Significant discoveries at UT Southwestern have set the foundation for the first molecular genetic and biological classification of sporadic renal cell carcinoma of clear -cell type (ccRCC), the most common type. Leveraging this innovation, we seek to assess the prognostic and predictive value of a mutated gene we have discovered, build the first immunocompetent animal model of ccRCC reproducing the genetics of human tumors, and identify novel targets for drug development. We discovered that the tumor suppre ssor gene BAP1 is mutated in 15% of sporadic ccRCC and that BAP1-deficient tumors tend not to have mutations in a second tumor suppressor gene PBRM1 (mutated in 50% of ccRCC). We developed and validated immunohistochemistry tests and found that whereas BAP1-deficient tumors tend to be of high grade, PBRM1- deficient tumors are typically of low grade. In patients with localized disease, BAP1 loss was associated with significantly worse prognosis (HR for RCC-specific death, 3.1; 95% CI, 2.3-4.1; p=6.77?10-14). By leveraging samples from the International mRCC Database Consortium, a consortium that has already introduced changes in clinical practice, we seek to determine whether BAP1 loss leads to more aggressive tumors even in the metastatic setting. Based on our previous discovery that BAP1 loss is associated with mTORC1 activation, we will also test whether BAP1 is a biomarker of responsiveness to mTORC1 inhibitors clinically. Notably, both BAP1 and PBRM1 genes are located in the proximity of VHL (which is inactivated in >80% of ccRCC) in a region on chromosome 3p that is deleted in the vast majority of ccRCC. This may explain a longstanding paradox ? why do humans with VHL germline mutations develop kidney cancer, but not Vhl+/- mice? We found that in mice, Bap1 and Pbrm1 are on different chromosomes than Vhl. Thus, LOH of the Vhl region in the mouse would still leave two copies of Bap1 and Pbrm1. We predicted that combined inactivation of Vhl and Bap1 (or Pbrm1) would cause ccRCC in the mouse but have been prevented from fully testing this hypothesis due to renal failure and perinatal lethality of mice with conditional loss of Bap1 in the kidney. However, conditional loss of Vhl is tolerated up to a year of age and VhlF/F;BapF/+ mice develop microscopic RCC. To bypass perinatal lethality and obtain macroscopic tumors, we will inactivate Vhl and Bap1 in the adult nephron. Finally, BAP1 is lost in tumors and consequently is not a suitable target for therapy. BAP1 is a deubiquitinase, and to develop the next generation of therapies, we will identify BAP1 substrates implicated in renal cancer. If successful, these aims will identify patients most likely to respond to mTORC1 inhibitors, help stratify patients with metastatic disease, lead to the first faithful immunocompetent animal model of ccRCC, and, following the path from gene discovery to drug development of Project 1, pave the way for the next generation of targeted therapies.
Metastatic kidney cancer is incurable. However, the discovery of mutated genes and an understanding of how they trigger tumor development have led to a new set of drugs and a doubling of life expectancy. We have discovered a new gene mutated in an aggressive form of kidney cancer and seek to (1) determine its impact on the prognosis and treatment of patients with metastases, (2) disrupt it in the mouse to generate the first animal model resembling kidney cancer in humans, and (3) understand how it causes cancer so we can identify targets for the next generation of drugs.
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