U54 Projects Funding Period (2015-2020)
CURRENT PILOT PROJECTS:
The Use of a Zebrafish Germ Cell Tumor Mutant to Identify Putative Genetic Mutation Drivers in Human Testicular Germ Cells Tumors
Project Leads: Kellee Siegfried, PhD (UMass Boston), Christopher Sweeney, MBBS (DF/HCC) and Eliezer Van Allen, MD (DF/HCC)
Testicular Germ Cell Tumors (TGCTs) are the most common type of cancer affecting younger men between the ages of 20 and 40 years old. TGCTs typically respond well to current treatments, yet about 5% of cases are resistant. Furthermore, current treatments can have many adverse side effects that extend later in life warranting the need for improved, more targeted therapies. However, the genetic and molecular causes of TGCTs are largely unknown. To develop improved treatments for this disease requires a better understanding of the molecular underpinnings of TGCT formation. The aims of the project are to uncover mutations that drive TGCT tumorigenesis and/or increase susceptibility, and identify putative causative variants in human TGCTs through two main approaches: 1) develop an animal model with a high incidence of TGCTs, and 2) genome sequencing of tumor samples derived from patients. TGCTs consist of several subtypes, only one of which has an available mammalian model. Strikingly, two zebrafish mutant lines have been identified that give rise to seminoma-type TGCT, which is the most common TGCT. We identified a novel zebrafish mutant line with a high incidence of TGCTs, named zgt (zebrafish germ cell tumor). This mutant is distinct from known zebrafish TGCT mutants and thus provides novel inroads to discovering molecular mechanisms underlying TGCT formation. To test for drivers of TGCTs in humans, this pilot proposes a genomic sequencing approach of patient samples with the goal of discovering mutations that arise during TGCT formation and thus may drive tumorigenesis. To facilitate identification of rare alleles, the project will use the knowledge gained from studies of our zebrafish model to guide targeted searches for mutations in human patient samples.
Advancing Disparities-Focused Cancer Genomics Research: Understanding the Role of Somatic Mutations in Prostate Cancer in African-Caribbean Men
Project Leads: Changmeng Cai, PhD (UMass Boston), Franklin Huang, MD, PhD (DF/HCC) and Alexandra Shields, PhD (DF/HCC)
African-Caribbean men may have the highest incidence of prostate cancer in the world, yet there have been no studies on somatic mutations in prostate cancer that have included this subpopulation. The identification of somatic mutations and genomic alterations that may be driving cancer growth is essential to developing new targeted therapies. There may be mutations and/or alterations in this high prevalence population that have as yet been undiscovered in this population that may be helpful in understanding the prostate cancers more likely to be experienced by men of Caribbean ancestry. To address this critical need, we propose to conduct a cancer genomics pilot with samples contributed by Jamaican men with aggressive primary prostate cancer. Specific aims are to: (1) determine the somatic genomic landscape of prostate cancers in African-Caribbean men, with sequencing to be performed in partnership with the Genomics Core of the DF/HCC-UMB U54; and (2) conduct a functional characterization of FOXA1 mutations across African ancestry. The proposed analyses will be the first that allows for a characterization of the genomic mutations and alterations in this important subpopulation that experiences some of the highest prostate cancer rates in the world, and provide preliminary data for a highly competitive future R01. In this future R01, we will be sufficiently powered to assess the correlation of mutational events with clinical outcomes and functional characterization of genes identified as recurrently mutated in African-Caribbean from this study, and compare mutational frequencies and outcomes across groups of different geographical ancestry.
Understanding barriers to initiation and adherence to adjuvant endocrine therapy in young breast cancer survivors of diverse racial, ethnic, and socio-economic backgrounds
Project Leads: Jessica Whiteley, PhD (UMass Boston) and Shoshana Rosenberg, PhD (DF/HCC)
Endocrine therapy (ET) has been shown to reduce the risk of breast cancer recurrence and mortality in women who have hormone sensitive tumors. Despite the benefits of ET, it is well established that young age and racial/ethnic, as well as socio-economic disparities, affect adherence to ET in women with early-stage breast cancer, with these populations less likely to take their ET as prescribed. An understanding of why women do not start ET (non-initiation), stop ET early (nonpersistence), or do not take their ET as indicated (non-adherence), as well as how psychosocial and behavioral factors may affect adherence in young, underserved women can inform both the timing and content of targeted multi-level interventions aimed at optimizing adherence to recommended treatments. Using semi-structured interviews, we will aim to determine barriers and facilitators to ET.
Determining the Feasibility and Acceptability of a Combined Storytelling Narrative Communication and HIV-tailored Smoking Cessation Intervention for Women Living with HIV
Project Leads: Sun Kim, RN, PhD (UMass Boston), Rosanna DeMarco, PhD, RN, APHN-BC, FAAN (UMass Boston) and Mary Cooley, PhD, RN, FAAN (DF/HCC)
HIV has transformed into a chronic illness due to the advent of effective treatments in the absence of a cure. As a result, the prevalence of non-AIDS defining cancers (NADCs), including lung cancer, has increased three-fold among people living with HIV. NADCs now account for 50% of all cancers among the people. Smoking is one of the major contributing factors to lung cancer and smoking prevalence is substantially higher in this population than the general U.S. population. Smoking prevalence does not differ by gender among people living with HIV. Women of color, particularly African American women represent the majority of women living with HIV (WLHIV) followed by Latinas. WLHIV smoke at a rate 3 times higher than that for the general U.S. female population (e.g., 51% vs. 16%). The proposed study has two phases: 1) the development of a storytelling narrative communication (SNC) intervention that will be added to an established HIV-tailored smoking cessation intervention and 2) a two-arm randomized controlled trial (RCT) of the HIV-tailored intervention plus the SNC Intervention compared with the HIV-tailored intervention only. We will develop three SNC videos with three to five WLHIV who will be talking about their personal struggles with smoking and success in quitting. Our preliminary study revealed that the established HIV-tailored intervention was effective only for short-term (≤ 2 months) abstinence. Many relapsed to smoking between the 2nd and 6th month of quitting. We propose that the SNC intervention will be an effective strategy to sustain their quit efforts for long-term abstinence (≥ 6 months). A total of 60 WLHIV will be recruited and randomly assigned to either the experimental arm (a combination of HIV-tailored and SNC interventions) or the control arm (HIV-tailored intervention only).
CURRENT FULL PROJECTS:
Post-transcriptional Regulation of the Tumor Suppressor Gene PTEN by Competing Endogenous RNAs (ceRNAs)
Project Leads: Rahul Kulkarni, PhD (UMass Boston), Kourosh Zarringhalam, PhD (UMass Boston) and Pier Paolo Pandolfi, MD, PhD (DF/HCC)
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is one of the most commonly altered tumor suppressor genes in human cancers. It has been shown that tumor susceptibility is highly sensitive to cellular PTEN levels, thereby highlighting the importance of molecular mechanisms for PTEN regulation. Recent research has uncovered a novel mechanism for post-transcriptional regulation of PTEN via a network of microRNAs (miRNAs) and competing endogenous RNAs (ceRNAs). Currently known ceRNAs that regulate PTEN are limited to protein-coding mRNAs and a quantitative framework for modeling PTEN regulation by ceRNAs is lacking. The project proposes to develop computational and experimental approaches for the discovery and analysis of both non-coding and coding ceRNAs of PTEN. The proposed research will lead to the identification of multiple ceRNAs of PTEN and focus on their role in controlling cellular PTEN levels and their impact on tumor susceptibility. The long-term objective is to develop novel therapeutic approaches for cancer-based on elevating cellular PTEN levels using ceRNA-based regulation. The specific aims are to: 1) Develop a quantitative model for kinetics and regulation of PTEN by ceRNAs; 2) Develop quantitative models of post-transcriptional regulation of PTEN by ceRNA networks; and 3) Develop protocols for controlling PTEN using ceRNAs and determine the impact on tumor susceptibility.
EL CENTRO: Engaging Latinos in the Center of Cancer Treatment Options
Project Leads: Deborah Schrag, MD and Dr. Andrea Enzinger, MD (DF/HCC) and Ana Lindsay, Ph.D. (UMass Boston). Co-Is: Drs. Laura Hayman, PhD and Lisa Kennedy Sheldon, PhD (UMass Boston)
The objective of the study is to improve the quality of advanced cancer care and treatment decision-making for Latinos by developing a tailored video intervention to better inform patients about their illness, prognosis, and chemotherapy risks/benefits. Latinos with incurable cancer harbor markedly optimistic expectations of prognosis, and often receive palliative chemotherapy without understanding that it is unlikely to cure. Such misconceptions are much more prevalent among Latinos than Whites, and may contribute to Latino/non-Latino disparities in end-of-life (EOL) care such as lower rates of advance care planning, underutilization of hospice and greater intensity of EOL care. Latino advanced cancer patients face formidable cultural, linguistic, and structural barriers to accessing critical information about their disease and treatment options. Nevertheless, interventions to enhance Latinos’ understanding are few and underdeveloped. This project capitalizes on the chemotherapy informed consent (IC) process as a strategic opportunity to equip Latinos with a better understanding of their illness and treatment options. In prior work, a suite of videos and booklets will be adapted to support IC for common chemotherapy regimens used to treat advanced GI cancers, which balance attention to risks and benefits, offer context about underlying cancer, and include patient voices for Latinos-both Spanish and English speakers. In Aim 1) the study team will use a four-phase qualitative research process to ensure that IC tools meet the informational, cultural, and linguistic needs of Latinos with advanced GI cancer. In Aims 2 & 3) the resulting Spanish-English suite of IC tools will be tested to determine its effect on Latino patients’ and caregivers’ decision-making about cancer treatment and EOL care, and their satisfaction with communication processes and cancer care.