Publications & Presentations
The PI3Kα pathway is commonly mutated in cancer. PI3Kα inhibitors have shown clinical benefit in hormone receptor positive (HR+), HER2- breast cancer (BC) in Phase 3 studies, but are limited…
The PI3Kα pathway is commonly mutated in cancer. PI3Kα inhibitors have shown clinical benefit in hormone receptor positive (HR+), HER2- breast cancer (BC) in Phase 3 studies, but are limited…
Phosphoinositide 3-kinase α (PIK3CA) is one of the most mutated genes across cancers, especially breast, gynecologic, and head and neck squamous cell carcinoma tumors.
EGFR mutations are well validated clinical targets in non-small cell lung cancer (NSCLC). Osimertinib, a highly-selective EGFR mutation-targeting covalent drug, is increasingly used in the first line setting for patients with NSCLC bearing EGFR L858R mutation or exon 19 deletions (ex19del).
Small molecule drugs have enabled the practice of Precision Oncology for genetically defined patient populations since the first approval of Gleevec in 2001. Scientific and technology advances over this 20-year period have driven the evolution of cancer biology, medicinal chemistry, and computational data sciences.
Selective targeting of mutant PI3Kα is expected to improve anti-tumor activity and reduce toxicities associated with inhibiting the wild-type enzyme in normal tissues, which are frequently observed with alpelisib, the only approved drug for this target.
EGFR mutations are well validated clinical targets in NSCLC. Osimertinib, a highly-selective EGFR mutation-targeting drug, achieves an objective response rate of ~80% against cancers with L858R or exon 19 deletion. In contrast, patients with EGFR exon 20 insertion mutations exhibit response rates to currently approved or investigational therapies between 28%-52%. The suboptimal efficacy of existing EGFR inhibitors for patients with exon 20 mutations is likely due to poor mutant versus wild-type EGFR selectivity.
PI3Kα is highly mutated in cancer with the most prevalent mutation, H1047R, occurring in approximately 14% of breast cancers. This mutation causes hyperactivation of lipid kinase activity and downstream AKT signaling.
Therapeutic proof-of-concept for targeting PI3Ka mutations was established with alpelisib, an alpha-selective PI3K inhibitor that is equipotent against wild-type and mutant forms. However, the therapeutic benefit of alpelisib is limited by the inhibition of wild-type PI3Kα in normal tissues, resulting in dose-limiting toxicities including hyperglycemia.