Rational design of a STING agonist as a model for the implementation of a platform for the development of new immunotherapies against cancer

Abstract

Cancer remains a challenge to global public health, comprising the second leading cause of mortality worldwide. Currently, therapeutic strategies such as immunotherapy have returned hope to thousands of patients and oncologists who are battling the disease. There are several types of immunotherapy sharing a goal in common, to empower the patient's immune system to fight the tumor. However, many strategies have presented isolated efficacy, are difficult to translate into the clinical routine and end up being inaccessible for the majority of patients. Other strategies, such as checkpoint inhibitors that have been successfully implemented into the clinic, are facing drug resistance, the main problem in the treatment of advanced disease. Nowadays, the knowledge of the molecular and immunological heterogeneity of the tumors has proven to correctly guide not only its prognosis but also its treatment. The promise is that this knowledge will be translated into strategies that potentiate existing immunotherapies and turn patients with highly resistant tumors into survivors. Given this scenario, there is an urgent need for the rational design of new immunotherapies with high efficacy, low toxicity and cost and easy translation to the bedside. The stimulator of interferon genes (STING) is a cytosolic receptor that plays a significant role in the immunity against viruses and other intracellular microorganisms. Recent evidence suggests that STING also plays an important role in antitumor immunity, since its activation induces the production of type I interferons by dendritic cells (DCs), which promotes antigen cross-presentation to cytotoxic T cells (CTLs) and the establishment of protective and long-lasting antitumor responses. The genes orchestrated by type I interferons are usually found in tumors of patients that effectively respond to treatments. Low STING expression in tumors derived from patients has been correlated with low number of tumor infiltrating lymphocytes (TILs) and unfavorable prognosis. STING agonism alone or in combination with other immunotherapies, such as checkpoint inhibitors, has resulted in complete regressions of poorly immunogenic murine tumors, a remarkable efficacy that might result in a new cancer immunotherapy era. Given the enormous antitumor potential of STING and considering the lack of agonists capable of activate the human protein, this project aims to develop a new pharmacological agonist of human STING and to investigate the cellular mechanisms that orchestrate the rupture of the immunosuppressive microenvironment mediated by STING in human's tumors. Results from preliminary data obtained from our library of novel compounds have pointed to prototype 8a as a hit compound to be the starting point for the design and develop of a new agonist of human STING. If successful, the culmination of this project will allow the implementation of a new platform for the rational design and development of new immunotherapies against cancer.