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Pramlintide: A Novel Therapeutic Approach for Osteosarcoma through Metabolic Reprogramming
Yuanzheng Yang1, Zhanglong Peng1, Elsa R Flores2
1Department of Pediatrics Research, Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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.
Insights
Pramlintide shows promise in treating osteosarcoma by targeting tumor cell metabolism. This FDA-approved drug, Pramlintide, inhibits glycolysis in osteosarcoma cells with specific genetic alterations, leading to tumor regression.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Osteosarcoma treatment outcomes have stagnated despite aggressive therapies.
- Over 80% of osteosarcoma tumors exhibit p53 deletion or mutation.
- Altered p63 and p73 are also observed in p53-deficient cancers.
Purpose of the Study:
- To investigate the efficacy of Pramlintide in osteosarcoma.
- To explore the role of islet amyloid polypeptide (IAPP) and its receptors in osteosarcoma response to Pramlintide.
- To determine if targeting tumor cell metabolism can induce osteosarcoma regression.
Main Methods:
- Analysis of p53, p63, p73, and IAPP expression in osteosarcoma cells.
- Assessment of IAPP receptor (CalcR, RAMP3) presence and function.
- In vitro studies evaluating Pramlintide's effect on glycolysis, proliferation, and apoptosis in osteosarcoma cells with varying glycolytic activity.
- In vivo studies using a subcutaneous osteosarcoma mouse model with intratumoral Pramlintide injection.
Main Results:
- Osteosarcoma cells exhibit altered p53, p63, p73, and decreased IAPP expression but possess functional IAPP receptors.
- Pramlintide significantly decreased glycolysis, proliferation, and increased apoptosis in osteosarcoma cells with high/mid glycolytic activity.
- Pramlintide treatment led to tumor regression in a subcutaneous osteosarcoma mouse model, evidenced by decreased Ki-67 and HIF-1α, and increased apoptosis.
Conclusions:
- Pramlintide effectively targets metabolic programming in osteosarcoma cells with specific genetic alterations and high glycolytic function.
- This metabolic modulation by Pramlintide inhibits tumor growth and induces apoptosis.
- Pramlintide represents a potential therapeutic strategy for a subset of osteosarcoma patients.
