Targeting PI3K: A Key Survival Gene in Solid-Tumor Cancers

click to enlarge Inhibiting tumor proliferation and survival by blocking the phosphatidylinositol-3-kinase (PI3K) pathway. PI3K and the mammalian target of rapamycin (mTOR) are important components of an intracellular signaling network, the PI3K-AKT-mTOR pathway, which regulates cellular metabolism, proliferation and survival. (Source: Novartis Pharmaceuticals Corp.)

The PI3K gene is a key component of the PI3K-AKT-mTOR cell-signaling pathway, which regulates cell metabolism, proliferation, and survival. The PI3K-AKT-mTOR pathway is activated in the majority of human cancers.¹ In cancers of the breast and lung in particular, high activation levels of this pathway have been associated with resistance to chemotherapy and poor prognosis.^2-3

Lung cancer and breast cancer are the leading and second-leading causes of death from cancer in women.⁴ Each year almost 1.4 million women will be diagnosed with breast cancer,⁵ and the number of women being diagnosed annually worldwide has almost doubled since the mid-1970s.⁴ The PI3K-AKT-mTOR pathway plays an integral role in metastatic breast cancer.⁶ Lung cancer is the most common cancer worldwide with 1.⁴ million cases per year.⁵ It is also the most common cause of death from cancer, resulting in 1.2 million deaths annually,⁵ accounting for one-quarter to one-third of cancer deaths in both men and women.^7,8 Of the patients affected, approximately 75% will have non-small cell lung cancer.⁹

Molecules that inhibit the PI3K pathway upstream of mTOR may be promising in the next wave of targeted cancer therapeutics. Novartis has a development strategy targeting PI3K, including co-development of companion diagnostics to aid in analysis of tumors for PI3K pathway status−mutation and protein expression analysis—and stratification of patients by pathway status-activated versus non-activated. Its PI3K inhibitor pipeline includes targeted oral anticancer agents aimed at distinct components of the PI3K-AKT-mTOR pathway. BKM120 and BEZ235 are investigational therapies being studied in Phase 1/2 clinical trials in patients with advanced solid tumors—both as monotherapy and in combination with other agents.

BKM120, a pan-PI3K inhibitor, is in Phase 1/2 trials for breast cancer, non-small cell lung cancer, endometrial cancer, and glioblastoma multiforme. BKM120 is a synthetic molecule that inhibits all four Class I PI3K isoforms, including the most common somatic PI3Kp110α; however, BKM120 does directly inhibit mTOR.¹⁰ Synergistic activity has been observed when BKM120 is combined with a MEK inhibitor in KRAS-mutant human cancer models.¹¹

BEZ235, a PI3K/mTOR dual inhibitor, is in Phase 1/2 trials for breast cancer. BEZ235 is a synthetic molecule that inhibits all four Class I PI3K isoforms, as well as the mTORC1 and mTORC2 complexes.¹²

Novartis has more than 40 PI3K inhibitor clinical trials under way at sites around the world, including investigator-initiated trials. In addition, a third PI3K inhibitor, BYL719, a selective inhibitor of PI3Kα, is in Phase 1/2 trials for advanced solid tumors.

References
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12. Maira SM, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008;7(7):1851-1863.