomarkers driving gene expression changes that underlie PCa therapy resistance and aggressiveness in at-risk populations. The central hypothesis is that differences in tumor DNA methylation patterns and population admixture are associated with drug response and aggressiveness in PCa. The rationale is that identifying the molecular basis of PCa differences will serve to reduce the burden of lethal PCa affecting Americans. Our goals will be accomplished through two Specific Aims: Aim 1) Investigate associations between aggressiveness and methylated genes in PCa, addressing health drivers of cancer outcomes in PCa patients and compare with methylation data from the Florida PCa biobank, and PCa patients from MCC, and TCGA. (1b) Evaluate differential DNA methylation on gene expression patterns. We will establish comparisons with previous data obtained from MCC and TCGA. (1c) Evaluate whether population admixture will modify the methylation level of specific methylated genes. Further, we will investigate whether genes that contain genetic variability determinants are associated with the aggressiveness of PCa and outcomes. 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 cell-based 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 PCa patients from our catchment areas previously treated with androgen deprivation therapy, androgen receptor-targeting agents, or taxane-based chemotherapy. The identification and validation of novel DNA methylation signatures associated with aggressive and drug-resistant PCa have the potential to improve risk stratification and treatment selection in patients with PCa.
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, 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 are 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 studies that have highly characterized ovarian cancer cases, allowing 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 will also 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 patients who experience chronic stress and distress.
Pilot Research Project 2: Understanding the biology of an ADCK4-NUMBL fusion in lung adenocarcinoma aggressiveness – Doug Cress, PhD (MCC) and Pedro Santiago, PhD (PHSU)
Lung malignancies are the leading cause of cancer death. We have identified an ADCK4-NUMBL cis-SAGe fusion transcript by screening a cohort of lung adenocarcinoma patients known to lack typical oncogenic drivers. Cis-splicing between adjacent genes (cis-SAGe) is an understudied biological mechanism associated with an increase in genomic complexity. We find that the ADCK4-NUMBL fusion transcript is detectable in normal immortalized lung epithelial cells and at various levels in seven lung cancer cell lines evaluated. Likewise, measurement of the ADCK4-NUMBL Exon 14-Exon 2 transcripts in RNA derived from tumors from patients with lung adenocarcinoma revealed significant variation. A cohort of 193 lung adenocarcinoma patients was divided into high and low ADCK4-NUMBL expression groups, and overall survival comparisons were made. Kaplan-Meier analysis revealed that patients with high RNA expression (above the median) of ADCK4-NUMBL have diminished overall survival (Log-rank p <0.001) compared to patients with low expression. ADCK4-NUMBL levels were elevated in self-identified Black patients (p = 0.01), in smokers (p = 0.03), and in patients with KRAS mutations (p <0.04). No differences in ADCK4-NUMBL expression were observed when comparing patients by sex, age, stage, or body mass index. NUMBL immunoprecipitation, gel electrophoresis, and mass spectrometry analysis support the conclusion that the endogenous ADCK4-NUMBL transcript produces a protein product. Enforced expression of the ADCK4-NUMBL Exon 14-Exon 2 protein in A549 cells results in accelerated cell proliferation. These preliminary findings lead us to hypothesize that the ADCK4-NUMBL transcript produces an oncogenic protein that contributes significantly to lung cancer aggressiveness in a subset of lung cancer patients. In this pilot study, we propose the following exploratory aims to probe deeper into this general hypothesis and generate a strong premise for a future R01 application.