Bench-Bedside-Bidirectional Investigation of a New Combinatorial Immunotherapy Strategy to Treat Platinum-Resistant Penile Cancer
Abstract
Scientific Objective and Rationale: In 2022, it is estimated that penile cancer will comprise 2,070 new cases and 470 deaths for American men. Despite being rare, the incidence of penile cancer has increased in developed countries, including the United States. Over the past 6 decades, and the largest increase was noted in men less than 65 years of age. A disease of geographic disparity, penile cancer can constitute up to 10% of male malignancies in some African, Asian, and South American areas. Penile cancer is highly morbid, often resulting in devastating disfigurement, and only half of the patients survive beyond 5 years. Very limited basic and clinical research has been devoted to the understanding and treatment of this rare but lethal disease. Currently in the clinic, surgery, radiation, and conventional chemotherapy are the only treatment options. For aggressive penile cancer that is resistant to platinum-based chemotherapy, there are no further treatment options. Therefore, there is an urgent need to better understand and develop effective therapies for platinum resistance penile cancer. Our research goals will be achieved through close collaborations between cancer biologists and medical oncologists. Our research objective is to develop an innovative therapy strategy that employs the combination of molecularly targeted therapy and cutting-edge immunotherapeutics to treat platinum resistance penile cancer. We have developed the critical experimental tools that enable us to explore the idea of treating penile cancer with combined targeted and immunotherapy for the first time. These tools include the first genetically engineered mouse models of penile cancer, with which we will be able to test therapies in animals with intact immune system. Our choice of targeted therapy for penile cancer is drugs known as poly(ADP-ribose) polymerase (PARP) inhibitors. PARP is an enzyme that is part of the cellular machinery responsible for the repair of damages, either spontaneously occurring or externally induced, to the DNA – the genetic materials of the cell. If a cell has mutations in genes involved in the DNA damage repair, the cell is rendered sensitive to the killing by a PARP inhibitor. In our recent genomic studies of human penile cancer, we identified that 23.5% cases of penile cancer harbored mutations in these genes. For the cases that do not have mutations in DNA repair genes, they are potentially still sensitive to PARP inhibitors, because PARP inhibitors can themselves induce DNA damage. The damaged DNA can then be sensed by the cells, and as a result, the cells will send signals to the immune system as if the cells are invaded by DNA-based viruses. This pathogen mimicry response can be exploited for cancer treatment through combining PARP inhibitor and immunotherapy (in this case, immune checkpoint inhibitors that won the Nobel Prize in Physiology/Medicine in 2018). Based on this rationale, we will first evaluate the effect of three PARP inhibitors that are approved by the U.S. Food and Drug Administration to treat other cancers (olaparib, niraparib, and talazoparib) on both mouse and human penile cancer cells, and we expect these drugs are active to stimulate the pathogen mimicry response. Next, we will test the antitumor efficacy of PARP inhibitor niraparib and immunotherapy anti-PD1 antibody, as single therapy or in combination, in our animal models of penile cancer. Finally, a highlight of our study (the bench-bedside-bidirectional approach) is that we will validate the biomarkers for the drug effects from PARP inhibitor and immune checkpoint inhibitor using the collected penile cancer specimens from NCT05526989. This clinical trial (the Principal Investigator is Dr. Chahoud) is the largest multicenter clinical trial that enrolls only patients with chemotherapy-relapsed penile cancer to receive the combination of immune checkpoint inhibitor therapy (anti-PD1 antibody Dostarlimab) and target
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310613
Entities
People
- Xin Lu
Organizations
- United States Army
- University of Notre Dame