In Journal of Clinical Oncology, Bendell et al present a clinical phase I dose-escalation study of the orally bioavailable phosphatidylinositide-3-kinase (PI3K) inhibitor NVP-BKM120. Over the last 2 years, preliminary conference reports have described the initial phase I clinical experience for several PI3K inhibitors with different selectivity profiles. The article from Bendell et al is the first full peer-reviewed publication reporting the phase I clinical results with a pan–class I selective PI3K inhibitor lacking activity against mammalian target of rapamycin (mTOR). Briefly, the authors report that NVP-BKM120 is well tolerated with an acceptable dosedependent safety profile. Toxicities reported were predominantly rash, hyperglycaemia, and mood alterations, which may reflect ontarget effects of PI3K inhibition in normal tissues. Dose-dependent molecular pharmacodynamic biomarker modulation was also reported, and there was evidence of biologic activity, including a single partial response and a number of patients with prolonged stable disease of at least 8 months duration. In this Understanding the Pathway article, we discuss the findings in the context of our present knowledge of pathogenic PI3K signaling in cancer, and we highlight topical issues in the field, particularly addressing currently unresolved questions concerning the optimal isoform selectivity of PI3K inhibitors and use of proof-of-mechanism and predictive biomarkers. PI3Ks are a family of mainly lipid kinases that regulate an intracellular signal transduction pathway—or, more accurately, a signaling network—which in turn controls many features of cell behavior, including growth, survival, motility, metabolism, and additional specialized functions (Fig 1). Four distinct PI3K subfamilies exist— commonly referred to as classes I, II, III and IV—categorized by their substrate specificities, primary structures, modes of regulation, and domain content. Of these, it is the class I isoforms (p110 , , , ) and class IV PI3K-related protein kinase mTOR that have become the most intensively examined PI3K family targets for small-molecule therapeutics. The key mechanistic rationale for this stems from the observation of frequent genetic and epigenetic activations of the PI3K pathway in cancer by a range of different molecular mechanisms (Fig 1). These findings strongly suggest that activation of the PI3K pathway is a critical step in oncogenesis, a view supported by multiple lines of experimental evidence. Since the identification of the fungal natural product wortmannin as a PI3K inhibitor, high-throughput screening of compound collections coupled to medicinal chemistry optimization, often supported by structure-based design, has led to the discovery and development of a plethora of chemically diverse inhibitors that possess a range of overlapping or distinct PI3K subtype selectivity profiles. Many of these are now progressing into early clinical trials. Proof-of-mechanism pharmacodynamic biomarkers used to demonstrate target engagement and pathway modulation are critical for the implementation of the pharmacologic audit trail, enabling rational optimization of dose and schedule of administration. The dose-dependent hyperglycemia reported for NVP-BKM120 is an example of a class effect consistent with PI3K pathway inhibition. Inhibition of PI3K abrogates the actions of insulin, mainly mediated by the PI3K p110 isoform, resulting in increased blood glucose and a compensatory release of insulin and C-peptide. Increased blood glucose has commonly been used as a pharmacodynamic marker of PI3K pathway inhibition; however, Bendell et al suggest that C-peptide levels may provide a better, indirect biomarker. Reduced [F]fluorodeoxyglucose levels in tumors detected by positron emission tomography also indicated a metabolic response, resulting at least in part from a direct effect of PI3K inhibition on glucose uptake. It is important to establish the degree and duration of PI3K pathway inhibition necessary to achieve durable antitumor effects. Molecular pharmacodynamic biomarkers of signaling output such as phosphorylation of ribosomal protein S6 (RPS6), PRAS40, 4E binding protein 1, and AKT (Fig 1) have been used as indicators of PI3K pathway inhibition in both tumor and surrogate tissues. We previously showed that concentrations of PI3K inhibitors required to block phosphorylation of downstream pathway proteins such as RPS6 are approximately 10-fold higher than those needed for inhibition of the more proximal AKT phosphorylation (Fig 1). Here, Bendell et al detected a 40% to 85% decrease of RPS6 phosphorylation in skin biopsies; there were no equivalent RPS6 biomarker data from tumors, so it is difficult to assess how this degree of inhibition in skin would relate to effects in malignant tissue. However, previous studies with another pan–class I PI3K inhibitor—GDC-0941—showed that a JOURNAL OF CLINICAL ONCOLOGY U N D E R S T A N D I N G T H E P A T H W A Y VOLUME 30 NUMBER 3 JANUARY 2
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Mar 13, 2013
Mohammad A Khanfar + 3
Open Access