Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that regulates fatty acid oxidation (FAO) and inflammation and is expressed by many cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) to a significant degree. PPARα is in a known, druggable pathway; fenobibrates, are PPARα agonists, and have been prescribed to treat dyslipidemia for decades. TPST-1120 is a PPARα antagonist that has a dual mechanism of action to kill tumors, cells, both by targeting cancer cells dependent upon the FAO metabolic pathway directly and harnessing a patient’s immune system.
Tempest and our research partners have demonstrated that blocking PPARα with TPST-1120 directly kills primary tumor cells and tumor cell lines in vitro. TPST-1120 induces tumor-specific immunity and promotes a more inflamed tumor microenvironment (TME) through inhibiting immunosuppressive cell populations including M2 macrophages, myeloid suppressor cells and regulatory T cells, which all utilize FAO.
TPST-1120 shifts the metabolic balance in the TME towards glycolysis and favors the bioenergetic needs of effector immune cell populations, including M1 tumor associated macrophages (TAMs) and effector T Cells (Teff), stimulating the development of tumor-specific immunity. Tempest is advancing TPST-1120 as a first-in-class antagonist tartgeting PPARα. TPST-1120 is progressing through both monotherapy and combination Phase 1 studies (NCT03829436).