2017 RIS Research Grants for UMN

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.

Radiation therapy is routinely prescribed for the local control and treatment of sarcomas. While radiation kills sarcoma cells, it can also enhance survival signals in some cells, leading to tumor cell resistance and tumor recurrence. Radiation resistance in tumor cells is mediated in part by the protein NFKB. Radiation can activate NFKB, which signals to repair radiation damage and increase tumor cell survival. Because direct NFKB inhibitors are associated with significant toxicity, drugs that down-regulate NFKB indirectly may provide a better means to overcome radiation resistance and improve tumor control. Recent work has shown that beta-adrenergic receptors (B-ARs) contribute to tumor growth and metastasis. Furthermore, B-ARs may promote tumor growth through activation of NFKB.
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.

Sarcoma has been known, in general, to be resistant to the conventional radiotherapy which treats tumors with a small dose of radiation/day five times a week for several weeks. On the other hand, stereotactic body radiotherapy (SBRT), which exposes tumors to a large dose of radiation for one to five times has been shown to be effective to control human sarcoma. SBRT not only directly kills tumor cells via DNA damages but also destroys tumor blood vessels, thereby it induces secondary and additional tumor cell death. The low oxygen environment in the tumors due to vascular damage after SBRT activates HIF-1a that enables the residual tumor cells to survive even in the low oxygen environment in the irradiated tumors. HIF-1a also promotes the formation of new blood vessels, thereby leading to recurrence and metastases of tumors.
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.

A breakthrough from our research has created new opportunities to improve management of patients with osteosarcoma (OS): we found that the presence of immune cells in tumors from OS patients is a significant predictor of delayed metastasis and improved survival. Similar findings were observed in OS from humans, dogs, and mice. However, we do not know what permits immune cells to reside within tumors or how they delay metastatic progression and death. To address these gaps in knowledge, we will test two hypotheses. The first is that mutations in OS create proteins that are both “new” and “foreign” to the immune system (neoantigens). The second is that, despite this immune stimulation, tumors eventually escape immune-mediated control.
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.