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Developmental Research Project: Discovery of potential immune-preventative targets for ovarian cancerIdhaliz Flores, PhD (PHSU) and José Conejo-Garcia, MD, PhD (MCC)

Developmental Research Project: The genomic and epigenetic predictors of aggressive prostate cancer in Puerto Rican menJong Park, PhD (MCC); Anders Berglund, PhD (MCC); Gilberto Ruiz-Deya, MD (PHSU); and Jaime Matta, PhD (PHSU)

Developmental Research Project: Developing and Testing a Spanish-Language Intervention to Reduce Cancer-Related Insomnia Brian González, PhD (MCC) and Jennifer Morales-Cruz, PhD (PHSU)

Pre-Pilot: Quantitative Sciences Collaborative ProjectJulie Dutil, PhD (PHSU); Steven Eschrich, PhD (MCC); and Jamie Teer, PhD (MCC) 

Pre-Pilot: The impact of Hurricane Maria on biopsychosocial outcomes and health care access of cancer patientsGuillermo Armaiz-Peña, PhD (PHSU); Mary Rodríguez-Rabassa, PsyD (PHSU); Idhaliz Flores, PhD (PHSU); Zindie Rodríguez, MD (PHSU); Heather Jim, PhD (MCC) 

Full Project: Using MC1R Genotype to Impact Skin Cancer Risk Behaviors in Hispanics/Latinos - Peter Kanetsky, PhD (Moffitt) and Brenda Soto, PhD (PHSU)

Full Project: Understanding how Mitotic Kinases Drive EMT in Breast Cancers Srikumar Chellappan PhD (Moffitt) and Harold Saavedra PhD (PHSU)

Pilot Project: Adrenergic Modulation of Ovarian Cancer Progression and Chemoresistance Alvaro Monteiro, PhD (MCC); Heather Jim, PhD (MCC) and Guillermo Armaiz-Peña, PhD (PHSU)

Pre-Pilot: Increasing HPV Vaccination Series Initiation and Completion Rates among Adolescent Hispanics in Tampa and Ponce - Susan T. Vadaparampil, PhD (MCC) and Lynnette A. Ruiz, PhD (PHSU)

Pre-Pilot: Low-dose computed tomography lung cancer screeningGwendolyn Quinn, PhD (MCC); Vani Simmons, PhD (MCC); Mary Rodríguez-Rabassa, PsyD (PHSU)

Full Project: Uncovering Breast Cancer Predisposition Factors in Puerto Rico - Alvaro Monteiro, PhD (MCC) and Julie Dutil, PhD (PHSU)

Pilot Project: Educational Intervention to Increase Genetic Counseling use in Hispanic Breast Cancer Survivors - Susan T. Vadaparampil, PhD (MCC) and Eida M. Castro, PsyD (PHSU)

Pilot Project: Infiltrating Immune Cells in Breast Cancer Subtypes - Shari Pilon-Thomas, PhD (MCC) and Jaime Matta, PhD (PHSU)

Full Project: Molecular Biology of Lung Cancer among Puerto Ricans Doug Cress, PhD (MCC) and Pedro Santiago, PhD (PHSU)

Pilot Project: Identifying Cancer Health Communication Channels for Hispanic Audiences - Gwendolyn Quinn, PhD (MCC) and Julio Jiménez, M.D. (PHSU)

Pre-Pilot: Breast cancer survivors’ knowledge, attitudes, and information needs about fertility and pregnancy - Gwendolyn Quinn, PhD (MCC) and Eida M. Castro, PsyD, MSc (PHSU)

Pre-Pilot: Characterization of the ovarian endometriosis chromatin states and its transcriptional regulatory functions in neoplastic transformationJanice Monteiro, PhD (France) and Ed Seto, PhD (George Washington Univ.)

Pilot Project: Neurokinin-1 receptor and its signaling components in colitis associated dysplasiaCaroline Appleyard, PhD (PHSU) and Jie Wu, PhD (MCC)

Pilot Project: BRCT Domains and breast cancer predispositionJaime Matta, PhD (PHSU) and Alvaro Monteiro, PhD (MCC)

Pilot Project: Development and assessment of hereditary breast cancer genetic screening tools for a minority population – Julie Dutil, PhD (PHSU); Rebecca Sutphen, MD (USF); and Jesus González Bosquet, MD, PhD (Univ. of Iowa)

Pilot Project: A role for pRb and Cdk5 as regulators of cell-to-cell adhesionPedro Santiago, PhD (PHSU) and Doug Cress, PhD (MCC)

Pilot Project: Cutaneous human papillomavirus infection and non-melanoma skin cancer in the US and Puerto RicoJaime Matta, PhD (PHSU) and Dana Rollison, PhD (MCC)

Developmental Research Project: Discovery of potential immune-preventative targets for ovarian cancer – Idhaliz Flores, PhD (PHSU) and José Conejo-Garcia, MD, PhD (MCC)

Endometriosis is a common gynecologic condition characterized by growth of estrogen-responsive endometrial-like tissue outside the uterus, forming lesions and ovarian cysts (endometriosis). To establish and survive ectopically, endometriotic tissue activates cellular, molecular and immune processes that are remarkably similar to those seen in cancer. While endometriosis is clearly not cancer (cell cycle control is not lost), it is associated with increased risk of ovarian cancer (OC) [OR=1.76], in particular with endometriod (OR=3.12) and clear cell (OR=5.17) but also with serous histology (OR=1.37). Immune cells in the ovarian carcinoma microenvironment spontaneously exert clinically relevant pressure against malignant progression. Work from the Co-PI’s lab have already identified B cells within ovarian carcinoma tissues producing antibodies with potential therapeutic value. As a precursor of OC, ovarian endometriosis provide a window of opportunity to understand if infiltrating B cells, through the production of antibodies and by influencing Natural Killer cell activity, could exert a protective role against endometriosis and thus against malignant progression.

Our general hypothesis is that antibodies produced in the ovarian endometrioma microenvironment will exhibit reactivity against endometriosis-specific proteins with potential as immunotherapeutic agents. Our overarching goal is to identify those targets, and also to obtain proof-of-principle data in support of boosting immune protection responses against malignant progression as a future immune-preventative intervention. Our goals will be accomplished via two specific aims. In aim 1, we will apply protocols already established in the co-PIs laboratory to define the specificities of IgG antibodies produced within the ovarian endometriosis microenvironment compared with those produced in OC. In aim 2, we will clone immortalized endometriosis-derived B cells and will test their therapeutic potential. In regard to outcomes, our results could open new avenues to exploit the humoral arm of the adaptive immune system for developing immunotherapy as a novel approach for treating this pre-malignant condition.

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Developmental Research Project: The genomic and epigenetic predictors of aggressive prostate cancer in Puerto Rican men – Jong Park, PhD (MCC); Anders Berglund, PhD (MCC); Gilberto Ruiz-Deya, MD (PHSU); and Jaime Matta, PhD (PHSU)

Incidence and mortality rates among Hispanic/Latino men with PCa are almost the same as non-Hispanic white (NHW) men. However, these data may be over-generalized because all Hispanic/Latino subgroups are aggregated into one broad group. Therefore, few studies focused on health disparity of PCa in Hispanic/Latino men.

Data from the PR Cancer Registry shows that in men, prostate cancer (PCa) is the #1 cancer, both in terms of incidence (39.9% of all cancer cases) and mortality (18.3% of all cancer deaths). Recent studies reported that Puerto Rican men have a higher rate of poor outcomes than NHW regardless of treatment and also after undergoing radical prostatectomy. Further Puerto Rican patients had significantly higher PCa specific mortality than non-Hispanic blacks.

Motivated by these intriguing data, we propose to investigate difference of epigenetic changes between PR and NHW men to identify PR-specific biomarkers for prostate cancer. Although PCa is normally characterized by slow progression about 20-30% of cases are associated by an aggressive phenotype associated with metastasis and death. A key molecular feature of this aggressive phenotype is the dysregulation of DNA repair genes. Detailed information on the ancestry structure within Hispanic/Latino men may help to predict outcomes and address PCa disparities among PR men. We will perform Ancestry analysis for PR men to observe their ancestry structure and examine by clustering patients into ancestral groups on the basis of AIM analyses.

We anticipate that our study will identify PR specific biomarkers, indicate prognosis of PR men. Our finding may help to design better strategies for PCa specific prevention and treatment. For future studies, this novel PR prostate cancer gene signature that includes DNA repair genes will be validated by larger PR cohorts.

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Developmental Research Project: Developing and Testing a Spanish-Language Intervention to Reduce Cancer-Related Insomnia – Brian González, PhD (MCC) and Jennifer Morales-Cruz, PhD (PHSU)

Over 200,000 women are diagnosed each year with breast cancer, the most common cancer among women in the US. Breast cancer survivors constitute the largest group of cancer survivors. Insomnia is a common and distressing symptom faced by breast cancer survivors. They report insomnia to be among the most important symptoms faced during breast cancer survivorship. Moreover, Hispanic women are more likely to experience insomnia, putting Hispanic breast cancer survivors at a significant disparity in quality of life.

Despite documented disparities in insomnia among Hispanics, we are unaware of a single available behavioral intervention to reduce insomnia among any Spanish-speaking population. The acute need for behavioral interventions for insomnia among cancer survivors and the apparent disparity in access to what is first-line treatment for insomnia underscores the urgent need to develop Spanish-language behavioral interventions for cancer survivors.

The proposed project aims to 1) gather qualitative data about how best to deliver a new Spanish-language behavioral intervention for insomnia in cancer survivors, 2) adapt an existing and empirically-supported intervention, the developer of which already has multiple ongoing collaborations with Dr. González, and 3) test this new intervention for feasibility and acceptability.

The project will lay the groundwork for grant applications for a larger, multi-site trial to test the efficacy of the new Spanish-language behavioral intervention for insomnia. It will also deepen the connections between behavioral scientists at PHSU and Moffitt.

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Pre-Pilot: Quantitative Sciences Collaborative Project – Julie Dutil, PhD (PHSU); Steven Eschrich, PhD (Moffitt); and Jamie Teer, PhD (Moffitt)

Genomic ancestry has been identified as a factor that contributes to explain race and ethnicity-associated disparities in disease prevalence, presentation and responses to treatment. Ancestry markers are important components for determining the admixture of genetic heritage for clinical and translational studies. Self-report or clinical annotation of patient race and ethnicity are not always clear on the contributions of various genetic backgrounds. As a result of decreasing cost of genome-wide genotyping arrays, statistical models and computational algorithms to infer global genetic ancestry proportions and locus-specific ancestry have been modified to process larger number of SNPs and incorporate haplotype information rather than using unlinked ancestry informative marker panels. However, this approach requires genome-wide genotyping array data, which is usually available only in the context of genome-wide association studies. With the ubiquity of sequencing experiments this data may already available. In particular, while whole exome sequencing can be generated as part of a translational study, increasingly sequencing panels generated as part of clinical care may be used instead.

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Pre-Pilot: The impact of Hurricane Maria on biopsychosocial outcomes and health care access of cancer patients – Guillermo Armaiz-Peña, PhD (PHSU); Mary Rodríguez-Rabassa, PsyD (PHSU); Idhaliz Flores, PhD (PHSU); Zindie Rodríguez, MD (PHSU); Heather Jim, PhD (MCC)

There is increasing recognition on the role of stress in carcinogenesis and cancer progression. For example, meta-analyses have shown that stress is a risk factor for cancer incidence and survival.(1, 2) In addition, data from our group suggest that chronic stress and depression accelerate growth of tumors and promote chemoresistance.(3-6) Conversely, meta-analyses have shown that use of beta blockers is associated with a decreased risk of mortality among cancer patients;(7, 8) these findings are supported by preclinical data showing that beta blockers abrogate the effects of stress hormones on cancer proliferation, invasion, and migration.(9) Taken together, these data provide a compelling rationale to better understand the role of psychological distress in cancer progression. However, existing observational studies have typically reported on distress due to life events such as death of a loved one or divorce. To date, there have been almost no data on cancer progression in the context of a severe traumatic stressor such as a natural disaster.

Hurricane Maria can be considered a traumatic stress paradigm. Maria made landfall in Puerto Rico on September 20, 2017 as a category 4 hurricane, killing at least 55 and causing an estimated $95 million in damage. Widespread devastation included loss of power and potable water infrastructure; destruction of buildings, bridges, and roads; lack of telecommunications and access to Internet; and closing of ports and airports. Lack of access to food and clean water has been a significant problem for residents, particularly those in rural areas. Mudslides rendered many roads in rural areas impassible, limiting relief efforts. Although statistics regarding psychological distress due to Hurricane Maria are not available, anecdotally traumatic stress and depression and anxiety are high among hurricane victims living in Puerto Rico, particularly those with cancer.

Hurricane Maria provides a unique opportunity to study the intersection of stress and cancer, specifically impact of traumatic stress on psychological distress, health disparities, and cancer biology. We hypothesize that a traumatic stressor such as Hurricane Maria worsens psychological distress due to underlying cancer, contributes to cancer health disparities, and exacerbates pro-inflammatory cytokine networks driving cancer progression and cancer-associated symptoms. Specifically, we will compare cancer patients who experienced Hurricane Maria (i.e., HM+) to matches samples of: 1) cancer patients who did not experience Hurricane Maria (HM-), and 2) individuals without cancer who experience Hurricane Maria (i.e., CA-). The HM+ group will consist of cancer patients treated at Ponce and nearby towns. The HM- group will consist of Hispanic/Latino Moffitt cancer patients who did not experience Maria, frequency-matched by age, gender, disease site, and stage to the HM+ group. The CA- group will consist of a friend or family member of each Ponce patient. The HM+ and CA- groups will complete assessments in clinic or via a home-based visit from the study team. All distressed participants will be offered psychosocial services. Study participants will complete demographic/clinic questionnaires and psychosocial surveys; they will also provide blood specimens at recruitment time and every three months for at least one year.

1) Chida Y, Hamer M, Wardle J, Steptoe A. Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat Clin Pract Oncol. Aug 2008;5(8):466-475.
2) Duijts SF, Zeegers MP, Borne BV. The association between stressful life events and breast cancer risk: a meta-analysis. Int J Cancer. Dec 20 2003;107(6):1023-1029.
3) Armaiz-Pena GN, Gonzalez-Villasana V, Nagaraja AS, Rodriguez-Aguayo C, Sadaoui NC, Stone RL, Matsuo K, Dalton HJ, Previs RA, Jennings NB, Dorniak P, Hansen JM, Arevalo JM, Cole SW, Lutgendorf SK, Sood AK, Lopez-Berestein G. Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth. Oncotarget. Feb 28 2015;6(6):4266-4273. PMC4414188
4) Armaiz-Pena GN, Allen JK, Cruz A, Stone RL, Nick AM, Lin YG, Han LY, Mangala LS, Villares GJ, Vivas-Mejia P, Rodriguez-Aguayo C, Nagaraja AS, Gharpure KM, Wu Z, English RD, Soman KV, Shahzad MM, Zigler M, Deavers MT, Zien A, Soldatos TG, Jackson DB, Wiktorowicz JE, Torres-Lugo M, Young T, De Geest K, Gallick GE, Bar-Eli M, Lopez-Berestein G, Cole SW, Lopez GE, Lutgendorf SK, Sood AK. Src activation by beta-adrenoreceptors is a key switch for tumour metastasis. Nature communications. 2013;4:1403. 3561638
5) Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. Aug 2006;12(8):939-944.
6) Kang Y, Nagaraja AS, Armaiz-Pena GN, Dorniak PL, Hu W, Rupaimoole R, Liu T, Gharpure KM, Previs RA, Hansen JM, Rodriguez-Aguayo C, Ivan C, Ram P, Sehgal V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK. Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer. Clin Cancer Res. Apr 1 2016;22(7):1713-1724. PMC4818718
7) Choi CH, Song T, Kim TH, Choi JK, Park JY, Yoon A, Lee YY, Kim TJ, Bae DS, Lee JW, Kim BG. Meta-analysis of the effects of beta blocker on survival time in cancer patients. J Cancer Res Clin Oncol. Jul 2014;140(7):1179-1188.
8) Zhong S, Yu D, Zhang X, Chen X, Yang S, Tang J, Zhao J, Wang S. beta-Blocker use and mortality in cancer patients: systematic review and meta-analysis of observational studies. Eur J Cancer Prev. Sep 2016;25(5):440-448.
9) Huang XY, Wang HC, Yuan Z, Huang J, Zheng Q. Norepinephrine stimulates pancreatic cancer cell proliferation, migration and invasion via beta-adrenergic receptor-dependent activation of P38/MAPK pathway. Hepatogastroenterology. May 2012;59(115):889-893.

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Full Project: Using MC1R Genotype to Impact Skin Cancer Risk Behaviors in Hispanics/Latinos - Peter Kanetsky, PhD (Moffitt) and Brenda Soto, PhD (PHSU)

Numbers of skins cancers, including melanoma, and squamous and basal cell carcinoma are on the rise among Hispanic/Latinos (H/L).  Limiting exposure to the sun and artificial sources of ultraviolet radiation and having routine skin examinations can help reduce morbidity and mortality resulting from skin cancers.  Genetic variation in a gene called the melanocortin-1 receptor (MC1R) is a good indicator of risk of skin cancer, and this holds true for individuals who do not easily burn, have a tendency to tan, have darker hair color, and/or have fewer freckles.  To determine whether knowledge and feedback of MC1R genotype can play a role in the promotion of behaviors linked to risk reduction and early detection of skin cancers, we will recruit 400 H/L participants from Ponce, Puerto Rico and 400 from Tampa, Florida.  Study participants will receive mailed health education materials containing either i) generic information about skin cancer risk, risk reduction and early detection or ii) personalized (precision) genetic information about skin cancer risk, risk reduction and early detection anchored in results from MC1R genotyping.  Participants will then be asked questions about prevention behaviors after three months and again after nine months.  The results of this project will help inform whether genetic screening targeted to the general H/L population of can positively influence risk behaviors associated with skin cancer.

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Full Project: Understanding how Mitotic Kinases Drive EMT in Breast Cancers - Srikumar Chellappan PhD (Moffitt) and Harold Saavedra PhD (PHSU)

Americans of Hispanic and African heritage are at higher risk to develop molecular subtypes of breast cancer that associate with poor prognosis, including triple-negative (ER-PR-Her2-) and Her2+ breast cancers relative to Non-Hispanic whites.  Increased chromosome instability (CI) in most cancers correlates with poor clinical outcomes and higher levels of CI is observed in poor-prognosis HR- breast cancers relative to luminal subtypes.  Centrosome amplification, or the accumulation of 3 or more centrosomes within a cell, and defective mitosis are two principal drivers of chromosome instability.  Centrosome amplification correlates with invasion, metastasis, poor clinical outcomes, and HR- subtypes. Interestingly, we identified TTK and TBK1 kinases as regulators of centrosome amplification in cancer cells.  TTK and TBK1 are centrosome/mitotic regulators, and our preliminary data show that these two mitotic kinases can significantly influence epithelial to mesenchymal transition (EMT), an activity never described for mitotic kinases.  Silencing of TTK reduces phosphorylation of SMAD3 upon TGF-b stimulation, suppressing regulators of EMT.  In a similar fashion, recent studies from the Chellappan lab identified TBK1 physically interacts with the E2F1 transcription factor, which induces the expression of TTK, and EMT genes like vimentin, fibronectin, ZEB-1, and ZEB2.  Further, depletion of TBK1 could significantly reduce the expression of MMP2 and MMP9, suggesting that kinases involved in mitosis like TTK and TBK1 can contribute significantly to the EMT and metastasis of tumors Since inhibitors are available for TTK and TBK1, it would be feasible to target these kinases to combat HR- breast cancers. This project proposes to examine if elevated levels and activity of TTK and TBK1 enhance tumor growth, epithelial to mesenchymal transition (EMT) and metastasis, and that such events correlate with prognostic molecular subtypes and survival outcomes of H/L breast cancer patients from Puerto Rico. Data resulting from this project will allow the identification of pathways influenced by mitotic regulators in breast cancer cells driving invasion and metastasis, and will provide potential prognostic markers for high-risk breast tumors in Hispanics/Latinos.               

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Pilot Project: Adrenergic Modulation of Ovarian Cancer Progression and Chemoresistance - Alvaro Monteiro, PhD; Heather Jim, PhD (Moffitt) and Guillermo Armaiz-Peña, PhD (PHSU)

There is growing evidence for the role of stress in cardiovascular pathologies, cancer, and other diseases. Work from our group and others has shown that psychological states such as chronic stress or depression may accelerate growth of existing tumors and promote chemoresistance. Importantly, a significant number of ovarian cancer patients are clinically depressed or lack social support. These emotional states have been linked to sustained activation of the sympathetic nervous system and decreased survival. Our group has shown that activation of the sympathetic nervous system leads to increased levels of norepinephrine and epinephrine in the tumor microenvironment and ovarian cancer progression by inducing pro-tumoral pathways. Our preliminary data in cancer cell lines suggest that norepinephrine significantly changes the expression of genes implicated in ovarian cancer and attenuates cisplatin-induced ovarian cancer cell apoptosis.  Given the importance of BRCA1-regulated DNA repair mechanisms in cisplatin response, adrenergic regulation of BRCA1 expression in tumors may also impact ovarian cancer progression and resistance to platinum-based therapy. However, the underlying mechanisms behind these observations are not completely understood. In this pilot we will test this hypothesis by achieving the following aims: 1) To dissect the effects of adrenergic signaling in ovarian cancer cells and 2) To explore the association between perceived stress and depressive symptomatology with tumor catecholamines, DNA damage, and BRCA1 protein expression. This proposal provides a unique approach to explore the link between stress and ovarian cancer outcomes at both the tumor level and the patient level. This proposal will provide the groundwork for additional research on precision medicine by linking psychological risk factors with underlying tumor biology.

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Pre-Pilot: Increasing HPV Vaccination Series Initiation and Completion Rates among Adolescent Hispanics in Tampa and Ponce - Susan T. Vadaparampil, PhD (Moffitt) and Lynnette A. Ruiz, PhD (PHSU)

HPV vaccination rates offer a cost effective strategy for drastically reducing HPV disease burden; including the prevention of HPV-caused cervical, vulvar, vaginal, and anal cancers; precancerous cervical, vulvar, vaginal, and anal lesions; and genital warts. While rates of vaccine series initiation are higher in Hispanics both in the United States (U.S.) and Puerto Rico (PR), series completion remains an ongoing issue. Healthy People 2020 goals of 80% of 13-15 year old adolescents receiving all three doses of the HPV vaccine series are unlikely to be attained without additional intervention. A recent study conducted in safety- net clinics in Texas found that educational materials describing the HPV vaccine were effective for Hispanic populations in promoting HPV vaccine uptake. While this intervention holds promise for increasing HPV vaccine initiation rates in the Hispanic population, future refinement of the content (e.g., greater emphasis on series completion and male vaccination) and approach (i.e., a set of booklets/videos timed to coincide with series doses at 1 month and 6 months) may also facilitate series completion rates. In addition, our previous research demonstrates the importance of adapting Spanish educational materials within Hispanic sub-ethnic populations. Our goal with this pilot project is to adapt educational materials focusing on HPV- vaccine series completion and male vaccination tailored for the Hispanic population in Tampa, FL and Ponce, PR.

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Pre-Pilot: Low-dose computed tomography lung cancer screening – Gwendolyn Quinn, PhD (MCC); Vani Simmons, PhD (MCC); Mary Rodríguez-Rabassa, PsyD (PHSU)

The clinical availability of detecting early-stage lung cancers via CT screening, combined with growing organizational support and insurance coverage, has created an unprecedented opportunity to reduce lung cancer mortality. Wide scale implementation of lung cancer screening requires (Aberle, Abtin, & Brown, 2013): i) trans-disciplinary teams of clinical and imaging personnel; ii) primary care provider influence; and iii) community engagement. Thus, early in the diffusion of incorporating lung cancer screening is the necessary engagement of primary care providers and high-risk individuals. Moreover, given the disproportionate burden of lung cancer on minorities, the inclusion of diverse populations is priority. It is noteworthy that minorities have the highest rates of smoking-related cancer mortality, yet lowest screening rates. Understanding lung screening barriers among diverse populations is necessary to reduce disparities. As of January 2015 the Affordable Care Act requires that private insurance companies cover CT screening based on the USPSTF-recommended guidelines (US. Preventive Services Task Force). Thus, lung cancer screening will be widely available to high-risk individuals and creating a comprehensive program is imperative to address patient needs and future research. Understanding lung screening barriers across diverse populations is necessary to reduce existing disparities. This study will recruit both an ethnic/racial diverse sample and primary care providers to inform effective approaches to reach and engage high-risk populations. Our approach engages the community in meaningful ways, important to establishing acceptability and implementation of guidelines.

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Full Project: Uncovering Breast Cancer Predisposition Factors in Puerto Rico - Alvaro Monteiro, PhD (Moffitt) and Julie Dutil, PhD (PHSU)

In women, breast cancer is the most common invasive cancer worldwide with over 1 million new cases annually. Significant progress has been made in the identification of genetic factors that influence the risk of breast cancer. These include the two major predisposition genes BRCA1 and BRCA2, the tumor suppressor TP53, as well as many other genes. Intriguingly, most of these genes play important roles in the system that protects cells from damage to DNA. Damage to DNA can happen due to external environmental factors (e.g. radiation, cigarette smoking, and sun exposure). Individuals carrying defects in these genes are then less well equipped to fix breaks to their DNA and more prone to cancer.

Importantly, defects in the system that guards cells against damage to DNA and facilitate the development of tumors can be also exploited for treatment. For example, drugs that inhibit PARP1 (also participates in repairing damage to DNA) are highly effective for BRCA-linked tumors. Treatment with PARP inhibitors leads to the inactivation of an alternative way for DNA repair, leaving the tumor cells with a diminished ability to resist DNA damage induced by chemotherapy. Because the BRCA-mediated DNA repair is still intact in normal non-tumor cells, side effects are minimal. This strategy can be extended, provided that we know which genes that participate in DNA damage repair are defective in individual tumors. 

Unfortunately, there is a dearth of information regarding which genes are preferentially inactivated in breast cancer in Puerto Rico (PR). Thus, our long term goal is to identify these genes and develop methods to accurately identify women at increased risk of developing breast cancer in PR. Our objectives are a) to identify the inherited changes that play a role in the DNA damage repair and are frequently inactivated in breast cancer in PR; and b) to identify the additional somatic (not inherited) changes prevalent in tumors arising in Puerto Rico that could inform therapeutic decisions. 

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Pilot Project: Educational Intervention to Increase Genetic Counseling Use in Hispanic Breast Cancer Survivors - Susan T. Vadaparampil, PhD (Moffitt) and Eida M. Castro PsyD, MSc (PHSU)

Several professional organizations have established criteria to identify BC survivors at increased risk for hereditary breast and ovarian cancer (HBOC) due to germline mutations in known cancer susceptibility genes such as BRCA 1 and BRCA 2 (BRCA). Previous studies have documented the presence of BRCA mutations in U.S. Hispanic women and proven risk management strategies for BRCA carriers. However, high-risk BC survivors Hispanics participate in genetic counseling (GC) and testing (GT) at strikingly lower rates than non-Hispanic Whites. Our team has documented that lower uptake of GC and/or testing among Hispanic BC patients may be due to less patient and provider awareness/referral of and access to genetics services, insurance, language, and cultural barriers. In order to address this issue, alternatives to current models that fail to promote uptake and participation of Hispanic women in genetic counseling should be provided. Alternative approaches should include identification, referral, and delivery of GC for high–risk BC survivors that address geographical, linguistic (1% of U.S. genetic counselors are Hispanic/Latino), and logistic access barriers.  A recent study demonstrated that telephone GC could provide an opportunity to remove geographical, linguistic (e.g., readily available bilingual professional), and logistic access barriers (e.g., appointment availability) aside from being a cost-effective strategy to increase access to GC. In addition, data from our pilot study (U54CA163068) highlights that brief mailed educational communications are an effective strategy to reaching Hispanics with health information.  Our goal with this pilot project is to test an educational approach to increase uptake of telephone GC among high-risk Hispanic BC survivors in Tampa, FL and Ponce, Puerto Rico.

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Pilot Project: Infiltrating Immune Cells in Breast Cancer Subtypes - Shari Pilon-Thomas, PhD (Moffitt) and Jaime Matta PhD (PHSU)

The majority of studies on breast cancer subtyping and the prognostic value of immune infiltrates have included Caucasian women with little information generated in Hispanic breast cancer patients. The current project seeks to understand molecular differences among breast cancers of Hispanic and Caucasian women, specifically focusing on: 1) prevalence of intrinsic molecular subtypes and risk factors and 2) distribution and type of infiltrating immune cells by subtype.  Our hypothesis is that Hispanic breast cancer patients will have distinct (1) incidences of breast cancer subtypes and (2) distributions of immune infiltrates in each one of these subtypes. This research project brings together our expertise in tumor micro-environments, breast cancer genomics and immune cell biology.  We have access to currently banked samples as well future accrual of bio-specimens from the Puerto Rico Bio-bank and the Moffitt Cancer Center Tissue Core that provide a unique resource for studying breast cancer in Hispanic patients.  Our long-term goals are to develop bio-markers for breast cancer disease progression and to determine which Hispanic breast cancer patients would benefit from personalized immunotherapy.

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Full Project: Molecular Biology of Lung Cancer among Puerto Ricans - Doug Cress, PhD (Moffitt) and Pedro Santiago, PhD (PHSU)

While lung cancer is a leading killer among all ethnic groups, emerging data suggest that the genetic mutations that drive lung cancer differ in frequency and nature among different ethnic groups. As one example, recent work demonstrates that when compared to Whites, Latino and Asian populations have a much higher rate of mutations in the gene coding for the Epidermal Growth Factor Receptor involved in the response to proliferation-inducing signals. At this point it is not clear why different ethnic groups differ in the genetic mutations that drive their lung cancers. However, understanding these mutations is of paramount importance as their nature determines treatment choices and could predict therapeutic outcomes. This is particularly important as novel anti-cancer drugs emerge that specifically target the protein products of these mutant genes. Therefore it will become increasingly important to understand the specific nature of mutations that drive lung cancer among various ethnic groups in order to make treatment as ethnic-specific, and therefore as effective, as possible. Currently, there are no significant databases addressing the mutations that drive lung cancer among Puerto Ricans, even though lung cancer is the leading cancer killer among Puerto Rican men and second killer among Puerto Rican women. This project will fill this knowledge gap by utilizing tumor tissue samples from Puerto Rican lung cancer patient to characterize and catalog mutations and epigenetic changes in candidate genes known to play an important role in lung cancer formation such as TP53, EGFR, CDKN2A and KRAS. This will produce valuable data on the genetics and the molecular biology of lung cancer in Puerto Ricans, which will in turn affect genetic testing and treatment recommendations for Puerto Ricans patients if the alterations characterized in this project can be clinically targeted and their molecular consequences characterized.

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Pilot Project: Identifying Cancer Health Communication Channels for Hispanic Audiences - Gwendolyn Quinn, PhD (MCC) and Julio Jiménez, MD (PHSU)

Results from our previous U56 outreach projects and other public health research indicate that reaching Puerto Rican audiences requires more culturally appropriate, direct interpersonal communication methods than traditional US mainland-based cancer communication channels (e.g., distribution of educational materials). To this end, we will focus our examination on effective and efficient health communication methods.

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Pre-Pilot: Breast cancer survivors’ knowledge, attitudes, and information needs about fertility and pregnancy - Gwendolyn Quinn, PhD (MCC) and Eida M. Castro, PsyD, MSc (PHSU)

Breast cancer is the most common malignancy among women in developed countries. Improvements in screening programs and new treatment advances have contributed increased survival. Since breast cancer is also the most common cancer among reproductive aged women, an increasing number of survivors have not yet started or completed their families when diagnosed. Therefore, identifying concerns regarding future reproductive health, fertility and consequences of adjutant therapies are paramount to quality of life. 

Understanding survivor’s knowledge, attitudes and informational needs towards this topic is essential to aid health care professionals in devising better educational tools, improving patient-provider communication and supplying needed information for improved decision making. Such tools will aid patients and survivors in making educated decisions about reproductive health issues such as fertility and childbirth which ultimately will improve quality of life. There is a need to overcome the methodological limitations of previous research on this topic. These include use of small sample sizes, reliance on qualitative interviews describing women’s attitudes about fertility-related issues, without determining the degree of endorsement of such attitudes. Finally, there is need to examine culturally and linguistically diverse samples. 

The primary aim of this study is to examine young breast cancer survivors’ knowledge, attitudes, informational needs and decisions about fertility and pregnancy among breast cancer survivors using self-report questionnaires. In addition, we aim to identify if clinical, demographic factors, or quality of life ratings, influence the reproductive decisions and attitudes of survivors. This study has begun and is on-going under the direction of Dr. Vania Goncalves in Portugal (University of Coimbra). Dr. Gwendolyn Quinn and Dr. Eida Castro will replicate this study at Moffitt Cancer Center and Puerto Rico and compare results between these diverse populations. 

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Pre-Pilot: Characterization of the ovarian endometriosis chromatin states and its transcriptional regulatory functions in neoplastic transformation – Janice Monteiro, PhD (France) and Ed Seto, PhD (George Washington Univ.)

Endometriosis is a benign gynecologic condition that is known to have transformation potential. Although women with ovarian endometriosis have twice the risk for developing ovarian cancer, the carcinogenic pathways by which endometriosis associated ovarian carcinoma (EAOC) develops remain poorly understood. Epigenetics is an important player in the progression from a pre-malignant to a malignant phenotype. We will investigate the role of histone modifications in modulation of gene expression in ovarian endometriosis (OE), endometriosis-associated ovarian cancer (EAOC), and adjacent histologically normal tissues (normal adjacent, NA). 

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Pilot Project: Neurokinin-1 receptor and its signaling components in colitis associated dysplasia – Caroline Appleyard, PhD (PHSU) and Jie Wu, PhD (MCC)

Colorectal cancer is one of the leading cancers in Puerto Rico, second only to prostate and breast cancer. Inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease have been linked to the development of colorectal cancer. Evidence obtained by us and others have suggested that substance P (SP) and its high affinity receptor neurokinin-1 receptor (MK-1R, tachykinin receptor 1) play a pivotal role in inflammatory bowel diseases. Both NK-1R and cyclooxygenase-2 (Cox-2) are upregulated in patients with inflammatory bowel diseases. However, the roles of NK-1R-mediated signaling pathways in the pathogenesis of precancerous and cancerous lesions in ulcerative-associated colorectal cancer are not known. The long-term goals of this research project are to understand molecular mechanisms of ulcerative colitis-associated colorectal cancer and to target key signaling molecules in the development of ulcerative colitis-associated colorectal cancer for preventive and therapeutic intervention. The current study is designed to test the central hypothesis that NK-1R plays a key role in upregulation of Cox-2 in our rat model of colitis-associated dysplasia, and that the epidermal growth factor receptor (EGFR) and Src family tyrosine kinases (SFKs) are involved in NK-1R signalizing in colon carcinoma cells, and in the development of precancerous lesions in this model of colitis-associated dysplasia.

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Pilot Project: BRCT Domains and breast cancer predisposition – Jaime Matta, PhD (PHSU) and Alvaro Monteiro, PhD (MCC)

In women, breast carcinoma is the most common invasive cancer worldwide, accounting for 20% of all malignancies. DNA repair is a critical defense system in the human body aimed at protecting the integrity and stability of the genome by its protection from the harmful effects of cancer-causing agents (9). A significant step in identifying individuals at increased risk for cancer was the isolation of highly penetrant tumor suppressor genes responsible for hereditary cancer syndromes. Thus, prevention strategies need to shift from the identification of unique inactivating mutations with strong effects to estimating the result of small effects in a large number of variants in a pathway or in a network. Mutations in BRCA1, a DNA repair gene, account for 40-45% of all hereditary cases and for ~80% of cases in families with multiple breast and ovarian cancers. However, the current evidence suggests that susceptibility to most sporadic cancers result from a multiplicative effect of moderate risk variants in more than one gene. Recent results have led to the proposal that the DNA Damage Response (DDR) acts as an anti-cancer barrier in tumorigenesis . A protein domain called BRCT (BRCA1 C-terminal domain), which recognizes phosphopeptides, is present in a variety of proteins involved in the DDR. Therefore, our general hypothesis to be tested here is that breast cancer risk in individuals without mutations in BRCA1 or BRCA2 can be at least partly attributable to diminished DNA repair capacity (DRC) regulated by BRCT genes.

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Pilot Project: A role for pRb and Cdk5 as regulators of cell-to-cell adhesion – Pedro Santiago, PhD (PHSU) and W. Douglas Cress, PhD (MCC)

Our work points to a novel role for the retinoblastoma tumor suppressor protein (pRb) as an inducer of the assembly of adherens junctions. Our data show that pRb, acting via the cyclin-dependent kinase 5 (Cdk5), is required to sustain elevated levels of adherens junction proteins -catenin and N-cadherin and to assemble them into adherens junction structures. A dual role for pRb as both a cell cycle repressor and as inducer of adherens junction assembly raises the extremely exciting prospect that, in at least some tumor types, inactivation pRb’s tumor suppressive capacity could play a significant role not only during initial tumor formation by providing targeted cells with a replicative advantage over normal cells, but also during later stages of tumorigenesis by provoking the disruption of cell-cell interactions consequently leading to metastasis. In order to better understand the mechanisms by which pRb regulates adherens junction assembly, we plan to elucidate the mechanism by which pRb activates Cdk5, an activation step of central importance for the pRb-mediated assembly of adherens junctions., and determine whether pRb can regulate the assembly of adherens junctions by controlling the transcription of -catenin, N- and E-cadherins genes.

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Pilot Project: Cutaneous human papillomavirus infection and non-melanoma skin cancer in the US and Puerto Rico – Jaime Matta, PhD (PHSU) and Dana Rollison, PhD (MCC)

Non-melanoma skin cancer (NMSC), the most common cancer in US men and women, is associated with increased risks of other cancers and high treatment costs at a national level. In addition to sun exposure and older age, immunosuppression is a risk factor for NMSC. Approximately 75% of NMSC’s occurring in transplant patients contain human papillomavirus (HPV) DNA, suggesting that cutaneous HPV infection may be a cofactor in the etiology of NMSC among immunosuppressed individuals. Although prevalence estimates for HPV in NMSC tissues among immunocompetent individuals range from 35% to 45%, the role for HPV infection in the development of NMSC is unclear, since few seroepidemiologic have been published, most of which were conducted in predominately Caucasian populations with minimal sun exposure. Importantly, chronic sun exposure may affect cutaneous HPV infection, and HPV oncoproteins may promote progression of a pre-malignant lesion initiated by UV radiation. We propose to investigate circulating antibodies to cutaneous HPV types as a risk factor for non-melanoma skin cancer within two chronically sun-exposed populations of different ethnic compositions. Specifically, antibodies to cutaneous HPV types will be measured in 100 NMSC cases and 100 controls recruited from dermatologists’ offices and health fairs in Puerto Rico, and in 100 NMSC cases and 100 controls identified from patients at the dermatology and skin screening clinics of the University of South Florida and H. Lee Moffitt Cancer Center & Research Institute in Tampa, FL. The objectives of this study are to demonstrate the feasibility of data collection and to obtain estimates of HPV antibody prevalence in NMSC cases and controls from both populations to be used in sample size calculations for future grant applications. Additionally, potential interactions between HPV infection and known skin cancer risk factors, such as tanning ability and DNA repair capacity will be explored. The importance of conducting this study within the context of these two populations must be emphasized, since both are chronically sun-exposed and ethnically diverse. The ultimate goal of this research is to further our understanding of the relationship between HPV and NMSC, so that additional prevention strategies for NMSC may be developed.

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