Class I phosphatidylinositol 3-kinases (PI3Ks) have emerged as important cancer drug targets. Class I PI3Ks are heterodimers comprising a catalytic subunit (p110α, β, δ, or γ) and a regulatory subunit. In normal cells, the PI3K pathway is tightly controlled, but many cancers harbor genetic changes that result in the deregulated activation of the PI3K pathway that enable tumors to metastasize and invade normal tissues, continue to grow under conditions of low nutrients or low oxygen, and to resist chemotherapy and radiation therapy.1-4 Tumor-specific alterations to components of the PI3K pathway include genetic or epigenetic changes that increase the expression or activity of the enzymatic subunits of PI3K or block the activity of the tumor suppressor PTEN (phosphatase and TENsin homolog)—an enzyme that regulates the activity of class I PI3Ks.
Because of the importance of this pathway to tumor cell growth and survival, several pharmaceutical companies are developing small molecules that inhibit the catalytic activity of PI3K. PX-866 is a small molecule, pan-inhibitor of PI3Ks under development at Oncothyreon. PX-866 functions as an irreversible inhibitor of PI3K by forming a covalent bond with the p110 subunits of PI3K. In humans and preclinical models, PX-866 is metabolized to produce an active metabolite, 17-OH, that is a more potent PI3K inhibitor than the parent drug and retains the same irreversible mechanism of action.
Preclinical studies have shown that PX-866 is efficacious in numerous mouse xenograft models of human cancers as a single agent and in combination with chemotherapy, radiation, and targeted cancer drugs, such as EGFR inhibitors. Results from a single-agent Phase 1 open-label, dose-escalation study of PX-866 in patients with advanced metastatic cancer demonstrated that PX-866 was well-tolerated using both an intermittent and continuous (daily) dosing schedule, and that 8 of 19 evaluable patients treated with continuous dosing achieved stable disease as their best response. Results from the Phase 1 portions of Phase 1/2 trials indicated PX-866 was well-tolerated in combination with cetuximab and in combination with docetaxel. No dose-limiting toxicities were seen and the recommend daily dose of PX-866 is the same as the single-agent daily maximum-tolerated dose of 8 mg.
Oncothyreon is conducting a broad development program of PX-866, evaluating the compound as a single agent and in combination with other agents in multiple cancer types. Current trials include a randomized Phase 2 trial of PX-866 in combination with cetuximab in patients with progressive colorectal cancer or progressive, recurrent, or metastatic squamous cell carcinoma of the head and neck (SCCHN) and a randomized Phase 2 trial of PX-866 in combination with docetaxel in patients with non-small cell lung cancer or SCCHN. In each of these trials, the two indications are being randomized and evaluated separately. In addition, the National Institute of Canada Clinical Trials Group is conducting Phase 2 trials of PX-866 in patients with relapsed glioblastoma and castration-resistant prostate cancer, respectively. Finally, Oncothyreon recently initiated a Phase 1/2 trial of PX-866 in combination with vemurafenib in patients with metastatic melanoma.
1. Engelman JA. Targeting PI3K signaling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550-562.
2. Ghayad SE, Cohen PA. Inhibitors of the PI3K/Act/motor pathway: new hope for breast cancer patients. Recent Pat Anticancer Drug Discov. 2010;5(1):29-57.
3. Liu P, et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8(8):627-644.
4. Sarker D, et al. Targeting the PI3K/AKT pathway for the treatment of prostate cancer. Clin Cancer Res. 2009;15(15):4799-4805.