A trio of studies has converged on a common pathway, headed by the PPAR co-activator PGC-1α, to fight cancer and chronic infections by manipulating either T cell immunotherapies or the tumors themselves. While the findings reveal new biology underlying T cell exhaustion, they could also open the door to therapeutics against a hitherto under-exploited target.
PGC-1α is a transcriptional co-activator commonly referred to as the “master regulator of mitochondrial biogenesis.” Its overexpression has been shown to improve outcomes in preclinical models of a wide range of diseases, including atherosclerosis, acute kidney injury (AKI) and cancer, although some studies have shown the opposite - by demonstrating high PGC-1α activity helps tumor cells thrive.
The regulator lies downstream of a wide range of signaling pathways, including SIRT1, AMPK and nitric oxide (NO) synthases. As a co-activator, it helps transcription factors such as PPARγ, PPARα and NRF2 induce expression of genes that promote mitochondrial biogenesis, fatty acid oxidation, and protection from reactive oxygen species.
While several PGC-1α activators and co-regulators have been targeted commercially for treatment of metabolic, cardiovascular and other diseases, no companies have disclosed clinical programs directly targeting PGC-1α.
Now, three papers