Activation of the PAM (PI3K/AKT/mTOR) pathway has been implicated in a wide variety of human cancers, including carcinomas of the breast, prostate, lung, endometrial, colon, and ovary.
Activities associated with this pathway involve the regulation of diverse cellular processes, including cell proliferation, survival, cytoskeletal organization, and glucose transport. Overactivation of the pathway is frequently present in human malignancies and plays a key role in cancer progression.
Each of the four catalytic isoforms of class I PI3K preferentially mediate signal transduction and tumor cell survival based on the type of malignancy and the genetic or epigenetic alterations an individual patient harbors. Due to the multiple subcellular locations, activities, and importance of the different PI3K complexes in regulating many types of cancer cell proliferation, control of PI3K activity is an important target in cancer therapy.
mTOR also serves as a central regulator of cell metabolism, growth, proliferation, and survival. mTOR is a downstream effector of PI3K and regulated by hormones, growth factors, and nutrients, that is contained in two functionally distinct protein assemblies: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). In cancer, dysfunctional signaling leads to various constitutive activities of the mTOR complexes, making mTOR an important therapeutic target.
A hallmark of the PAM pathway – an important target in cancer therapy – is its various activation mechanisms
The important role the PAM pathway plays in cancer has led to significant investment in the development of many different PI3K, AKT, and mTOR inhibitors for solid tumors. However, developing efficacious and well-tolerated therapies that target this pathway has been challenging. This reflects the inherent adaptability and complexity of the PAM pathway, where numerous feedforward and feedback loops, crosstalk with other pathways, and compensatory pathways enable resistance to PAM pathway inhibition. A major challenge in developing PAM pathway inhibitors has been achieving sufficient pathway inhibition while maintaining an acceptable safety profile.
To address the challenges of targeting the PAM pathway, we are developing a potential first-in-class multi-target PAM inhibitor that:
Gedatolisib is a pan-class I isoform PI3K and mTOR inhibitor with low nanomolar potency for the p110α, p110β, p110γ, and p110δ PI3K isoforms, as well as mTORC1 and mTORC2, that induces comprehensive blockade of the PAM pathway. Its mechanism of action and pharmacokinetic properties are highly differentiated from other currently approved and investigational therapies that target PI3Kα, AKT, or mTORC1 alone. We believe this will enable gedatolisib to treat a broader patient population than these single-target inhibitors.
Ex vivo studies found that gedatolisib inhibited higher levels of PI3K/AKT/mTOR involved signaling activity than approved single target PI3K, AKT, or mTOR therapies, regardless of PIK3CA mutational status. Synergistic activity with selected targeted therapies has been observed in nonclinical studies.
Gedatolisib’s initial clinical development program is focused on the treatment of patients with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 -negative (HER2-), advanced or metastatic breast cancer and patients with metastatic castration resistant prostate cancer. Unlike PI3K or AKT therapies that are only approved to treat patients with PIK3CA or PTEN mutations, gedatolisib is under development for patients with and without PIK3CA mutations.
Simultaneous inhibition of the PAM (PI3K/AKT/mTOR) pathway with gedatolisib, the CDK4/6 pathway with palbociclib, and the estrogen receptor pathway with fulvestrant, is intended to disrupt complex cooperation between these pathways to inhibit tumor growth.
Available evidence indicates that resistance to CDK4/6 inhibition is a transient adaptive mechanism, most likely involving the PAM pathway. Continuing CDK4/6 inhibition in combination with PAM inhibition in patients who progressed on their prior CDK4/6 inhibitor is expected to both block the reactivated CDK4/6 pathway and prevent adaptive activation of the PAM pathway.
Patients whose disease progressed on a CDK4/6 inhibitor may thus potentially benefit from continued treatment with a CDK4/6 and ER inhibitor when it is combined with a PAM inhibitor as their next line of therapy.
Simultaneous inhibition of the PAM (PI3K/AKT/mTOR) pathway with gedatolisib and the AR pathway with darolutamide is intended to disrupt complex cooperation between these pathways to inhibit tumor growth.
The cancer driving PAM pathway is activated in the majority of mCRPC tumors. Since the PAM and AR pathways cross-regulate each other through reciprocal negative feedback, resistance to AR inhibition can be induced through the activation of PI3K/AKT/mTOR signaling.
Gedatolisib in combination with an AR inhibitor is being evaluated in clinical studies in patients whose disease has progressed on prior AR inhibitor therapy.
