Using Isotretinoin and Phosphodiesterase-5 Inhibitors to Enhance the Antitumor Immune Response and Immunotherapy for Lung Cancer
Abstract
Despite improvement in outcomes with the use of chemotherapy and radiotherapy and targeted systemic therapy in treating advanced lung cancer, the overall survival remains still poor. Most therapeutic regimens involve toxic compounds exerting their effects on both the tumor and healthy tissue. Chemotherapeutics are often given at the maximum tolerated dose, not the dose that is most effective at killing the tumor. Importantly, resistance to the drug often occurs, at which point patients and families are faced with the heartbreaking news that tumors that were previously shrinking or undetectable are now growing again. Myeloid derived suppressor cells are frequently responsible for drug resistance in lung cancer treatment. The overall objective of this project is to explore whether the treatment with isotretinoin and phosphodiesterase- 5 inhibitors such as tadalafil (Cialis) and sildenafil (Viagra), as well as amiloride, drugs used for non-cancer applications with recently discovered beneficial side effects involving inhibition of immunosuppressive properties of myeloid-derived suppressor cells, alone or in combination, will induce tumoricidal effect and anti- tumor immune response and enhance the efficacy of anti-PD-1 immunotherapy for lung cancer. The proposal addresses the Lung Cancer Research Program 2019 Area of Interest, “Identifying innovative strategies for prevention and treatment of lung cancer.” Successful outcome of this research will determine whether inducing differentiation and inhibiting immunosuppressive properties of myeloid-derived suppressor cells in the tumor microenvironment with isotretinoin, as well as with phosphodiesterase-5 inhibitors and amiloride, will be a promising approach in enhancing lung cancer immunotherapy, in particular in patients with non-small lung cancer. Because these compounds are clinically approved for other applications such as chronic acne, erectile dysfunction, benign prostate hyperplasia, cardiac hypertrophy, pulmonary hypertension, edema, and high blood pressure, it will be relatively fast to set up new clinical trials. Given that isotretinoin, phosphodiesterase-5 inhibitors and amiloride have less cytotoxic side effects compared to chemotherapy and radiotherapy, they could be safely used in synergistic combinations with existing therapies including but not limited to anti-PD-1 immunotherapy, which are compromised by immunosuppressive properties of myeloid derived suppressor cells and ultimately may have a significant impact on reducing lung cancer mortality in military Service members, Veterans, and their dependents.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010688
Entities
People
- Grzegorz Sowa
Organizations
- Curators of the University of Missouri
- United States Army