Following are public and technical abstracts for the Targeting TFE3 project funded by the Department of Defense Kidney Cancer Research Program (KCRP) for 2017.
Principal Investigator: Roberto Pili
Institution: Indiana University, Indianapolis
Funding Mechanism: Idea Development Award — Established Investigator
Award Amount: $630,000
Public Abstract
This project addresses specific Areas of Emphasis including “rare cancer” and “targeted therapies.” Translocation renal cell carcinoma is a rare type of kidney cancer in the adult but more common in children. This type of tumor is quite aggressive, and the standard therapies utilized for the most common types of kidney cancer do not work. Over the years, several studies have identified a specific alteration in the genome of these tumors. Briefly, the DNA undergoes a “cut and paste” phenomenon that leads to the expression of malignant proteins, called TFE3-Os. Our lab has recently established the growth of one of these tumors in mice and determined that these malignant proteins are responsible for the aggressive behavior of these cancers. Our proposal plans to further understand how these malignant proteins work in the translocation renal cell carcinoma and to identify some potential drugs that can be eventually tested in patients.
Taken together, the principal objective of the proposed research is to improve our understanding of these rare but deadly kidney cancers. Overall, this study will help the patients with translocation kidney cancer in the near future. In particular, the proposed research is relevant to active duty Service members, their families, Veterans, and other military beneficiaries by providing new therapeutic tools for a rare disease on the rise because of our increased capability of its diagnosis.
Technical Abstract
Background: Translocation Renal Cell Carcinoma (tRCC) represents a rare subtype of kidney cancer associated with aggressive behavior and poor clinical outcome. The prevalence of this disease is high in pediatric kidney cancer, representing 20% to 40% of total cases of pediatric RCC. It is noteworthy that the true incidence of this disease in adults is likely underestimated, as a significant number of patients undergoes histological misclassification. TRCC is characterized by gene fusions resulting from chromosomal rearrangement involving TFE3 (Xp11.2 locus) or TFEB (6p21 locus), with various partner genes. Despite the identification of multiple TFE3 gene fusions in tRCC (i.e., PSF-TFE3, NONO-TFE3, and PRCC-TFE3) there are no effective targeted therapies for patients with tRCC. Importantly, the oncogenic role of the transcriptional deregulation by the TFE3 gene fusion product, a chimeric protein (TFE3-O), remains not fully understood. Our long-term goal is to delineate the role of distinct TFE3-Os in tRCC. Our preliminary data show that a patient-derived xenograft model of PSF-TFE3-tRCC exhibits upregulation of the PI3K/AKT/mTOR signaling pathway. Interestingly, inhibiting wild type TFE3 (TFE3-wt) alone downregulated this pathway but was insufficient to stop the oncogenic feature of cells bearing PSF-TFE3 fusions. This observation suggests an important role for other genetic alterations, presumably TFE3-O, that cooperate with wild type TFE3 in patients with tRCC. Our preliminary data also suggested distinct signaling pathway deregulation in cells with different TFE3 fusion partners. However, our preliminary data further suggested common cooperation between TFE3-wt and TFE3- O in each cell with different TFE3 fusion partners, which may be the key event in tRCC oncogenesis.
Area of Emphasis: This IDA application addresses specifically the areas of “rare cancers” and “targeted therapies.”
Hypothesis and Objective: Our central hypothesis is that TFE3-Os play a key role in tRCC oncogenesis, and distinct TFE3-Os are responsible for different signaling pathway deregulation. Taken together, we hypothesize that inhibiting interaction between TFE3-O and TFE3-wt may prevent its oncogenic mechanism of action thus offering new targeted therapy opportunities. The overall objectives of this application are to (1) characterize the role of chimeric TFE3-O proteins resulting from TFE3 fusion to genes associated with pre-mRNA splicing factor machinery, PSF, NONO, and PRCC in tRCC oncogenesis; (2) identify common mechanisms of action of these TFE3-O; and, (3) develop novel therapeutic strategies targeting TFE3-Os.
We will test our central hypothesis and thereby accomplish the objectives of this application by pursuing the following Specific Aims: (1) To determine the biological role of TFE3-O resulting from TFE3 fusions with pre-mRNA splicing factor genes. (2) To identify small molecule inhibitors targeting TFE3-O dimerization.
Study Design: We will utilize a knock-in, knock-down, and knock-out strategy combining TFE3-Os with a next-generation sequencing approach to dissect their role in tRCC oncogenesis. We will develop a novel biosensing system combined with our established patient-derived spheroid models to identify a small molecule inhibitor that prevents TFE3-O protein-protein interaction. Ultimately, we will test the lead compound in our established tRCC patient-derived spheroid and xenograft model.
Innovation: This study is innovative because it establishes a potential common role of TFE3-Os in tRCC oncogenesis regardless of a different TFE3 fusion partner. We expect that these studies will provide (1) the role of TFE3-O in tRCC; (2) potential common mechanisms of TFE3-O despite different TFE3 fusion partner; and (3) novel small molecule inhibitor suitable for universal therapeutic intervention in certain subtypes of tRCC. Taken together, the results from this project will provide useful information that can be translated in the clinical setting and have an impact in the treatment of tRCC patients.
Impact: Insight into the common mechanisms of action of TFE3-Os is impactful as it will lead to discovery of novel targeted therapeutics for tRCC. We believe that this project addresses the current challenge in rare kidney cancer treatment that may affect the general population but have a particularly profound impact on the health and well-being of military service members, veterans, and their beneficiaries by improving the outcome of kidney cancer. This IDA application addresses specifically the FY17KCRP Areas of Emphasis “rare cancers” and “targeted therapies.”