Targeting KRAS-Mutant Lung Cancers Using Novel Biologics
Abstract
Background: Lung cancer is the 3rd most common cancer in the United States (U.S.) and the leading cause of cancer-related deaths in the U.S. and worldwide. Nearly 8,000 Veterans are diagnosed with lung cancer each year, and approximately 5,000 succumb to this disease. Thus, devising new and more effective therapies for lung cancer is a critical unmet need for veterans as well as the larger U.S. population. Area of Emphasis: This proposal will specifically address the FY22 LCRP Area of Emphasis to identify innovative strategies for the treatment of lung cancer as well as identify innovative strategies for the prevention of recurrence of or metastases from lung cancer. Objectives/Hypothesis: We hypothesize that AAV delivery of specific RAS inhibitory monobodies will provide a powerful approach to inhibit KRAS-mutant lung tumor cells and reduce the mortality of patients harboring such tumors. We also propose that this novel gene therapy method will provide an effective approach to reduce resistance that emerges upon treatment of KRASG12C mutant lung cancers with sotorasib. Specific Aims: We propose two specific aims to address this hypothesis: (1) obtain proof-of-concept data that AAV delivery of KRAS-inhibitory monobodies suppresses KRAS-mediated signaling and transformation in vitro and (2) obtain preclinical data on the efficacy of AAV-monobody vectors for reducing tumor burden and mortality in KRAS-mutant lung cancer. Study Design: We will develop AAV-monobody vectors to deliver expression constructs to tumor cells to inhibit the mutant KRAS. As negative controls we will also assess the effects of AAV encoding GFP alone or a GFP-tagged negative control monobody termed Mb(Neg). These reagents will be used to infect NSCLC cell lines in vitro to assess the ability to inhibit these cells. Next, we will assess their ability to inhibit lung tumor development in a genetically engineered mouse model in which and oncogenic KRAS allele drives lung tumor development. AAV vectors will be delivered to the lungs of the GEMMs to assess their ability to inhibit tumor development and progression in vivo. In addition, we will utilize patient derived tumor organoids to assess the inhibitory activity of the AAV vectors on human tumor samples. Together these studies will determine the translatability of this approach to human lung cancer patients. Innovation: Our proposal combines several innovative technologies (AAV gene therapy and RAS inhibitory biologics) to establish an entirely new therapeutic approach for treating primary and metastatic lung cancers. These technologies include unique KRAS inhibitory monobodies developed by the O’Bryan lab and the AAV gene therapy vectors generated from the Meyer lab that will enable delivery of each of these powerful anti-KRAS biologics to lung tumors and metastatic lesions in vivo. Given the incidence and mortality of lung cancer cases, the deadly nature of this disease, and the higher incidence of lung cancer in the Veteran population, successful development of this technology will benefit service members, Veterans, their families and the American public. Impact: We anticipate that this research will have a significant impact on the treatment of lung cancer patients, for both Veterans and the general U.S. population. Although sotorasib was recently approved for treatment of KRASG12C mutant lung cancers in early 2021, this drug is limited to only those patients harboring a KRASG12C mutant protein. Furthermore, resistance inevitably develops following treatment with this targeted therapy, often times due to emergence of additional RAS mutations . The beauty of our proposed therapy is that NS1 inhibits all KRAS mutants and R15 inhibits >50% of mutant KRAS alleles observed in human cancer and thus both monobodies would be effective against a larger number of KRAS-mutant lung cancers and not limited to just KRASG12C mutant tumors. In addition, it would also likely be e
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310774
Entities
People
- John O Bryan
Organizations
- Medical University of South Carolina
- United States Army