Periodic Reporting for period 1 - PalmitoMet (Targeting Palmitic Acid Signaling Machinery to Inhibit Metastatic Cancer)
Reporting period: 2023-12-01 to 2025-05-31
Despite recent therapeutic advances, cancer is the second leading cause of death worldwide and it will probably become the first one by 2060. Significantly, 9 of 10 cancer-associated deaths are attributed to metastasis, for which there is currently no effective cure. The metastatic cascade may be modulated by specific macroenvironmental cues. For example, we and others have found that increasing lipid exposure to cancer cells can trigger signaling cascades that prime cancer cells into a metastatic program. Specifically, we have found that palmitic acid, but not other fatty acids, promotes metastasis in several tumors, and that metastatic initiating cells require a lipid metabolism reprogramming driven by an epigenetic remodeling. We also have solid evidence that fatty acids not only promote metastasis by providing energy to metastatic cells, but also by specifically modulating protein lipidation. In this sense, palmitic acid overexposure increases protein palmitoylation signaling in metastatic cells and targeting a specific node of this signaling, our target of interest (ToI), reduces tumor growth and metastatic burden in an orthotopic model of oral cancer, which may represent an unexplored solution to combat metastasis. However, no specific inhibitors against our ToI are known. Thus, PalmitoMET aims to identify novel molecules capable of inhibiting our ToI and test them in different preclinical models of metastasis, with the aim to bring them closer to the clinic.
We have successfully developed two orthogonal high-throughput screening platforms against our ToI based on enzymatic activity and binding assays. Based on these assays we have screened over 140,000 compounds from our chemically diverse library (including FDA-approved drugs, natural compounds, enzyme inhibitors…) and have found 240 compounds capable of inhibiting our ToI which are being further assessed to potentially become first-in-class drugs for cancer therapy. In parallel, we have successfully generated an inducible knock-down model in oral cancer cells and demonstrated the feasibility of targeting our ToI in a therapeutic setting when tumors have already originated.
Our set of inhibitors found during this project have the potential to become first-in-class drugs. Developing an accessible and effective therapy for metastatic cancer will have a direct impact on the good health and well-being of thousands of patients. We will provide them with a novel solution capable of improving survival rates and enhancing their quality of life. At the same time, this novel solution introduces a groundbreaking approach in the metastatic field by targeting the lipid signaling machinery, a strategy identified in our lab, proving the promotion of cutting-edge research and fostering scientific innovation. Furthermore, we aim to reduce inequalities by developing an accessible and affordable therapy, bridging gaps between high- and low-income populations. As our ultimate goal is to bring this therapy to market through a spin-off, we will create new quality jobs and establish strategic collaborations at both national and international levels leveraging their expertise and contributing to increasing the biotech ecosystem.