PAM Pathway
Focused on comprehensively blocking the PAM pathway in cancer
The PI3K/AKT/mTOR (PAM) signaling pathway regulates diverse cellular processes, including cell proliferation, survival, and metabolism. When the PAM pathway becomes dysregulated and overactivated, it supports cancer cell survival and proliferation by enabling increased glucose consumption and protein synthesis. A wide variety of human cancers, including carcinomas of the breast, prostate, endometrial, ovarian, and head and neck, have been found to involve the PAM pathway.
One indicator of the importance of the PAM pathway as a cancer driver is reflected in the high proportion of tumors that have a PAM genomic alteration. Nearly 40% of all tumors have a PAM alteration, including approximately 50% of breast and prostate tumors and up to 70% of endometrial tumors.
The important role the PAM pathway plays in cancer has led to significant investment and the development of many different PI3K, AKT and mTOR inhibitors for solid tumors. However, developing therapeutics that target the PAM pathway is complex because it includes multiple components (e.g. PI3K isoforms (α, β,δ, γ), AKT, mTORC1/2) that provide functional redundancy.
This built-in redundancy allows the PAM pathway to adapt so that it can continue to promote cancer-driver activities when it is not comprehensively inhibited. This limits the efficacy of therapeutics that only target a single PAM component. Designing therapies that blockade this pathway comprehensively has been challenging and stymied researchers for nearly two decades.
The PAM pathway has multiple components that make it difficult to block completely.
Nonclinical studies have shown that multi-target inhibition of the PAM pathway is more effective in reducing tumor cell proliferation than single-target inhibitors in breast, prostate, and endometrial, and ovarian cell, regardless of whether a PAM pathway alternation is present.
To address this challenge, Celcuity's drug, gedatolisib, inhibits the PAM pathway by inhibiting all class I PI3K isoforms (α, β, δ, γ) and mTOR complexes mTORC1 and mTORC2.
