Targeting Small Cell Lung Cancer by Focal Adhesion Kinase Inhibitor GSK2256098
Abstract
The area(s) of emphasis is to identify innovative strategies for the prevention of recurrence of or metastases and identify innovative strategies for the treatment of lung cancer. Lung cancer is the second most common cancer in humans. Among different subtypes of lung cancers, small cell lung cancer (SCLC) is the most aggressive subtype, defined by rapid growth, high rate of metastasis, and resistance to existing therapies. Due to the very limited therapeutic options available and a high chance of recurrence, the death rate is very high in SCLC patients compared to other subtypes of lung cancer. Activating the body’s immune cells by immune checkpoint inhibitor immunotherapies has shown promising results in lung cancer patients. However, SCLC patients show very limited response to immune checkpoint inhibitor immunotherapies. A predicted reason is that 95% of SCLC tumors do not possess immune cells, which are vital to the success of immunotherapies. Novel therapeutic strategies capable of increasing recruitment of immune cells to the SCLC tumors might act in synergy to immunotherapies and regress tumors. Focal adhesion kinase signaling is hyperactive in SCLC patients compared to other lung cancer subtypes. Hyperactive focal adhesion kinase signaling activates fibroblast cells present inside and around the tumor mass to inhibit immune cell recruitment and functions. In this proposal, we are analyzing whether GSK2256098 could be used against SCLC. GSK2256098 is a pharmacological inhibitor of focal adhesion kinase, which is safe, well tolerated and Food and Drug Administration (FDA)-approved for human use. We propose that focal adhesion kinase inhibitor GSK2256098 in combination with anti-checkpoint inhibitor therapy may enhance the clinical response in SCLC patients by restoring recruitment and tumor killing ability of immune cells. We will test the ability of GSK2256098 to inhibit tumor-promoting properties of fibroblasts in culture plates. We will also determine the effects of GSK2256098 on activating anti-tumor immune response in mice injected with SCLC patient-derived tumor and human immune cells. In addition, we will determine the therapeutic efficacy of GSK2256098 in combination with immunotherapy. In the short term, these studies will provide the novel information about anti-tumor immune suppression in SCLC. In the long term, these studies will provide valuable insight for the development of innovative immunotherapy regimes against immunotherapy refractory SCLC. The use of FDA-approved GSK2256098 will help in its quick transition from the laboratory to clinics. Due to exposure of environmental carcinogens and tobacco smoking, lung cancer incidence is higher, and the survival rate is lower in military personnel compared to civilians. A majority of SCLC incidences are linked to tobacco smoking. SCLC tends to recur earlier with acquired resistance to therapy resulting in the shortest survival among different lung cancer subtypes. These studies will have a short-term as well as long-term effect for military personnel and beneficiaries by overcoming drug resistance and immune-suppression observed in deadly SCLC disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110319
Entities
People
- Dinesh Ahirwar
Organizations
- Ohio State University
- United States Army