Gabriel Lopez-Berestein - US grants

Development of additional drugs for treatment of dandidiasis.

Significant disparities in cancer incidence and outcomes exist among ethnic minority populations. The overall Goal of this U54 Application is to establish a comprehensive long-term mutually beneficial partnership between the University of Texas M.D. Anderson Cancer Center (MDACC) and the University of Puerto Rico Cancer Center (PRCC). This partnership was initiated three years ago through the support of a supplement to MDACC P30 grant. Specific Objectives of the current proposal include: a) development of independent cancer research investigators through collaborative research projects, and b) establishment of a stable, long-term mutually beneficial collaborative relationship between MDACC and PRCC in the areas of cancer research, training and education. Efforts will be focused on the following areas: 1) Cancer research: the major programs and pilot projects address (a) molecular epidemiology of Head and Neck Cancer, and Breast Cancer, (b) cancer biology related to Breast Cancer, and (c) areas of cancer disparity in minority populations such as Acute Pro-myelocytic Leukemia; 2) Cancer Research training and education programs are described for undergraduate, graduate and post-doctoral students in areas of Cancer Biology, Outreach, and Epidemiology. PRCC and MDACC will continue the establishment of a comprehensive bi-directional training program that will increase the number of Hispanic students interested in cancers in cancer research. In addition, PRCC faculty will receive research training at MDACC; PRCC faculty will increase sensitivity of MDACC faculty to cultural differences among Hispanic groups, a particularly important benefit as Houston's and Texas's Hispanic population continues to grow. Infrastructure activities will include the frequent use of video conferences, library services support, and establishment of a tissue bank. Outstanding individuals agreed to serve as internal advisors and in the Program Steering Committee. The partnership will enhance the opportunities of both institutions to apply for R01s, SPORES, PO1s and R25 Cancer Education grants with an emphasis on reducing cancer disparities among populations. Finally, one of the major long-range goals of the partnership is for PRCC to regain its status as an NCI-designated Cancer Center.

[unreadable] DESCRIPTION (provided by applicant): This is a resubmission for The University of Puerto Rico Comprehensive Cancer Center (UPRCCC) and The University of Texas M. D. Anderson Cancer Center (MDACC) Partnership for Excellence in Research Grant, which addresses comments and recommendations from the 1) summary statement, 2) NCI Site Visit, and 3) IAC and PSC Committees. Areas strengthened in this application include: leadership, communication, committee oversight, evaluation, career development and mentorship. Funds granted in this award will be used to: 1) support 3 full projects in cancer biology and prevention and 1 pilot project in epidemiology, 2) enhance existing collaborations and establish new collaborations, 3) increase faculty/trainee participation in the training program, 4) expand efforts in our Outreach Program to impact a larger audience, and 5) fortify and stabilize the infrastructure developing at the UPRCCC. Research grants included target 1) developing new cancer imaging techniques, 2) regulating RNA in eukaryotic cells, 3) reducing cancer risk through combined alcohol and tobacco treatment and 4) assessing the role of insulin resistance syndrome as a risk factor for endometrial cancer. The Outreach Program, which was added into the original grant mid-year 3, has been expanded to include cancer related to tobacco, as well as breast, cervical and HPV. The Training Program has also been expanded in scope to impact more faculty and trainees through a comprehensive career development and mentorship training program. The original grant (2002) was awarded to establish a comprehensive long-term mutually beneficial relationship to target and eradicate cancer health disparities. The two short term objectives of the original application were met: 1) develop independent cancer research investigators and 2) establish a strong working relationship based on mutual benefit, identified strengths and reciprocity. The 3rd long-term objective of the Partnership is to regain NCI-designation for the UPRCCC. Thus far, the Partnership has set the foundation for a dynamic collaboration dedicated to enhancing each partner's strengths and eliminating each partner's weaknesses. The Partnership has also served as the catalyst for two major laws passed in Puerto Rico, one of which resulted in the allocation of funding for establishing the infrastructure and recruiting top notch faculty to the UPRCCC. As of 2008, the Partnership is far from reaching its long-range goal of regaining NCI-designation for the UPRCCC. Funding for the U54 resubmission is critical to maintain the momentum of the Partnership's joint efforts in Cancer Research, Training and Outreach. [unreadable] [unreadable] [unreadable] [unreadable]

Outcomes-oriented Evaluation Methodology To strengthen the current evaluation process of the Planning and Evaluation Core (PEC), the Pis have recruited an experienced evaluator from the UPR School of Public Health's Center for Evaluation and Sociomedical Research (CESR), which is a centralized UPR resource, to serve as one ofthe co-leaders. CESR staff members are trained on the latest techniques and approaches to evaluation as well as guidelines to tailor evaluations to fit specific research projects and programs across the cancer continuum (prevention, early detection, diagnosis, treatment and survivorship). CESR is a recognized leader in the science and practice of evaluation of training programs and basic, translational and population-based research, as well as the development of novel innovative approaches to measure success and identify areas that require immediate attention from the Partnership's Pis. CESR currently leads the evaluation processes of the Puerto Rico Clinical and Translational Research Consortium Grant and the CDC's Comprehensive Control Plan. Strategically, this approach leverages the integration of UPR-centralized resources for sustainability and it creates an evaluative culture within the Partnership for effective monitoring, evaluation and analysis of outcomes.

DESCRIPTION (provided by applicant): The overall goal of this initiative is to investigate the cellular uptake, trafficking, and sub-cellular localization of different classes and subtypes of nanoparticles (NPs) with well-defined physiochemical properties for the creation of a reference table that relates the sub-cellular distribution of NPs to their intrinsic physiochemical properties across a range of cell lines. The subcellular fate of NPs is relevant both in terms of the therapeutic efficacy and biosafety of the NPs. The effective impact of size, shape, charge, and chemical composition of nanomaterials, in the presence of serum opsonins, on both cellular entry and subsequent subcellular localization will be investigated. The expected outcome of this project is to create a reference table that accelerates the transition of nanomaterials from the bench to the clinic by rapidly expanding our knowledge of the effect of a material's intrinsic characteristics on its intracellular destination. The final product, a comprehensive table of NPs and their subcellular locations, will guide the future development of NP drug delivery systems for rapid expansion of biomedical applications, including cancer therapy, cardiovascular imaging, and gene therapy. PUBLIC HEALTH RELEVANCE: What this project seeks to deliver is a multi-dimensional reference table that relates the subcellular distribution and toxicity of NPs to their intrinsic physiochemical properties across a range of diverse cells and cell lines. It is our hope that the data generated from this project will serve as a resource for future research and encourage model development and new insights into nanotechnologies for imaging and drug delivery.

The University of Texas Health Science Center at Houston (UTHSC-H), The University of Texas M.D. Anderson Cancer Center, Rice University and Albert Einstein College of Medicine have joined forces to form the Texas Center for Cancer Nanomedicine (TCCN). The TCCN brings together a multi-disciplinary, internationally recognized team of investigators to develop and translate nanotechnology-enabled innovation for improving the traditionally dismal outcome of ovarian and pancreatic cancers. The main research focus areas of the TCCN are: Multifunctional Nano-Therapeutics and Post-Therapy Monitoring Tools (Area 2 of the CCNE RFA), and Devices and Techniques for Cancer Prevention and Control (Area 3). By natural synergies of the underlying nano-platforms, the TCCN's investigations in focus areas 2 and 3 automatically provide a cadre of approaches for Area 1: Early Diagnosis Using In-Vitro Assays and Devices and In-Vivo Imaging Techniques. The TCCN has four projects and three cores. Projects 1 and 2 directly address ovarian cancer, and Projects 3 and 4 directly address pancreatic cancer. In each oncology focus area, one project involves multifunctional nanoplatforms for the delivery of bioactive agents to the tumors (Project 1- ovarian and Project 3- pancreatic), and the other, targeting approaches to the cancer-associated vascular endothelia (Project 2- ovarian and Project 4- pancreatic), for imaging and therapy. Both adenocarcinoma (Project 3) and endocrine pancreatic malignancies (Project 4) are considered in the TCCN. All Projects integrate fundamental investigations in cancer biology, nanotechnology platform development, and pharmaceutical sciences, albeit to different degrees. The cores are the Biomathematics Core, Targeting Core and Nanoengineering Core. All projects and Cores integrate with each other through the sharing of research results and nanotechnology platforms. This integration allows the TCCN to achieve clinical translation of its research breakthroughs, and aggressively manage the risks that are naturally associated with any highly innovative program at a rapid pace. To fuel translation to the clinic, several TCCN investigators have successfully developed spin-off companies based upon their research. Collectively, with a combination of synergistic projects supported by cores that provide services to each project and a track record of successful bench-to-bedside translation, the TCCN is uniquely positioned to bring forth highly effective nanotechnology platforms for prevention, therapy and monitoring of ovarian and pancreatic cancers.

PROJECT TITLE: Mulfistage Vectors (MSV) for Ovarian Cancer Therapeufics PROJECT SUMMARY: Because ovarian cancer is fifth leading cause of cancer deaths in women and a leading cause of death from gynecologic cancers in the United States, it is necessary to develop novel therapeufic agents and strategies beyond convenfional chemotherapy for the treatment of advanced ovarian cancer. Nanotechnology meets this necessity because of the possibility to develop novel therapeufics. Project 1 alms to demonstrate the feasibility for translafion of a novel biocompatible nano-delivery system for efficient in vivo siRNA and drug delivery to achieve control of tumor growth and angiogenesis for a prolonged period. Project 1 will use the innovafive "multi-stage" approach, using biodegradable porous silicon particles as a carrier of therapeufic nanoparticles, which will offer a paradigm shift from convenfional nanotechnology based drug delivery by improving unfavorable pharmacokinefics of nanoparticles. Additionally, Project 1 aims to monitor therapeufic responses. Project 1 presents how novel nanotechnologies offer unequaled solufions to such undisputable necessity. The investigators will develop nanochip technologies to establish proteomic profiles to effectively monitor therapeufic responses and complement these with the development of sensifive gold-gold nanoshells to image tumor microvasculature with superb resolufion to monitor tumor vasculature response to therapy. Moreover, the investigators will utilize core-crosslinked polymeric micelles to detect and image active apoptosis in vivo, indicative of response to most anti-cancer therapies. The proposed work will greatly contribute to fill the existing gap between discovery of basic cancer biology and nanotechnology

anticancer research; University of Texas M D Anderson Cancer Center;

DESCRIPTION (provided by applicant): This is a renewal application for the Partnership for Excellence in Cancer Research between The University of Puerto Rico (UPR) and The University of Texas MD Anderson Cancer Center (MDACC). The Partnership proposes structured initiatives to further enhance the research infrastructure within these two institutions to reduce the burden of cancer health disparities. Funds granted in this award will be used to support two full and one pilot research projects. The first full project examines the role of West African ancestry in prostate cancer risk and aggressiveness. Pilot data show an association of several ancestral genetic markers, body mass index, and socioeconomic status with higher-grade prostate cancer. The second full project focuses on magnetic nanoparticle based hyperthermia for ovarian cancer. Pilot project data show a marked decrease in the associated tumor size when treated with nanoparticles. The pilot study is a smoking cessation intervention in oncology clinics. Together, these projects comprise a multidisciplinary research portfolio representing the T l to T3 stages of the translational research continuum. Partnership funds will also be used to: 1) enhance existing collaborations and establish new collaborations; 2) restructure the training pipeline to include customized career development tracks for physicians, scientists and physician scientists interested in cancer medicine to accelerate the development of a critical mass of faculty for the UPR Comprehensive Cancer Center (UPRCCC); 3) implement a cancer education curriculum; and 4) maintain and expand the Outreach Program, including core services and an outreach research project designed to reduce the burden of colorectal cancer among Puerto Ricans. Thus far, the Partnership has established a dynamic collaborative team that is working towards fortifying and stabilizing the developing infrastructure at the UPRCCC as evidenced by a newly constructed UPRCCC Research Center (opened 6/2009); the UPRCCC hospital will be completed in 2016. Funding for a second renewal is critical to cement and build on the substantial momentum and success achieved by the Partnership over the last ten years. The Partnership is poised to fulfill its long-term goal of positioning the UPRCCC to become a frontrunner in addressing health disparities that affect Hispanic populations across the cancer continuum (prevention, early detection, diagnosis, treatment and survivorship). RELEVANCE: This renewal seeks to foster and support an existing collaboration between the UPR and MDACC. By addressing differences in incidence, prevalence, mortality, and burden of cancer that exist among Hispanic populations in the US, the Partnership strives to reduce these disparities through efforts in Cancer Research, Training, Education and Outreach. Partnership contributions will also aid in building a stronger national cancer program through the development of a pipeline of well-trained, Hispanic cancer researchers.

DESCRIPTION (provided by applicant): This is a renewal application for the Partnership for Excellence in Cancer Research between The University of Puerto Rico (UPR) and The University of Texas MD Anderson Cancer Center (MDACC). The Partnership proposes structured initiatives to further enhance the research infrastructure within these two institutions to reduce the burden of cancer health disparities. Funds granted in this award will be used to support two full and one pilot research projects. The first full project examines the role of West African ancestry in prostate cancer risk and aggressiveness. Pilot data show an association of several ancestral genetic markers, body mass index, and socioeconomic status with higher-grade prostate cancer. The second full project focuses on magnetic nanoparticle based hyperthermia for ovarian cancer. Pilot project data show a marked decrease in the associated tumor size when treated with nanoparticles. The pilot study is a smoking cessation intervention in oncology clinics. Together, these projects comprise a multidisciplinary research portfolio representing the T l to T3 stages of the translational research continuum. Partnership funds will also be used to: 1) enhance existing collaborations and establish new collaborations; 2) restructure the training pipeline to include customized career development tracks for physicians, scientists and physician scientists interested in cancer medicine to accelerate the development of a critical mass of faculty for the UPR Comprehensive Cancer Center (UPRCCC); 3) implement a cancer education curriculum; and 4) maintain and expand the Outreach Program, including core services and an outreach research project designed to reduce the burden of colorectal cancer among Puerto Ricans. Thus far, the Partnership has established a dynamic collaborative team that is working towards fortifying and stabilizing the developing infrastructure at the UPRCCC as evidenced by a newly constructed UPRCCC Research Center (opened 6/2009); the UPRCCC hospital will be completed in 2016. Funding for a second renewal is critical to cement and build on the substantial momentum and success achieved by the Partnership over the last ten years. The Partnership is poised to fulfill its long-term goal of positioning the UPRCCC to become a frontrunner in addressing health disparities that affect Hispanic populations across the cancer continuum (prevention, early detection, diagnosis, treatment and survivorship). RELEVANCE: This renewal seeks to foster and support an existing collaboration between the UPR and MDACC. By addressing differences in incidence, prevalence, mortality, and burden of cancer that exist among Hispanic populations in the US, the Partnership strives to reduce these disparities through efforts in Cancer Research, Training, Education and Outreach. Partnership contributions will also aid in building a stronger national cancer program through the development of a pipeline of well-trained, Hispanic cancer researchers.

Early recruitment of underrepresented minorities from underserved communities into biomedical and health research training and education is essential to ensure that society's diversity is reflected in those professions. Given the critical cancer health disparities faced in Hispanic populations, in this 2^ competitive renewal of the Training Program between UPR and MDACC we will continue to develop a comprehensive pipeline of trainees from undergraduates to postgraduates to increase the number of Hispanic clinicians, scientists, physician scientists and health professionals knowledgeable and committed to careers in cancer research and medicine, as well as foster a faculty career development and mentoring program for junior faculty and for senior faculty transitioning to careers in cancer research. The UPR and MDACC Co-leaders have designed the training program to focus on several key areas including biomedical, clinical and translational research. Training methodology will include didactics, research experiences, enrichment opportunities, an MD/PhD program, postgraduate biomedical and clinical training, and training in cancer prevention and health disparities. The training program will be supplemented and enhanced by a new Cancer Education Core which offers a core curriculum in cancer and didactics in cancer health disparities. This separate core will develop a curriculum in cancer that will be integrated into the training program. Career development will enhance existing programs to build both academic skills such as grant writing, publishing in high impact peer-reviewed journals, and giving effective presentations, as well as professional skills in negotiating and effective communication. Senior faculty transitioning to a career in cancer research and medicine will participate in the career development program. The Training and Career Development Core (TCDC) will collaborate with the planning evaluation core to use outcomes-based logic modeling to evaluate qualitative and quantitative data so as to measure impact of the programs. Qualitative surveys will be utilized to obtain feedback from trainees and junior faculty on their immediate and long-term needs and interests, as well as to rate their experiences participating in various programs. A clear plan will be developed and implemented to enable the UPRCCC to independently sustain outstanding training and career development programs in cancer medicine and research. The TCDC, along with the new Education Core (Section E,2), functions as an integrated training, career development, and education program to fill a knowledge gap and foster a bridge to success for the next generation of Hispanic cancer researchers and physicians.

Cl. Outcomes-oriented Evaluation Methodology To strengthen the current evaluation process ofthe Planning and Evaluation Core (PEC), the Pis have recruited an experienced evaluator from the UPR School of Public Health's Center for Evaluation and Sociomedical Research (CESR), which is a centralized UPR resource, to serve as one ofthe co-leaders. CESR staff members are trained on the latest techniques and approaches to evaluation as well as guidelines to tailor evaluations to fit specific research projects and programs across the cancer continuum (prevention, early detection, diagnosis, treatment and survivorship). CESR is a recognized leader in the science and practice of evaluation of training programs and basic, translational and population-based research, as well as the development of novel innovative approaches to measure success and identify areas that require immediate attention from the Partnership's Pis. CESR currently leads the evaluation processes of the Puerto Rico Clinical and Translational Research Consortium Grant and the CDC's Comprehensive Control Plan, Strategically, this approach leverages the integration of UPR-centralized resources for sustainability and it creates an evaluative culture within the Partnership for effective monitoring, evaluation and analysis of outcomes.

DESCRIPTION (provided by applicant): The role and therapeutic potential of ZNF304 in Ovarian Cancer Through siRNA lethality screening, we recently discovered that ZNF304 gene, a novel transcription factor, is required for ovarian cancer survival. More importantly, we found that expression of ZNF304 gene is significantly associated with poor prognosis and markedly shorter overall survival (OS) of ovarian cancer patients when we analyzed The Cancer Genome Atlas (TCGA) ovarian cancer patient database (n=500). We also found that ZNF304 protein is highly overexpressed in all 5 different ovarian cancer cells including paclitaxel and cisplatin resistant clones and its expression was not detectable normal ovarian epithelium. In vitro silencing of ZNF304 by siRNA significantly inhibited cell proliferation and invasion of ovarian cancer cells, suggesting that ZNF304 may be an important gene driving ovarian cancer progression and transformation thus may be an potential therapeutic target in ovarian cancer. We hypothesize that ZNF304 expression is involved in disease progression by driving expression of critical cellular proteins that promote cell proliferation, survival and invasion/ metastasis in ovarian cancer cells. We also hypothesize that that ZNF304 is potential novel molecular target in ovarian cancer due to its clinical significance and multiple effects in regulation of critical cellular proteins and signaling pathways. Thus therapeutic silencing of this gene by systemically administered siRNA nanotherapeutics will effectively inhibit tumor growth and enhance efficacy of standard chemo therapies in human metastatic ovarian cancers orthotopic models. In specific aim 1, we will determine the role and molecular mechanism of ZNF304-induced proliferation, invasion and ovarian cancer cells. In aim 2, we will determine therapeutic potential of ZNF304 and validate it as a molecular target in ovarian cancer models by therapeutically targeting it systemically administered tumor-targeting siRNA nanotherapeutics in ovarian cancer models. For this purpose we will generate regular and AXL-specific thioaptamer-conjugated nanoliposomal vectors incorporating ZNF304 siRNA to target siRNA vectors to ovarian tumors and also provide dual anti-tumor effect strategy as AXL kinase, which is a molecular target associated with shorter patient survival based on our preliminary data. Understanding the role of ZNF304 in ovarian cancer biology, poor prognosis and therapeutic potential would provide foundation for focusing further on this gene and developing clinically applicable therapeutic approaches.

This is an application for the 2nd competitive renewal ofthe Partnership for Excellence in Cancer Research (Partnership) between the University of Puerto Rico (UPR) and the University of Texas MD Anderson Cancer Center (MDACC), two institutions which share a singular vision to eradicate cancer health disparities in underserved communities and socio-economically disadvantaged populations in Puerto Rico, Houston, and Latin America in general. This application represents a true partnership in which both institutions profit from distinct expertise and mutual benefits in the creation and implementation of fully integrated team science, outreach, training, career development, and education initiatives. As a continuation of the National Cancer Institute's (NCI) noteworthy commitment and investment to elevate the University of Puerto Rico Comprehensive Cancer Center (UPRCCC)* to a competitive level on par with other national cancer programs, this application outlines steps to: 1) solidify, strengthen and expand the relationship between UPR and MDACC and 2) transition the UPRCCC into an independently-functioning and self-sustaining institution. Without this long-standing, synergistic partnership as a catalyst for change, some of the objectives met thus far would have taken years to accomplish: other objectives would not have even been possible. Key elements of this application to advance the Partnership include: ? An evidence-based logic model approach (Section C) for tracking and evaluating Partnership outcomes; ? Multidisciplinary collaborative research projects (Section D) that represent stages of the translational research continuum (Tl to T3) according to NCI's Translational Research Working Group; ? A comprehensive cancer-focused training and career development core (Section E) to attract, engage and retain trainees and junior faculty as part of a training pipeline for future faculty positions with the UPRCCC; ? The development of a new educational curriculum, Core Curriculum in Cancer Medicine, Science, and Health Disparities, (Section E.2) to enhance the knowledge, skills and cultural competencies of current and future clinicians, scientists and physician-scientists; ? Outreach efforts (Section F) to build community capacity for the implementation and sustainability of cancer control programs; and ? A Biostatistics, Epidemiology and Bioinformatics Core (Section G), which augments and improves upon existing infrastructure developed during the last renewal. To facilitate the UPRCCC's transition towards independence, UPR and UPRCCC Pis took on a leadership role in developing the specific aims with the full support of the MDACC Pis. Over the next five years, both institutions recognize that while the Partnership will remain a joint effort, it will become imperative for the UPR and UPRCCC Pis to give impetus to developing, advancing, and advocating the UPRCCC's cancer-focused missions in research, training, education, and outreach. Therefore, with the goals ofthe U54 PAR in mind, a critical outcome to measure the success of this Partnership at the end of this renewal is whether or not the UPRCCC is sufficiently prepared and positioned to become a frontrunner in addressing the unequal burden of cancer that effects Hispanic populations across the cancer continuum (prevention, early detection, diagnosis, treatment and survivorship).

Abstract: The overarching goals of the Outreach Program are twofold: 1) to provide core support to the U54 for training on community-based participatory research (CBPR), direct community outreach and education, and capacity building for implementation and sustainment of evidence-based cancer control programs, and; 2) to conduct an outreach research project to reduce the burden of colorectal cancer among Puerto Ricans. This proposal describes both outreach core activities (under Aim 1) and the required outreach research project (Aim 2) as follows: AIM 1: Expand the existing CCCOP to provide core support to the U54 infrastructure, clinical research projects, and trainees with respect to direct community outreach, researcher and community capacity building, CBPR training, and participant recruitment and retention. AIM 2: Develop and evaluate the effectiveness, cost effusiveness, and budget impact of a tailored intervention to increase CRCS in PR among patients of FQHCs. Reducing morbidity and mortality associated with cancer in PR requires continuous efforts to address cancer-related behaviors and environmental conditions such as health care access. For example, although colorectal cancer (CRC) is the second leading cause of cancer-related mortality in women and the third in men,^ and is largely preventable through screening and treatment of precancerous polyps, colorectal cancer screening (CRCS) is significantly underutilized in PR among age-eligible patients compared to their U.S. counterparts. The proposed Outreach Program represents a continuation and extension of the Puerto Rico Cancer Control Community Outreach Program (CCCOP) which began as a pilot project in 2006 and expanded to a full U54 Outreach Core in the current funding cycle. The CCCOP will use existing community partnerships, infrastructure, data, and programs to 1) provide training on community-based participatory research (CBPR) to researcher, trainees and community partners, 2) conduct direct community outreach and education, 3) build capacity for implementation and sustainment of evidence-based cancer control programs in communities and primary care settings, 4) leverage existing data, partnerships and progress to expand research and intervention activities in the identified priority areas, and; 5) conduct an outreach research project to reduce the burden of colorectal cancer among Puerto Ricans. Through collaboration with community partners, the U54 Outreach Core will continue to identify innovative outreach strategies to reach the most vulnerable and underserved populations. These strategies include the use of community health educators, interactive and mobile technologies, and collaboration with Federally Qualified Health Centers (FQHCs). We will provide training and technical assistance to community partners, trainees and researchers on issues such as identifying cancer control needs, developing or adapting evidence based interventions, implementation, and evaluation. We will also focus on increasing community participation in clinical trials and biobanking in PR in order to promote effective prevention, diagnostic, and treatment methods for cancer The cancer burden in PR is well documented by the CCCOP, and there is a significant need for continued community outreach efforts and research to reduce it. The CCCOP is committed to continue work in multiple cancer control topics as part of its Outreach Core, and to strengthen these outreach activities by prioritizing research. As a result, interventions developed through outreach efforts and community-based participatory research (CBPR) approaches can be rigorously evaluated, adopted, implemented and maintained to have the greatest possible impact on the health of Puerto Ricans.

Abstract The long term goal of this project is to formalize a graduate degree curriculum based on cancer medicine, cancer science and cancer health disparities. The main goal is to enhance research capacity at UPRCCC by development of an Education Core that complements and is integral to the Training and Career Development Core. Although UPR offers a wide variety of basic science courses, no specific courses or customized curricula are offered that address topics in cancer medicine, science, and health disparities. The proposed educational curriculum will provide a foundation in these topics that initially will complement education received by the students pursuing careers in science, biomedical sciences, medicine and other health sciences careers who are enrolled in UPR and the collaborating institutions. The Education Core will provide this academic offer by different strategies; short intensive courses, core curricular sequences composed of modules (one module by semester), seminar series and scientific meetings, among others. All ofthe educational activities offered and coordinated by the Education Core will account to registered, credit granting courses, at UPR. Two short courses have already been developed, originally as part ofthe Training Program, one on Cancer Biology and one in Cancer Genetics. These take advantage ofthe availability of expert faculty from the partnering institution, MDACC, along with the expertise and experience of the UPRCCC on the particularities of the Hispanic populations. Based on the successful experience with these intensive short courses, plans are directed towards the creation of additional courses in topics such as. Emerging Technologies in Cancer Medicine, Cancer Prevention and Cancer Health Disparities. Another innovation proposed is a modular curricular core on skills necessary to be successful in research, aimed to offer fundamental knowledge to undergraduate students interested in pursuing careers related to cancer and health disparities. One module will be offered each semester; Responsible Conduct of Research, Enhancing verbal, analytical reading and writing skills. Fundamental Skills for Research & Introduction to Biostatics and Bioinformatics. The intent is that the trainees complete the sequence of modules in two (2) years. Although the Education Core is based on the University of Puerto Rico System, the idea is to develop collaboration with other accredited academic institutions in Puerto Rico, starting with the Ponce School of Medicine. One of the objectives of the Educational Core is to lay the foundation for the development of a formal graduate program at UPR with a curriculum based on cancer medicine, cancer science and cancer health disparities.

As the central point for administration, the primary purpose of the Administrative Core (AC) is to provide strategic leadership and oversight to develop, implement, coordinate and manage all Partnership activities. The AC'S mission is to be a recognized leader and resource in providing quality customer service to meet the needs of both internal and external target audiences integral to the Partnership's success. It is designed as a support core to provide assistance with the daily activities of the Partnership, as well as to facilitate short-term and long-term strategic planning and prioritization for the successful achievement of Partnership initiatives. The AC also serves as the primary vehicle for the receipt and distribution of all media materials (press releases, brochures, newsletters) and documentation (spreadsheets, proposals, progress reports, and other requests) in addition to providing administrative support for the Planning & Evaluation Core (PEC).

The Biostatistics, Epidemiology and Bioinformatics Gore (BEBiC) will provide professional expertise in biostatistics, epidemiology and bioinformatics for all research studies within the Partnership. The Gore will be a comprehensive, multilateral resource for data acquisition and management, design of laboratory experiments, epidemiological studies and clinical trials, statistical analysis, and publishing translational research generated by the Partnership. The BEBiC will incorporate sound experimental design principles within all projects and programs; carry out data analyses using appropriate statistical methodology; and contribute to interpretation of results through written reports and frequent interaction with project and program co-leaders. The Core will provide an integrated data management system to facilitate communication among all projects and cores, which will be customized to meet the needs ofthe Partnership. This process includes prospective data collection, data quality control, data security, and patient confidentiality. Thus, from inception to reporting, projects and programs will benefit from collaboration with the BEBiC. In addition, the BEBIC will organize different workshops related with the statistical and bioinformatics needs for every research study, particularly with all types of regression modeling and variable selection, survival analysis and optimization of dynamic treatment regimes, clinical trials, sample size, power calculations and statistics and algorithms for bioinformatics. Also, the BEBiC's personnel will develop new statistical methodologies in cancer research according to the projects needs.

Per PAR guidelines, translational research projects are strongly encouraged. As such, the Partnership's Developmental Core is comprised of projects that together represent a multidisciplinary, translational research portfolio as defined by the NCI's Translational Research Working Group. Projects selected represent the T1 to T3 stages ofthe translational research continuum that emphasizes efforts to reduce, and ultimately, eliminate cancer health disparities.

DESCRIPTION (provided by applicant): RNA molecules are secreted in extracellular spaces (exRNAs) and act as endocrine signals altering the phenotypes of cancer cells. In this application we will focus on the class of small non-codingRNAs named microRNAs. We propose an innovative therapeutic concept: the depletion of oncogenic microRNAs from malignant cells by enhancing their secretion as exRNAs or blocking suppressor microRNAs' delivery in extracellular space by blocking secretion mechanisms. Our main goal is to develop new strategies using combined miRNA and siRNA to maximize therapeutic benefit by affecting the production of exRNAs. Our proposal centers on the identification and targeting of specific tumor-derived exRNA and exosomes leading to novel therapies and improved therapeutic outcomes. In UH2 phase of the grant, using ovarian cancer (OC) cell lines and cells derived from OC patient tumors, we will identify novel exRNA-based cancer therapeutic lead candidates by siRNA library genome-wide screening based on secretion measurements, by small RNA deep sequencing in paired samples from tumors, plasma and ascites from the same patient, and by functional studies for the lead exRNA candidates. In the UH3 phase, we will achieve pre-clinical optimization by testing the exRNA lead(s) identified in the UH2 for antitumor efficacy in well-established OC murine orthotopic models and their safety using well-established preclinical protocols. The aims in exploratory UH2 phase are designed to identify and validate the function of novel exRNA therapeutic candidates for pre- clinical studies. In UH3 phase, we will formulate the methods for the validation of the assays to determine the activity, pharmacology in tissue and plasma to establish dosage schedules in animal models for the design of rational anti-tumor approaches. Using our nanoliposomal delivery technology, we will also conduct target modulation and efficacy studies to generate clear evidence regarding the safety of exRNA-based therapeutic candidates in the proposed dose range. Our approach, by using a new category of regulatory exRNAs- miRNAs, could substantially enhance therapeutic efficacy for cancer treatment. We will also demonstrate, for the first time, the use of nanoliposome-siRNA-exRNA targeting to generate a synergistic boosting effect for treatment of cancers. While we are focusing on OC due to the high mortality associated with this malignancy, our findings have applications for any type of cancer. This proposal brings synergistic capabilities of scientists working for over a decade in the fields of miRNA (Dr. Calin), siRNA (Dr. Sood), nanoparticle delivery (Dr. Lopez-Berestein), and exosome biology (Dr. O'Halloran). The team has the expertise and synergistic drive to achieve novel exRNA therapeutic development by performing highly innovative research, and has developed RNA-based therapies in the past.

DESCRIPTION (provided by applicant): RNA molecules are secreted in extracellular spaces (exRNAs) and act as endocrine signals altering the phenotypes of cancer cells. In this application we will focus on the class of small non-codingRNAs named microRNAs. We propose an innovative therapeutic concept: the depletion of oncogenic microRNAs from malignant cells by enhancing their secretion as exRNAs or blocking suppressor microRNAs' delivery in extracellular space by blocking secretion mechanisms. Our main goal is to develop new strategies using combined miRNA and siRNA to maximize therapeutic benefit by affecting the production of exRNAs. Our proposal centers on the identification and targeting of specific tumor-derived exRNA and exosomes leading to novel therapies and improved therapeutic outcomes. In UH2 phase of the grant, using ovarian cancer (OC) cell lines and cells derived from OC patient tumors, we will identify novel exRNA-based cancer therapeutic lead candidates by siRNA library genome-wide screening based on secretion measurements, by small RNA deep sequencing in paired samples from tumors, plasma and ascites from the same patient, and by functional studies for the lead exRNA candidates. In the UH3 phase, we will achieve pre-clinical optimization by testing the exRNA lead(s) identified in the UH2 for antitumor efficacy in well-established OC murine orthotopic models and their safety using well-established preclinical protocols. The aims in exploratory UH2 phase are designed to identify and validate the function of novel exRNA therapeutic candidates for pre- clinical studies. In UH3 phase, we will formulate the methods for the validation of the assays to determine the activity, pharmacology in tissue and plasma to establish dosage schedules in animal models for the design of rational anti-tumor approaches. Using our nanoliposomal delivery technology, we will also conduct target modulation and efficacy studies to generate clear evidence regarding the safety of exRNA-based therapeutic candidates in the proposed dose range. Our approach, by using a new category of regulatory exRNAs- miRNAs, could substantially enhance therapeutic efficacy for cancer treatment. We will also demonstrate, for the first time, the use of nanoliposome-siRNA-exRNA targeting to generate a synergistic boosting effect for treatment of cancers. While we are focusing on OC due to the high mortality associated with this malignancy, our findings have applications for any type of cancer. This proposal brings synergistic capabilities of scientists working for over a decade in the fields of miRNA (Dr. Calin), siRNA (Dr. Sood), nanoparticle delivery (Dr. Lopez-Berestein), and exosome biology (Dr. O'Halloran). The team has the expertise and synergistic drive to achieve novel exRNA therapeutic development by performing highly innovative research, and has developed RNA-based therapies in the past.

The long term goal of this project is to formalize a graduate degree curriculum based on cancer medicine, cancer science and cancer health disparities. The main goal is to enhance research capacity at UPRCCC by development of an Education Core that complements and is integral to the Training and Career Development Core. Although UPR offers a wide variety of basic science courses, no specific courses or customized curricula are offered that address topics in cancer medicine, science, and health disparities. The proposed educational curriculum will provide a foundation in these topics that initially will complement education received by the students pursuing careers in science, biomedical sciences, medicine and other health sciences careers who are enrolled in UPR and the collaborating institutions. The Education Core will provide this academic offer by different strategies; short intensive courses, core curricular sequences composed of modules (one module by semester), seminar series and scientific meetings, among others. All of the educational activities offered and coordinated by the Education Core will account to registered, credit granting courses, at UPR. Two short courses have already been developed, originally as part of the Training Program, one on Cancer Biology and one in Cancer Genetics. These take advantage of the availability of expert faculty from the partnering institution, MDACC, along with the expertise and experience of the UPRCCC on the particularities of the Hispanic populations. Based on the successful experience with these intensive short courses, plans are directed towards the creation of additional courses in topics such as. Emerging Technologies in Cancer Medicine, Cancer Prevention and Cancer Health Disparities. Another innovation proposed is a modular curricular core on skills necessary to be successful in research, aimed to offer fundamental knowledge to undergraduate students interested in pursuing careers related to cancer and health disparities. One module will be offered each semester; Responsible Conduct of Research, Enhancing verbal, analytical reading and writing skills. Fundamental Skills for Research & Introduction to Biostatics and Bioinformatics. The intent is that the trainees complete the sequence of modules in two (2) years. Although the Education Core is based on the University of Puerto Rico System, the idea is to develop collaboration with other accredited academic institutions in Puerto Rico, starting with the Ponce School of Medicine. One of the objectives of the Educational Core is to lay the foundation for the development of a formal graduate program at UPR with a curriculum based on cancer medicine, cancer science and cancer health disparities.

DESCRIPTION (provided by applicant): This is a renewal application for the Partnership for Excellence in Cancer Research between The University of Puerto Rico (UPR) and The University of Texas MD Anderson Cancer Center (MDACC). The Partnership proposes structured initiatives to further enhance the research infrastructure within these two institutions to reduce the burden of cancer health disparities. Funds granted in this award will be used to support two full and one pilot research projects. The first full project examines the role of West African ancestry in prostate cancer risk and aggressiveness. Pilot data show an association of several ancestral genetic markers, body mass index, and socioeconomic status with higher-grade prostate cancer. The second full project focuses on magnetic nanoparticle based hyperthermia for ovarian cancer. Pilot project data show a marked decrease in the associated tumor size when treated with nanoparticles. The pilot study is a smoking cessation intervention in oncology clinics. Together, these projects comprise a multidisciplinary research portfolio representing the T l to T3 stages of the translational research continuum. Partnership funds will also be used to: 1) enhance existing collaborations and establish new collaborations; 2) restructure the training pipeline to include customized career development tracks for physicians, scientists and physician scientists interested in cancer medicine to accelerate the development of a critical mass of faculty for the UPR Comprehensive Cancer Center (UPRCCC); 3) implement a cancer education curriculum; and 4) maintain and expand the Outreach Program, including core services and an outreach research project designed to reduce the burden of colorectal cancer among Puerto Ricans. Thus far, the Partnership has established a dynamic collaborative team that is working towards fortifying and stabilizing the developing infrastructure at the UPRCCC as evidenced by a newly constructed UPRCCC Research Center (opened 6/2009); the UPRCCC hospital will be completed in 2016. Funding for a second renewal is critical to cement and build on the substantial momentum and success achieved by the Partnership over the last ten years. The Partnership is poised to fulfill its long-term goal of positioning the UPRCCC to become a frontrunner in addressing health disparities that affect Hispanic populations across the cancer continuum (prevention, early detection, diagnosis, treatment and survivorship). RELEVANCE: This renewal seeks to foster and support an existing collaboration between the UPR and MDACC. By addressing differences in incidence, prevalence, mortality, and burden of cancer that exist among Hispanic populations in the US, the Partnership strives to reduce these disparities through efforts in Cancer Research, Training, Education and Outreach. Partnership contributions will also aid in building a stronger national cancer program through the development of a pipeline of well-trained, Hispanic cancer researchers.

? DESCRIPTION (provided by applicant): Recently, small interfering RNA (siRNA) technology has emerged as a remarkable therapeutic tool for sequence specific targeted silencing of genes and now is considered as a novel class of therapeutics for molecular therapy of cancer. This technology offers the potential of hitting targets that are currently inaccessible or undrugabble by conventional small-molecule inhibitors, antibodies or larger drugs. Despite being amongst the most common oncogenes in human cancers and present in about 90% of PDAC cases, to date mutated KRAS oncogene has not been effectively targeted and clinical options for inhibiting its activity still remains to be developed. To meet this challenge, we recently developed novel long-acting slow release nanoparticle platforms including, 1) Stealth Liposomal Nanoparticles (SLNP) and 2) Dual- Assembly Nanoparticles (DANPs) can target siRNA into in vivo tumors and robustly silence target genes up to 2 weeks after a single injection. We identified KRAS siRNA sequences with notable potency in knocking-down KRAS expression (>90%) in several in vivo tumor models. AXL-RTK is widely expressed by PDAC by AXL-aptamer coated long-acting NPs incorporating KRAS siRNA will provide dual function and antitumor effect by increasing uptake and providing addition therapeutic effect for PDAC. Our central hypothesis is effective knockdown of mutant KRAS by highly versatile long-acting tumor-cell targeted siRNA nanotherapeutics will enhance the uptake, provide robust gene silencing and have a significant dramatic impact tumor growth due to dual antitumor/metastatic effect. Our long-term goal is to develop safe and effective tumor-targeted therapeutic siRNA-therapeutics for the molecular targeting of KRAS. Overall these studies may provide the proof-of-concept for targeting KRAS with cancer. Because our novel nanoplatforms for delivering siRNA-therapeutics were very reliable and safe in mice, thus this approach can be easily translated into Phase I Clinical Trials for BC patients. Our goal in this project is to develop clinically applicable, safe and effective nanotherapeutic tools to achieve robust and prolonged KRas silencing and demonstrate antitumor efficacy in in preclinical models that mimic human disease.

Project Summary With the traditional therapies for ovarian cancer (OC) that include surgery followed by cytotoxic chemotherapy patient survival is still extremely poor and 5-year survival rate is less than 30%. Therefore, new treatment strategies are needed to cure or improve dismal patient survival. Recent clinical and experimental evidence including ours indicate that the monocyte-macrophage axis (MMA) and tumor-associated macrophages (TAMs) play a significant role in tumor growth and progression by contributing to angiogenesis, invasion/metastasis, and drug resistance. We found OC patients with increased numbers of circulating monocytes and intratumoral TAMs have poor clinical outcomes and significantly shorter patient survival. Our studies also indicate that the tumor microenvironment and TAMs are attractive therapeutic targets in ovarian and other cancers and reduction of TAMs inhibits angiogenesis, invasion and metastasis, and drug resistance in ovarian cancer models. Overall data indicate that in contrast to the conventional drugs that target only tumor cells, targeting tumor microenvironment is required to achieve maximal anti-tumor efficacy. Also, lack of critical molecular targets for this purpose and together with a lack of effective delivery systems, biological barriers for drugs, including poor tissue-specific delivery, toxicity, and the inability to deliver high concentrations of therapeutics into tumor microenvironment, therapeutic strategies fail to cure OC. The use of siRNA bearing- nanoparticles targeted to the tumor and the microenvironment is a particularly attractive approach for targeting molecular targets, reprogramming the tumor microenvironment and development of the most effective therapeutic strategies for OC. To directly address these unmet needs we recently developed various nanoparticle (NP) platforms including, (1) long-acting, slow-release dual assembly NPs (DANPs); (2) serum resistant AXL-receptor binding-aptamers for development of targeted therapies in OC and validated each NP- based approach in multiple OC tumor models with robust and sustained target silencing and significant antitumor efficacy. In this study we will test the hypothesis that the blockade of the tumor and tumor microenvironment interactions by highly versatile NPs that encase therapeutic cargos will provide significant antitumor activity and enhance the efficacy of current regimens in OC. Thus we will determine mechanism of TAM regulation and determine the biological and therapeutic efficacy of targeting MMA/TAMs using highly targeted dual effect NPs in OC models as well as by applying mathematical models.

Project Summary/Abstract On September 2017, Hurricanes Irma and María devastated the Caribbean region, particularly Puerto Rico (PR), causing widespread destruction and resulting in massive resource losses and high economics costs. During the emergency recovery phase, research activities were limited, which lead to a disruption in ongoing cancer prevention and control initiatives that were being implemented with the aim to decrease the burden of cancer health disparities in the island. Despite our significant impact on community engagement, outreach, and training, the impact of Hurricane María in September 2017 and its aftermath affected significantly our recruitment, follow-up completion, and the evaluation of the cost-effectiveness of our project ¡Salud!, Por la Vida. Given that the recruitment venues for our program (Federally Health Qualified Clinics (FQHCs)) served as emergency operation centers, study recruitment has been delayed. As of December 1st, 2018, we have completed 47% of the recruitment. Therefore, the request for funds under the Supplement to Recover Losses Due to Hurricanes Harvey, Irma, and Maria Under the Bipartisan Budget Act of 2018 (PA-18-936) is to support the completion of the behavioral trial. Therefore, the aims for this supplement are to complete the recruitment of the group for the randomized intervention trial (377 participants) to assess the effectiveness of the intervention on Colorectal Cancer Screening (CRCS) completion (aim 1) and to assess the cost- effectiveness and budget impact of the CRCS intervention (aim 2). If granted, this project will provide a much-needed support to increase CRCS among vulnerable populations and will help increase awareness of the importance of resuming screening practices as now the island continues to recover from the catastrophic impact.