SUMMARY OF INVENTION
Activating mutations in the kinase subunit PIK3CA are known to play a critical role in tumor biology and PIK3CA has emerged as a druggable target with Novartis’ Piqray (alpelisib; BYL719) approved in advanced HR+/HER2- breast cancer patients bearing a PIK3CA mutation. However, toxicities associated with PIK3CA inhibition including fatigue and hyperglycemia have significantly limited their full clinical potential. To expand their therapeutic index, MSK researchers have developed several novel PIK3CA inhibitors in collaboration with the Tri-Institutional Therapeutics Discovery Institute (Tri-I TDI).
Available inhibitors have unique biochemical properties such as rapid systemic clearance (i.e. TDI-5181) or poor permeability (i.e. TDI-8020) that can be selectively delivered into the tumor vasculature when formulated in fucoidan-based nanoparticles (for more information on fucoidan-nanoparticles see MSK SK2013-082). Lead inhibitor TDI-5181 demonstrated comparable levels of inhibition to BYL719 in both biochemical and cellular assays. When encapsulated in fucoidan-nanoparticles, TDI-5181 established similar levels of anti-tumor activity in a Cal-33 xenograft model to encapsulated BYL719 while minimally affecting changes in plasma glucose levels.
- TDI-5181 is highly selective; only 15 kinases (out of 615) displayed inhibition activity over 35% at 10 μM.
- Encapsulation of TDI-5181 in fucoidan nanoparticles reduced systemic metabolic toxicities associated with PI3K inhibition.
Aberrant activation of the PI3K pathway is observed in several cancers. In particular, activating mutations are observed in approximately 40% of patients with ER+ breast cancer and 34-56% of head and neck squamous cell carcinoma patients. As one measure of the potential market, the American Cancer Society estimates that 2/3 of all breast cancers are hormone-receptive positive, with most of these being ER+.
STAGE OF DEVELOPMENT
PCT/US2019/054679 filed on Oct. 4, 2019; Nationals pending in U.S., Canada, Europe, Australia
- Daniel A. Heller, PhD, Cancer Nanomedicine Laboratory Head, MSK
- Maurizio Scaltriti, PhD, Former Associate Director of Translational Science , MSK
James Delorme, PhD