Harnessing Phosphoinositide Signals Against Disease
Researchers have long recognized the important roles played by lipids called phosphoinositides (PIs) in normal and diseased cell functioning. But it’s been hard to pinpoint promising therapeutic targets within the complex web if PI signaling pathways. At Petra Pharma, pioneers in the field of PI signaling are pursuing that goal.
Phosphoinositide (PI) pathways regulate fundamental processes of cellular growth and metabolism. The importance of PI signaling in human health is underscored by the many diseases that arise from PI pathway deregulation. PI-modifying enzymes are among the most frequently mutated proteins in cancer.
Nonetheless, very few drugs have been developed that successfully disrupt oncogenic signaling in PI pathways. Petra believes that a refined understanding of the highly complex biology of these pathways is necessary to target the right steps, mutations or branches in the pathways to yield effective and safe therapies.
Of particular significance is the discovery by Dr. Cantley’s laboratory that PI3K mediates the cellular actions of insulin, with important ramifications on the ability of PI3K inhibitors to kill cancer cells. Specifically, treatment with PI3K inhibitors results in an increase in blood glucose which in turn stimulate a spike in insulin levels. This feedback loop reactivates PI3K in cancer cells and attenuates the anti-tumor activity of PI3K inhibitors.
Recent research by Dr. Cantley and his collaborators show that combining PI3K inhibitors with ketogenic diet or glucose-lowering agents prevent the glucose/insulin spike and results in dramatic enhancement of anti-tumor efficacy in animal models.
Petra is exploiting this groundbreaking scientific insight to maximize the anti-tumor effects of its PI3K inhibitors by:
- Combining a targeted alpha-specific PI3K inhibitor with a glucose-lowering agent to defeat the glucose-insulin feedback loop
- Targeting specific PI3K mutation(s) to completely avoid activation of the glucose-insulin feedback loop
Petra’s alpha-specific PI3K inhibitor and mutant-selective PI3K inhibitor are being developed as treatments for patients with PIK3CA-mutated tumors.
Reference: Hopkins BD, Pauli C, Du X, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018;560:499-503.
Petra is also targeting PIP4K2 to overcome late-stage autophagy, a recycling feature that enables the progression and survival of established tumors. Autophagy protects tumor from therapeutic stresses such as chemotherapy and radiotherapy and many tumors appear to be autophagy-dependent, meaning that their survival is dependent on their ability to use the autophagy pathway as a source of nutrient replenishment [Chude CI, Amaravadi RK. Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors. Int J Mol Sci. 2017;18(6):1279.]
The initial focus of clinical development of Petra’s PIP4K2 inhibitors will be on patients with hematologic malignancies.
- Petra has developed highly potent, selective, and drug-like inhibitors of PIP4K2 enzymes
- Cell lines and freshly isolated human hematomologic cancers display a high rate of sensitivity to PIP4K2 inhibitors
- PIP4K2 inhibitors are active in xenograft studies and well tolerated beyond efficacious doses
- Several solid tumor cell lines are also sensitive to PIP4K2 inhibition
The founders and partners of Petra bring together comprehensive understanding of the biology of PI signaling with the most advanced drug discovery technologies in the world.