U54 Projects Funding Period (2010-2015)
CURRENT PILOT PROJECTS:
Assessing the Familial Financial Burden of Hematopoietic Stem Cell Transplantation
Abstract: Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for many blood cancers, especially those that have relapsed or are refractory to treatment. While the literature suggests that the costs of HSCT to the medical system are great, few studies have assessed the financial burden of HSCT on patients and their families. Understanding the familial financial burden of HSCT is important because it has been hypothesized that increased financial stress contributes to poor transplant outcomes. The acquisition of such data and the strategies patients pursue to alleviate financial stress may eventually help to reduce post-HSCT morbidity and mortality. Characterization of poor outcomes resulting from different types of familial financial burden could then result in an actionable plan to address this little-understood area of cancer-related health disparities. We thus propose to develop and administer a survey to adult HSCT patients at two high-volume centers, with the aim of characterizing familial financial burden at six months post-HSCT, and to investigate differences in this burden across socio-demographic characteristics of patients and caregivers. We will also investigate the association of familial financial burden with HSCT-related health outcomes at one year, assessing factors such as relapse, development of graft versus host disease (GVHD), and overall survival. We hypothesize that patients and families will experience substantial financial burden post-HSCT, that this burden will differ with baseline socio-demographic characteristics and by gender of patient (versus caregiver), and that those with higher levels of burden will experience worse HSCT-related outcomes.
A National Faith Community Atlas on End-of-Life Spiritual Care: Informing a Religious Community Educational Intervention to Address End-of-Life Cancer Disparities
Abstract: Previous studies show that spiritual support by clergy and religious communities leads unintentionally to more aggressive care at the end of life (EOL), particularly among Black and Latino patients. This two-year community cancer outreach pilot project will qualitatively interview an ethnically- and denominationally-diverse representation of clergy and faith community nurses regarding their attitudes, values, and practices in caring for cancer patients facing terminal illness, and then conduct a first-of-its kind national survey of clergy on end-of-life spiritual care. In addition, a core consortium of six leading clergy-training centers in Atlanta, Boston, and Chicago will develop an educational training intervention. The purpose of the proposed study is to – utilizing mixed qualitative and quantitative methods – describe the EOL spiritual care attitudes and practices of religious community leaders and to employ these data to inform the development of a spiritual care educational intervention for religious leaders. This intervention will then be rigorously tested in a subsequent proposal and widely disseminated to clergy in the U.S. The aim of this educational intervention is to partner with religious communities to transform religious community spiritual care to terminally-ill congregants in a religiously-sensitive and medically-informed manner, and ultimately reduce the receipt of aggressive interventions at the end of life, particularly among Black and Hispanic patients.
Integrated modeling of post-transcriptional regulatory networks of the tumor suppressor gene PTEN
Abstract: PTEN is one of the most commonly altered tumor suppressor genes in human cancers. It has been shown that even subtle decreases in PTEN levels significantly increase tumor susceptibility, whereas elevation of PTEN levels induces a tumor-suppressive metabolic state. Cellular control of PTEN expression thus plays a critical role in cancer. At the post-transcriptional level, PTEN expression is known to be regulated by multiple
microRNAs (miRNAs). Recent research has further demonstrated that microRNA-based regulation of PTEN can be modulated by the expression of competing endogenous RNA (ceRNA) targets. Several protein-coding RNAs that function as PTEN-regulating ceRNAs have now been experimentally validated. However the role of non-coding ceRNAs of PTEN has not been explored so far and a predictive quantitative model for regulation of PTEN by ceRNAs is currently lacking. The development of integrated computational and experimental approaches to address this gap in the field will lead to new discoveries and quantitative methods for analyzing the role of PTEN in cancer susceptibility, diagnosis and treatment. The goal of this proposal is to discover
novel non-coding ceRNAs of PTEN and to quantitatively analyze their role in controlling PTEN levels and tumor susceptibility. We will develop an integrated approach combining bioinformatics, mathematical modeling and experiments that will provide excellent interdisciplinary training and mentoring for the students and researchers involved in the project. The proposed research will develop software tools and modeling approaches that lead to new discoveries and significant advances in current research on non-coding RNAs in cancer biology.
CURRENT FULL PROJECTS:
Synthesis and Screening of Chemical Libraries for Discovery of Novel Bromodomain Inhibitors
Abstract: Bromodomains are a class of epigenetic reader proteins which recognize acetyl-lysine marks on chromatin. These proteins are an important part of cellular gene regulation machinery and are frequently important in cancer. Inhibition of the association of BET family bromodomains with chromatin using small-molecule chemical probes has recently been proven to be a powerful tool in the study of chromatin biology. These molecules provide promising leads toward novel therapeutics. Fluorous library synthesis of aryl-3-5-dimethylisoxazoles provides a method to rapidly synthesize a library of potential bromodomain ligands. Combined with a powerful biochemical assay platform to detect bromodomain binding, this library affords the opportunity to discover small molecule ligands for a number of important bromodomains. Synthesis of more complex, focused libraries based on these hits will enable optimization of the potency and selectivity required to ultimately generate novel chemical probes.
Nursing Post-Doctoral Program in Cancer and Health Disparities
Abstract: The Nursing Post-Doctoral Program in Cancer and Health Disparities is designed to address the urgent need for more minority and non-minority nurse researchers prepared to teach at the university level and conduct independent nursing research. Through the U56, we have developed and implemented an Accelerated BSN-to-PhD Program. Building on and extending this Program, the Post-Doctoral Program leverages the resources and strengths of this partnership and has emerged as a nationally recognized post-doctoral research training program, designed to ensure a diverse and highly trained workforce to meet the nation’s need for nurse scientists and academicians committed to understanding and addressing cancer health disparities.
Developing a Resiliency Program for Medical Interpreters in Cancer Care
Providing quality comprehensive cancer care, in the context of an increasingly ethnically and racially diverse patient population, is challenging. Cancer disparities in cancer treatment and outcomes are well established, and limited English proficiency (LEP) patients are at risk for lower quality cancer care. Interpreters are a critical link to quality cancer care for LEP patients, and stress levels are high among these medical interpreters. This can result in interpreter burnout, which is of concern since retention of experienced interpreters is a key component of quality cancer care delivery. Thus, we propose to conduct a 2-phase study with 3 DF/HCC sites (MGH, DFCI, and BWH) to develop a psychoeducational resiliency training program. In Phase 1 we will conduct 6 focus groups (2 per site) to identify the psychosocial needs of medical interpreters working with cancer patients. In Phase 2 we will develop and test, using a randomized wait-list control pilot trial (n=60; 20 per site), a 4-session resiliency program to enhance interpreters’ skills to effectively manage and cope with stressful encounters. This proposal would build the cancer disparities research platform at UMASS Boston by creating a collaboration, led by Drs. Park (MGH) and Dr. Mutchler (UMASS Boston), which uniquely includes both a scientific investigation and development of an evidence-based treatment program. The study, which would provide training opportunities in direct cancer care settings, fits into the U54 mission in its focus on a critical, yet understudied aspect of cancer disparities—improving quality of cancer care through improving medical interpreters’ resiliency.
Design and Optimization of Molecular Photoacoustic Contrast Agents (MPACs) for In Vivo Imaging of Breast Cancer Tumors
Cancer is the most prevalent disease throughout the world. For successful diagnosis and treatment, a complete understanding of cancer cell growth is necessary. Several techniques have been developed that provide information on tumor location and activity with the help of administered contrast agents, e.g. magnetic resonance imaging (MRI), X-ray computed tomography (CT), positron emission tomography (PET). However, the
majority of imaging techniques require harmful ionizing radiation. Recently, an advanced ultrasound technique known as photoacoustic imaging (PAI; aka photoacoustic tomography) has been developed to similarly aid in the understanding of cancer cell growth. Advantageously, PAI does not require ionization radiation and can provide the location and metabolic activity of tumors with the help of contrast agents. The goal of this project is to develop an imaging modality which will quantitatively map breast cancer cells in vivo, minimizing biopsies required for fluorescent imaging techniques, e.g. fluorescence in-situ hybridization (FISH). Ultimately, by using PAI in concert with the FISH technique, a less invasive more accurate assay will be available for breast cancer diagnosis. In this proposal we plan to adapt a bottom up approach to develop molecular photoacoustic contrast agents (MPACs) through chemical modification of efficient and established fluorescent probes via conjugation with non-emissive functionalities in a hierarchical assembly with a gold nanoparticle (AuNP) core. We hypothesize that these AuNP-MPACS will effectively amplify the photoacoustic response of proven goldnanoparticles allowing us to minimize the quantity of nanoparticle administration reducing potential toxicity effects which is a current concern of the research community.
Latino End-of-Life Care: Patient, Provider, and Institutional Effects
Principal Investigators: Holly Prigerson (DFCI), Paul Maciejewski (BWH), Jan Mutchler (UMass Boston)
Abstract: Latinos receive more aggressive, burdensome end-of-life (EOL) care (eg, ICU stays, resuscitation) and less hospice care than non-Latino whites. The available evidence suggests that the EOL care Latinos receive may be suboptimal and inconsistent with their wishes, and inferior to the EOL care that whites receive. The overarching aim of this study is to identify the most promising targets for interventions designed to enable Latinos to receive: a) high quality EOL care, and b) care consistent with their values and preferences (“treatment goal attainment”). Our preliminary results, and those of others, suggest that there is a critical need for data at institutional, provider, and patient levels so that their relative influence can be discerned. The primary aims of the proposed study are to obtain multi-level data and use hierarchical linear modeling (HLM) to estimate patient, provider and institutional effects on Latino-white disparities in EOL care and treatment goal attainment.
In Vivo Analysis of Signaling Dynamics in the Notch Interaction Network
Principal Investigators: Spyridon Artavanis-Tsakonas (HMS), Alexey Veraksa (UMass Boston)
Abstract: The Notch signaling pathway plays a critical role in multiple cell fate decision events in metazoans, and recently has been implicated in the pathology of cancer in humans. Genetic and biochemical evidence has revealed a large network of modulators that are involved in establishing a precise level of Notch signaling and determining tissue- specific outcomes of pathway activation, from the interaction of the Notch receptor with its ligands Delta and Serrate to transcriptional regulation of the Notch target genes.
Covalent Fluorescent Probes for Cancer Cell Detection
Principal Investigators: Nathanael Gray (DFCI), Priscilla Yang (HMS), Wei Zhang (UMass Boston)
Abstract: Fluorescence imaging is a powerful tool that permits visualization of specific cell states within a population; however, existing methods for fluorescence labeling are not experimentally accessible for many biological systems. Furthermore, fluorescent small-molecule sensors of cell state may provide a valuable alternative with significant benefits relative to existing methods for fluorescence imaging. The overall goal of this project is to create fluorescent small molecule ATP-site directed probes that can selectively label particular kinases and serve as imaging probes of normal versus pathological cell state.
Promoting Utilization of Cancer Early Detection Methods among Latinos in Church: A Faith- Based Approach
Principal Investigators: Jennifer Allen (DFCI), Maria Idalí Torres (UMass Boston)
Abstract: This community-based participatory research outreach proposal represents a significant shift in focus, from intervention delivery on an individual level, to a focus on enhancing the capacity of community organizations to activate collective resources to translate available evidence to address their priorities and needs. Our aim is to develop an organizational-level intervention to enable communities to adopt, adapt, implement and sustain evidence-based interventions (EBIs) to address cancer disparities among Latinos.