Focal Adhesion Kinase Inhibition as a Novel Therapeutic Strategy for Laryngeal Squamous Cell Carcinoma
Abstract
This proposal addresses the Fiscal Year 2021 Peer Reviewed Cancer Research Program (PRCRP) Topic Area of head and neck cancer, specifically focusing on laryngeal squamous cell carcinoma (LSCC), a cancer of the voice box that disproportionately affects military personnel and is associated with risk factors such as tobacco use, alcohol use, and environmental exposures. Despite these associations, the underlying mechanisms that predispose patients to LSCC are not well understood. Identifying these mechanisms will improve the detection of patients at risk for LSCC and enable the development of more effective treatment options for those who have been diagnosed with LSCC. Treatment for LSCC typically involves multiple approaches, including surgical removal of the tumor with concurrent radiation therapy and chemotherapy, often using the common standard-of-care chemotherapy drug cisplatin. Unfortunately, there are limited therapeutic options for LSCC tumors that return after treatment, which occurs in 25%-50% of patients and may necessitate the removal of the voice box through a surgery that can cause permanent swallowing and speaking impairments and worsen overall quality of life. Therefore, novel therapies are desperately needed, and our goal is to provide a minimally toxic therapeutic drug for patients who have become unresponsive to combination therapy. Notably, a significant portion of patients diagnosed with LSCC are active-duty Service Members and Veterans, due to increased exposure to tobacco smoke, alcohol, and occupational carcinogens. Therefore, a new therapeutic approach to treating LSCC will be particularly beneficial to people who have served and are currently serving in the military, as well as their beneficiaries. We hypothesize that focal adhesion kinase (FAK), a protein integral for cell signaling and migration, as well as its associated proteins, contributes to tumor progression and treatment resistance in patients with LSCC. Interestingly, we searched The Cancer Genome Atlas database and found that FAK expression was notably higher in head and neck tumors, including LSCC tumors, as the disease stage increased (i.e., tumors with worse prognoses were more likely to have high FAK expression). This data supports our hypothesis that FAK is involved in the formation and spread of head and neck tumors and thus suggests that blocking the function of FAK using specific inhibitors may be effective for treating LSCC. In the proposed studies, we will identify FAK inhibitors that are effective against cisplatin resistant LSCC cell lines in 2D and 3D cell culture. In addition, we will identify genes that are uniquely expressed in LSCC cell lines exposed to cigarette smoke extract and/or cisplatin, which may elucidate the development of cisplatin resistance, especially in patients with a history of smoking. To further elucidate the role of FAK in LSCC, we will test the effects of promising FAK inhibitors against organoids (simplified versions of organs composed of multiple cell types in 3D culture) that we will generate using fresh tumor specimens collected from patients who undergo voice box removal at our hospital. Using the same specimens, we will develop zebrafish models of LSCC to examine the effects of the FAK inhibitors in vivo. We will also test the effects of the single most promising FAK inhibitor, alone and in combination with an immunotherapy drug, in a mouse model of LSCC. Finally, we will study how FAK inhibition affects the microenvironment of human LSCC tumors in formalin-fixed paraffin- embedded tumor specimens, LSCC cell lines, and patient-derived organoids. We expect that the studies performed with the support of the PRCRP Idea Award will generate data demonstrating the efficacy of FAK inhibitors in treating LSCC, thus providing a basis for a pre-Investigation New Drug (IND) submission and IND-enabling studies within 2 years. If successful, we anticipate that this preclinical work will lead to the init
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210450
Entities
People
- Erminia Massarelli
Organizations
- Beckman Research Institute of City of Hope
- United States Army