Targeting Resistance Mechanisms in SMARCB1-Deficient Tumors
Abstract
The SMARCB1 gene is inactivated in highly aggressive kidney cancers such as renal medullary carcinoma (RMC) and malignant rhabdoid tumors (MRT). RMC is the most common of these SMARCB1-deficient kidney malignancies and is overall the third most common kidney cancer in adolescents and young adults. Characteristically, RMC predominantly afflicts young individuals of African descent and is resistant to the therapies used for other kidney cancers. Less than 5% of patients diagnosed with RMC will survive beyond 3 years. Therefore, new therapies are desperately needed to help these patients. SMARCB1 is a very powerful tumor suppressor gene that normally restrains cells from uncontrollably dividing into aggressive tumors. Our group discovered that losing SMARCB1 makes cancer cells grow so rapidly that they begin to produce too much protein. This excessive protein needs to be disposed of by a garbage disposal system called the proteasome. If the proteasome system is inactivated by drugs called proteasome inhibitors then the SMARCB1-deficient cancer cells will accumulate too much protein and die. Based on this finding, we opened the first clinical trial worldwide specifically dedicated to testing a targeted therapy against SMARCB1-negative kidney tumors such as RMC and MRT. More specifically, we combine the proteasome inhibitor ixazomib with two chemotherapy drugs (gemcitabine and doxorubicin) that are known to work against these tumors. We opened this trial in August 2018 and in less than 2 years have already enrolled 23 out of the 30 patients needed to complete this trial. Although this new therapy is helping at least some patients with these deadly diseases, the tumors of most patients will eventually become resistant to the proteasome inhibitor. To understand why and how SMARCB1-deficient tumors develop this resistance, we obtained tumor tissues from patients enrolled in our clinical trial at three different times: (1) at baseline; (2) during therapy; and (3) after the cancer has become resistant. Our preliminary analysis of these tumors indicates that they engage very specific biological pathways that help them become resistant to proteasome inhibition. These pathways can potentially be targeted, thus restoring or enhancing the sensitivity of the SMARCB1-deficient cancers to our clinical trial therapy. As proven by our past experience of rapidly translating our laboratory findings into fast-accruing clinical trials for patients with SMARCB1-deficient kidney malignancies, we have a robust translational pipeline consisting of cell lines, animal models, and clinical expertise. Our team of scientists and clinical researchers now propose to collaborate to identify the next generation of therapies for these lethal cancers. We will use our human SMARCB1-deficient kidney cancer cells lines and primary tumors from patients grown in mice to determine if any drugs that are in development or already in the clinic may be useful in tumors that have become resistant to proteasome inhibition. We have also recently developed a genetically engineered mouse model of RMC that will allow us to more comprehensively examine how best to target specific vulnerabilities of these cancers. Our short-term goal is to obtain new insights into the mechanisms of resistance to proteasome inhibition in SMARCB1-deficient kidney malignancies that will allow us to identify new therapeutic targets, and perhaps even currently available drugs, that can be used to help these patients. This will be a major step forward toward the development and clinical use of new targeted therapies for these kidney cancers. Our long-term goal is to develop new clinical trials rationally targeting these mechanisms of resistance. The experiments we propose are feasible within the 3-year timeframe of the grant and are expected to advance the field of kidney cancer research by producing critical new knowledge on the biology of SMARCB1-deficient kidney malignan
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110951
Entities
People
- Pavlos Msaouel
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army