Synthetic Peptide Inhibitors of FABP5 for Treatment of Diet-Associated Cancer and Metabolic Disease

Background & Unmet Need

• mTORC1 signaling is central to linking nutrient availability and cell growth, and is implicated in the pathogenesis of obesity, metabolic disorders, and cancer, amongst other diseases
• Current inhibitors of mTORC1 demonstrate high levels of toxicity, a small therapeutic window, as well as the high rates of resistance in many tumor cells
• High fat diets, which contain high levels of omega-6 polyunsaturated fatty acids (ω6-PUFAs), have been associated with various health complications
• FABP5, a fatty acid sensor, directly activates mTORC1 signaling in response to omega-6-linolenic acid (ω6-LA), the most common form of ω6-PUFAs
• Unmet Need: Novel therapeutic approaches that can mitigate the health impacts of excessive dietary ω6-PUFA intake while avoiding the complications associated with direct mTORC1 inhibition

Technology Overview

• The Technology: A novel therapeutic approach targeting FABP5's activation of mTORC1 for treating triple-negative breast cancer (TNBC) and metabolic disorders.
• The inventors have engineered synthetic peptides targeting key epitopes of FABP5 that competitively inhibit its interaction with mTORC1
• The Discovery: FABP5 is significantly upregulated in TNBC, with elevated protein levels in both patient-derived xenografts and serum from TNBC patients
• FABP5 contains a conserved N-terminal motif that mediates direct interaction with mTORC1
• PoC Data: siRNA-mediated knockdown of FABP5 blocked ω6 LA-induced mTORC1 activation and reduced cancer cell proliferation.
• FABP5-targeting peptides selectively inhibited ω6-LA-stimulated growth in aggressive TNBC cells (HCC1806), while sparing normal breast cells

Technology Applications

• Personalized therapeutic strategy for TNBC and other cancer types with high FABP5 expression
• Preventative treatment for the delaying of “unhealthy” ageing symptoms brought about by hyperactivation of mTORC1
• Treatment of metabolic diseases, such as diabetes, that are caused by mTORC1 hyperactivation
• Abrogate side effects of high fat diet

Technology Advantages

• Allows for context-specific inhibition of mTORC1 signaling, potentially reducing side effects
• Allows for combination with existing standard-of-care treatments in TNBC
• Reduces the need for strict dietary interventions in treating certain metabolic diseases, improving patient compliance