Targeting DDX3 for triple-negative breast cancer treatment - Combinations of metabolic deregulation and immunotherapy are gaining prominence for treating immune- tolerant “cold” tumors, such as triple-negative breast cancer (TNBC). Evidence indicates that such treatments can activate the immune system and induce regression of distant untargeted tumors, i.e., an abscopal effect. In pre-clinical and clinical settings, chemotherapy and immunotherapy demonstrated superior treatment efficacy and immune-related progression-free survival. Furthermore, chemotherapy, such as cisplatin and doxorubicin, in combination with immunotherapy, exhibited clinically significant response rates. However, much more research is required to optimize treatment strategies and scheduling to determine how to induce a sustained systemic immune response with clinically meaningful outcomes. In this application, we will leverage the use of a DDX3 inhibitor, RK-33, to alter the metabolic tumor environment. We will combine this treatment with immunotherapy to create a tumor environment that favors an effective response to immunotherapy. We have demonstrated that DDX3 is involved in mitochondrial biogenesis in breast cancer cells and using RK-33 unambiguously generated mitotoxic effects with increased reactive oxygen species production leading to breast cancer cell death, including TNBC. Also, RK-33 converted high glycolytic TNBC tumors to low glycolysis, resulting in decreased extracellular lactate, which has been shown to facilitate an immune permissive microenvironment in TNBC. In addition, using an immunocompetent preclinical model of TNBC, we have demonstrated that RK-33 can alter the immune profile within a 4T1 tumor environment. As reprograming metabolic dependencies favors immune responses, we propose a therapeutic strategy combining RK-33 treatment with immunotherapy (anti-mouse PD-1 mAb). We propose to test this hypothesis with the following specific aims. Aim 1: Determining the effect of targeting DDX3 by RK-33 on metabolic reprogramming to improve cancer immunotherapy. Aim 2: Reprogramming the immune microenvironment by RK-33 to enhance TNBC treatment. Aim 3: Targeting the glycolysis-immune checkpoint axis as a potential treatment for TNBC. The goal is to disrupt the metabolic equilibrium of the tumor environment and generate an increased efficacy of immunotherapy in TNBC.
