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.
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.