Developing a Novel Therapeutic Target in Xp11.2 Translocation Renal Cell Carcinoma
Abstract
Objective and Rationale: Kidney cancer is the ninth most common type of cancer, and its global incidence is increasing annually. There are approximately 75,000 new cases of kidney cancer diagnosed each year in the United States, and approximately 14,000 deaths. Most common among kidney cancer types is clear cell kidney cancer, which comprises 75%-80% of kidney cancer. The remainder of kidney cancer is made up of many different subtypes, collectively known as non-clear cell kidney cancer. While many efforts have been made to increase the understanding of clear cell carcinoma, and treatments and outcomes in this disease have improved substantially over the last decade, the study of non-clear cell kidney cancer remains an unmet need. Among non-clear cell kidney cancer subtypes, one subtype is known as translocation renal cell carcinoma, which is characterized by a fusion protein (two genes form different chromosomes joined together). Translocation renal cell carcinoma (tRCC) is designated as a distinct subtype of kidney cancer in the current WHO classification (2016) and comprises 1%-5% of kidney cancers overall. It is more common in younger, female patients and more likely to present with advanced disease. There are currently no effective treatments for translocation kidney cancer and there is therefore a great need in this area. This proposal seeks to molecularly characterize a promising therapeutic target for tRCC. In preliminary studies, we conducted an analysis of published datasets and identified a poorly characterized gene, PKD1L2, that is highly selectively expressed only in tRCC. This gene shows very low or absent expression in normal kidney, other normal tissues, and other types of cancers. This suggests that expression of this gene is tightly linked to the unique biology of translocation kidney cancer. First, we will study whether PKD1L2 is directly activated by the oncogenic fusion gene (TFE3 fusion) that is characteristic of tRCC. Next, we aim to determine whether PKD1L2 is necessary for the survival of tRCC cells by inhibiting its expression and function. Finally, we will perform a series of experiments to clarify the mechanisms by which PKD1L2 is important for cancer cell survival. We will specifically test the hypothesis that tRCC cells, due to PKD1L2 expression, may have very high levels of a cellular antioxidant response, thus making them more resistant to dying by certain forms of oxidative stress, compared with normal cells and other types of cancer cells. Applicability of Research: This study will contribute to our understanding of the biology of translocation kidney cancer, which is aggressive, poorly understood, and understudied. This proposed project will characterize a potential therapeutic target in translocation renal cell carcinoma and pave the way for the development of targeted treatments in this disease subtype. PI Career Goals: My goal is to become a kidney cancer researcher who focuses on preclinical investigations that eventually can be translated to improve the survival of patients who are suffering from translocation kidney cancer. The proposed project allows me to receive scientific training, broaden my scientific skills, and broaden my horizons towards being an independent investigator in the kidney cancer research area. My mentor, Dr. Viswanathan, is a practicing genitourinary oncologist with an interest in kidney cancers, and he has significant experience with cancer research. I am receiving comprehensive training in an excellent environment since I joined in the laboratory in 2020. I will also receive senior co-mentorship from Dr. Toni Choueiri, an international leader in translation kidney cancer research. I will continue to receive training to further strengthen my research profile by working as a part of the broader, well-established research environment at the Dana-Farber Cancer Institute/Harvard Cancer Center. I believe this will allow me to mak
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210399
Entities
People
- Jiao Li
Organizations
- Dana–Farber Cancer Institute
- United States Army