Uncovering a Role for TFE3 Fusion Partners in Driving Translocation Renal Cell Carcinoma
Abstract
Objective and Rationale: Kidney cancer represents one of the 10 most common cancers in both men and women and there are over 60,000 new cases and 15,000 deaths from kidney cancer each year. One particularly aggressive subtype of kidney cancer is known as translocation kidney cancer and is characterized by a chromosomal abnormality whereby two genes from different chromosomes are abnormally brought together, or fused, causing a so-called chromosomal translocation. This translocation produces abnormal proteins, termed fusion proteins, that can cause cells to grow irregularly and lead to cancer. This subtype of kidney cancer disproportionately strikes children, young adults, and women. Devastatingly, this disease is frequently diagnosed at delayed stages, when it has already progressed and spread to other organs. Currently, we have a very limited understanding of the exact ways by which these fusion proteins cause translocation kidney cancer. As a result, there are no effective therapies for this aggressive disease. This proposal seeks to understand how the fusion proteins cause translocation kidney cancer, by carefully studying their functions and interactions with other parts of the cell. We also aim to investigate targeting these fusion proteins and disturbing their function as a way to induce the death of translocation kidney cancer cells. Herein we will pursue the following lines of experiments: In Aim 1, we will use a cutting-edge genome editing technology termed CRISPR/Cas 9 - base editing to introduce a series of alterations within the fusion proteins. Then we will measure the ability of these alterations to inhibit cancer cell growth. By doing so, we will identify important, potentially targetable, regions within the fusion proteins that are responsible for driving cancer. In Aim 2, we will study the interaction between the fusion proteins and other proteins and genetic material (DNA and RNA) in the cell. We will determine what effect these interactions have on maintaining cancer cell growth. Finally, in Aim 3, we will test the effect of inhibiting the interaction between the fusion proteins and RNA on the response to several chemotherapeutic agents. Since kidney cancer generally does not respond well to chemotherapy it is of critical importance to explore possible ways to enhance the response of these cancer. Together, these aims could potentially nominate new treatment regimens for patients affected by translocation kidney cancer either by repurposing currently available treatments or by inspiring the development of new, molecularly targeted drugs. Applicability of Research: This study will contribute to our understanding of the biology of translocation kidney cancer - an aggressive, poorly understood, and understudied type of kidney cancer. This will, in turn, advance the progress toward a cure for this specific type of cancer and ultimately prolong life and limit death from this devastating disease. In particular, findings from this work may pave the way for the development of targeted treatments that would be specifically tailored to the unique biology of this disease and that could potentially be given with increased selectivity and reduced side effects. PI Career Goals: My goal is to improve the survival of patients impacted by kidney cancer by committing my career to kidney cancer research. The proposed training plan will allow me to refine the scientific skills necessary to become a successful independent investigator in translational kidney cancer research. I will pursue scientific training under the mentorship of Dr. Srinivas Viswanathan, a genitourinary oncology-specialized clinician-scientist. I will also be co-mentored by Dr. Toni Choueiri, a world-renowned clinician investigator in the field of genitourinary oncology. My training will be further strengthened by working as a part of the broader well-established research environment at the Dana-Farber Cancer Institute, a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110302
Entities
People
- Shatha Abuhammad
Organizations
- Dana–Farber Cancer Institute
- United States Army