Engaging the immune system as a strategy for sarcoma therapy
Principal Investigator: Antonella Borgatti, DVM, MS Associate Professor, Department of Veterinary Clinical Sciences College of Veterinary Medicine and Masonic Cancer Center
Co-Investigator: Daniel Vallera, PhD, Professor, Radiation Oncology, School of Medicine and Masonic Cancer Center
STriKE (Sarcoma Trispecific NK Cell Engager) is a novel drug uniquely designed to activate and expand the immune cell at the site of the cancer allowing high specific killing and minimal damage to normal cells. New immunotherapy drugs are touted as crucial alternative approaches for chemotherapy-resistant sarcomas, the foremost problem in recurring cancer. STriKE kills sarcoma cells by stimulating the killing of immune natural killer (NK) cells while simultaneously targeting the tyrosine-kinase like orphan receptor1 (ROR1), overexpressed by sarcoma cells.
The major goals of this proposal are to better understand the engagement/role of the innate immune system in sarcoma therapy and bring a newly discovered drug to phase 1 clinical trial. We discovered that when the NK-stimulating cytokine IL-15 is used as a cross-linker positioned by a patent-pending set of flanking sequences, it provides a self-sustaining signal that activates patient immune NK cells and causes NK cells to expand and engage at the tumor site. This project has two specific aims:
1) Generate safety/efficacy and mechanistic data necessary for an FDA investigational new drug application using our established sarcoma xenograft model. Also, evaluate species cross specificity to determine if our established companion dog model could be used for testing.
2) Begin preparation of a clinical batch of drug for clinical testing in human patients. Dr. Vallera is responsible for drug manufacturing and ensuring that drug meets all FSA requirements for safety and efficacy in humans. Dr. Borgatti will lead the in vitro and in vivo validation for clinical testing.
Effects of beta-adrenergic receptor antagonists on sarcoma radiosensitivity
Principal Investigator: Jessica Lawrence, DVM DACVIM (Oncology) DACVR (Radiation Oncology), Associate Professor, Veterinary Clinical Sciences & Masonic Cancer Center
Collaborators: 1) Erin Dickerson, PhD, Associate Professor, University of Minnesota 2) Kathryn Dusenbery, MD, Professor & Head, Department of Radiation Oncology, University of Minnesota
Because commonly prescribed B-AR antagonists (B-blockers) have been shown to inhibit NFKB activity, we hypothesize that propranolol, a widely utilized B-blocker, will sensitize sarcoma cells to radiation therapy by decreasing NFKB activation, limiting sarcoma cell survival. This study investigates a readily available, well-tolerated, and inexpensive drug that may effectively improve radiation sensitivity to decrease tumor recurrence in sarcoma patients. Favorable results will support the clinical translation of B-blockers into current radiation therapy protocols.
Enhancement of the Response of Sarcoma to SBRT by Targeting HIF-1a
Principal Investigator: L. Chinsoo Cho, M.D. Professor, Department of Therapeutic Radiology/Radiation Oncology
Co-Investigators: Kathryn E. Dusenbery, M.D. Professor and Head, Department of Therapeutic Radiology/Radiation Oncology; Chang W. Song, PhD, Professor Emeritus, Department of Therapeutic Radiology/Radiation Oncology
Therefore, it is highly likely that effective inhibition of HIF-1a would significantly improve the efficacy of SBRT by preventing relapse and metastases. Our preliminary results clearly demonstrated that metformin (drug used for type 2 diabetes) and docetaxel and topotecan (well-known anticancer drugs), efficiently inhibit HIF-1a in cultured tumor cells and also in tumors. The purpose of our study is to find the most effective drug(s) among the three drugs mentioned above to enhance the efficacy of SBRT against sarcoma by inhibiting HIF-1a activity. Our study will lead to developing a novel and powerful strategy to improve the control of sarcoma with SBRT in combination with repurposed use of drugs which are already approved by FDA.
Defining the Immunologic Landscape of Spontaneous Canine Osteosarcoma
Principal Investigator: Jaime F. Modiano, VMD, PhD, Professor, Department of Veterinary Clinical Sciences College of Veterinary Medicine and Masonic Cancer Center
Project Collaborator: Aaron Sarver, PhD, Research Associate, Masonic Cancer Center
First, we will use a comparative approach to define the landscape of mutations in canine OS tumors and identify mutational patterns in tumors that are associated with increased immune cell engagement in dog “patients”. Next, we will identify recurrent neoantigens (shared among many tumors) and unique neoantigens (present only in one or a few tumors) that stimulate robust immune responses. Finally, we will determine the representation of these neoantigens in human OS tumors.
Our results will allow us to prioritize conserved neoantigens to develop new strategies for OS prevention and treatment. Specifically, recurrent neoantigens will be used in prophylactic strategies for OS prevention in high-risk populations, and those that are uniquely expressed by one or few tumors will be used in precision-based treatment platforms.