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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
1. Karar J, Maity A. PI3K/AKT/mTOR Pathway in angiogenesis. Front Mol Neurosci. 2011;4:51.
2. Gridelli C, et al. The potential role of mTOR inhibitors in non-small cell lung cancer. Oncologist. 2008;13(2):139-47.
3. Fang L, et al. Targeted therapy in breast cancer: what’s new? Swiss Med Wkly. 2011;141:w13231.
4. info.cancerresearchuk.org/cancerstats/reports/
5. info.cancerresearchuk.org/cancerstats/geographic/world/commoncancers/
6. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-9.
7. Jemal A et al., Cancer Statistics 2008. CA Cancer J Clin. 2008; 58:71–96.
8. info.cancerresearchuk.org/cancerstats/mortality/
9. Haque AK et al., CYP2E1 Polymorphism, Cigarette Smoking, p53 Expression, and Survival in Non-small Cell Lung Cancer: A Long Term Follow-up Study. Appl Immunohistochem Mol Morphol. 2004;12:315–322.
10. Maira M, et al. Biological characterization of NVP-BKM120, a novel inhibitor of phosphoinositide 3-kinase in phase I/II clinical trials. Poster presented at: 101st Annual Meeting of the American Association for Cancer Research; April 17-21, 2010; Washington, D.C.
11. Voliva CF, et al. NVP-BKM120, a novel inhibitor of phosphoinositide 3-kinase in phase I/II clinical trials, shows significant antitumor activity in xenograft and primary tumor models. Poster presented at: 101st Annual Meeting of the American Association for Cancer Research; April 17-21, 2010; Washington, D.C.
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.
Filed Under: Drug Discovery
