The Antidiabetic Agent Acarbose Improves Anti-PD-1 and Rapamycin Efficacy in Preclinical Renal Cancer.

Abstract

Simple SummaryAlthough immune-stimulatory and targeted therapies benefit many patients with metastatic kidney cancer, a sizeable proportion of patients fail to respond. Recent studies in mice demonstrate that nutrient-limiting dietary interventions can improve responses to chemotherapy. However, these studies did not investigate effects on metastasis, and the impact of these interventions on the response to immunotherapy or targeted therapies in kidney cancer is unknown. We therefore studied the effects of a glucose-limiting drug called acarbose, which is used to treat type 2 diabetes, in a spontaneously-metastasizing mouse model of kidney cancer. We found that acarbose slowed kidney cancer growth and promoted protective immune responses. In combination with either an immunotherapy or a targeted therapy used clinically to treat kidney cancer, acarbose led to improved treatment outcomes and reduced lung metastases. Our findings contribute to the emerging idea of using nutrition-based interventions to enhance responses to cancer treatments. Although immune checkpoint inhibitors and targeted therapeutics have changed the landscape of treatment for renal cell carcinoma (RCC), most patients do not experience significant clinical benefits. Emerging preclinical studies report that nutrition-based interventions and glucose-regulating agents can improve therapeutic efficacy. However, the impact of such agents on therapeutic efficacy in metastatic kidney cancer remains unclear. Here, we examined acarbose, an alpha-glucosidase inhibitor and antidiabetic agent, in a preclinical model of metastatic kidney cancer. We found that acarbose blunted postprandial blood glucose elevations in lean, nondiabetic mice and impeded the growth of orthotopic renal tumors, an outcome that was reversed by exogenous glucose administration. Delayed renal tumor outgrowth in mice on acarbose occurred in a CD8 T cell-dependent manner. Tumors from these mice exhibited increased frequencies of CD8 T cells that retained production of IFNγ, TNFα, perforin, and granzyme B. Combining acarbose with either anti-PD-1 or the mammalian target of rapamycin inhibitor, rapamycin, significantly reduced lung metastases relative to control mice on the same therapies. Our findings in mice suggest that combining acarbose with current RCC therapeutics may improve outcomes, warranting further study to determine whether acarbose can achieve similar responses in advanced RCC patients in a safe and likely cost-effective manner.