Identifying the Molecular Mechanisms Underlying HIF2-Independent Tumorigenesis in RCC
Abstract
The most common type of kidney cancer is called clear cell renal cell carcinoma (ccRCC). The major event initiating tumor growth is loss of a protein known as VHL. This occurs in more than 90% of ccRCC tumors. In normal tissues, VHL destabilizes other proteins called hypoxia inducible factors (HIFs). Upon loss of VHL in ccRCC tumors, the levels of HIFs increase, which causes activation of molecular pathways that promote tumor development. A particular HIF protein named HIF-2 alpha is the main driver of tumor development in ccRCC. In accordance with this, small molecules that inhibit HIF-2 alpha were developed and proved successful in stopping tumor growth in some ccRCC tumors. However, several studies show that not all ccRCC tumors respond to HIF-2 alpha inhibition. These observations indicate that HIF-2 alpha is not the only key factor in ccRCC tumors and that other unidentified factors contribute to tumorigenesis -- at least, in a subset of tumors. We expect this study to identify new factors that play key roles in tumorigenesis in ccRCC. We will also determine the functional significance of these novel drivers of tumor formation by investigating how their presence or absence affects tumorigenesis. The results of this study will be important for several reasons: (1) This study will increase our understanding of the biology of kidney cancer and reveal new factors and molecular pathways important for tumor development; (2) It will introduce new therapeutic avenues. Key factors that promote tumor development may serve as targets to develop therapeutic drugs. Similar to inhibition of HIF-2 alpha, the inhibition of other key tumorigenic factors may prove beneficial to patients; (3) Patients who may benefit from the discoveries of this study in the future are those who do not benefit from HIF-2 alpha inhibitors (estimated as 40%-60% of patients). The PI s goal is to become an independent investigator in kidney cancer at a research-intensive institution. The PI s research areas of interest are basic/discovery-based research with high potential for translation into the clinic. By performing the project proposed here, the PI will increase her depth and breadth of knowledge in kidney cancer. She will design and execute experiments that will help her gain important technical and critical thinking skills. She will also analyze and interpret the results of this study and will publish the results in reputable journals accessible to the broad scientific community as well as the public. Moreover, the PI will present the results of the study at scientific meetings to improve their dissemination. These will help the PI improve her written and oral communication skills and build a professional network that will be valuable in her next career steps. The mentor and the PI meet on a weekly basis to discuss the experimental design and review the data. Moreover, the PI regularly presents the results of her study at lab meetings to a larger group of researchers in the kidney cancer program of UT Southwestern. In addition to the mentor, several experienced postdoctoral fellows as well as a group of research scientists with expertise in various areas of kidney cancer research (including computational biologists, a statistician, and a pathologist) provide help and feedback. Together, these create a great training environment that provides strong support of the PI in this project and prepares her for success in her future career.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110631
Entities
People
- Faeze Saatchi
Organizations
- United States Army
- University of Texas Southwestern Medical Center