Novel PI3K Inhibitors Enter Human Studies

Agents in phase I trials target different isoforms of PI3K, whose pathway is one of the most commonly mutated in cancer.

Early experiences with 2 novel selective inhibitors of phosphoinositide 3-kinase (PI3K) that have reached clinical trials were discussed in sessions at the AACR Annual Meeting 2012 on April 1 and 2.

The inhibitors, BYL719 from Novartis, and GSK2636771 from GlaxoSmithKline (GSK), each work by targeting a specific form of the PI3K enzyme. The PI3K molecular pathway regulates cell proliferation and survival and is closely associated with many forms of tumorigenesis.

BYL719, claimed to be the first oral drug that strongly and selectively targets the PI3K-α isoform, was found to significantly inhibit cell growth and induced cell death in cancer cell lines and animal models. The drug was well tolerated in animals and has an improved safety profile compared with nonselective PI3K inhibitors, said Christine Fritsch of Novartis in Basel, Switzerland.

BYL719 is being investigated in patients with a variety of advanced solid tumors showing genetic alterations in PIK3CA, the gene that encodes the catalytic subunit of PI3K. (The targeted isoforms for both Novartis and GSK agents encode that catalytic subunit.)

The phase I clinical trial began in 2010 and has enrolled more than 25 patients to date. With daily dosing at various levels, the safety profile has shown mostly on-target toxicity, with manageable side effects, said Dejan Juric, MD, of Massachusetts General Hospital in Boston. Early results include a partial response in a patient with estrogen receptor–positive breast cancer and tumor shrinkage in 8 of 17 patients evaluated by positron emission tomography.

GSK's new agent works by targeting PI3K-β in tumors that are deficient in the tumor suppressor PTEN. Loss of PTEN protein is implicated in about 40% of glioblastoma, 50% of prostate, and 57% of endometrial cancers, the company said.

Patients with advanced solid tumors who are enrolled in the open-label, dose-escalation GSK2636771 study have been selected based on PTEN deficiency. The combination of PTEN deficiency and small-molecule PI3K-β inhibition aims to achieve a form of synthetic lethality, selectively killing just the targeted tumor cells, “an approach we can use to open up the therapeutic window,” said Richard Wooster, vice president and head of cancer metabolism drug discovery at GSK in Collegeville, PA. The company began accruing patients for phase I/IIa clinical trials in November 2011.