Pramlintide: A Novel Therapeutic Approach for Osteosarcoma through Metabolic Reprogramming

SIMPLE SUMMARY: Outcomes for patients with osteosarcoma have remained stagnant for more than 3 decades. Novel therapeutic agents are desperately needed. Osteosarcoma cells often express abnormal form of the p53, p63, and p73 genes, which promote glucose uptake, cell glycolysis, and rapid proliferation. Pramlintide, an FDA-approved drug for type 2 diabetes, interfered with tumor glycolysis leading to decreased cell growth and increased cell death. When we injected Pramlintide into osteosarcoma tumor nodules of the mice, the tumors were significantly smaller after 21 days while the control tumors continued to grow. Tumor hypoxia was also decreased. This is the first report showing the potential efficacy of Pramlintide against osteosarcoma, indicating that Pramlintide may be a novel therapeutic approach for patients with relapsed osteosarcoma. ABSTRACT: Despite aggressive combination chemotherapy and surgery, outcomes for patients with osteosarcoma have remained stagnant for more than 25 years, and numerous clinical trials have identified no new therapies. p53 deletion or mutation is found in more than 80% of osteosarcoma tumors. In p53-deficient cancers with structurally altered p63 and p73, interfering with tumor cell metabolism using Pramlintide (an FDA-approved drug for type 2 diabetes) results in tumor regression. Pramlintide response is mediated through upregulation of islet amyloid polypeptide (IAPP). Here, we showed that osteosarcoma cells have altered p63, p73, and p53, and decreased IAPP expression but have the two main IAPP receptors, CalcR and RAMP3, which inhibit glycolysis and induce apoptosis. We showed that in osteosarcoma cells with high- or mid-range glycolytic activity, Pramlintide decreased cell glycolysis, resulting in decreased proliferation and increased apoptosis in vitro. In contrast, Pramlintide had no effect in osteosarcoma cells with low glycolytic activity. Using a subcutaneous osteosarcoma mouse model, we showed that intratumoral injection of Pramlintide-induced tumor regression. Tumor sections showed increased apoptosis and a decrease in Ki-67 and HIF-1α. These data suggest that in osteosarcoma cells with altered p53, p63, and p73 and a high glycolytic function, Pramlintide therapy can modulate metabolic programming and inhibit tumor growth.