Development of PI3K inhibitors: lessons learned from early clinical trials

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway has an important role in cell metabolism, growth, migration, survival and angiogenesis. Drug development aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway has been fomented by observations that alterations in this pathway induce tumour formation and that inappropriate PI3K signalling is a frequent occurrence in human cancer. Many of the agents developed have been evaluated in early stage clinical trials. This Review focuses on early clinical and translational data related to inhibitors of the PI3K/AKT/mTOR pathway, as these data will likely guide the further clinical development of such agents. We review data from those trials, delineating the safety profile of the agents--whether observed sequelae could be mechanism-based or off-target effects--and drug efficacy. We describe predictive biomarkers explored in clinical trials and preclinical mechanisms of resistance. We also discuss key unresolved translational questions related to the clinical development of inhibitors of the PI3K/AKT/mTOR pathway and propose designs for biomarker-driven trials to address those issues.

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

“…The higher leptin sensitivity in metabolic control and the decreased growth of LR Δα mice also make PI3K a potential player in conditions of delay in growth and puberty in humans and in hypothalamic amenorrhea of women in negative energy balance. Our findings also emphasize the need for a systematic evaluation of PI3K action in whole-body physiology, as clinical trials are on the way to assess the effects of using PI3Kα inhibitors as a potential therapeutic target in oncology (62).…”

Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

“…Inhibitors of the PI3K/AKT/mTOR pathway have been developed and are being tested for their potential anticancer activity alone and in combination with other anticancer agents (44,45). Dose-dependent single-agent activity of LY3023414 was observed in xenograft models with different types of aberrant PI3K/mTOR pathway activation (e.g., PIK3CAmt, PTEN loss).…”

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

“…PI3K inhibitors that are used in the clinic can be classified into three categories, including pan-PI3K inhibitors, isoformspecific inhibitors and dual PI3K-mTOR inhibitors (reviewed in detail by Scott et al 2009). 66 To a lesser extent, the potential of using phospholipase D inhibitors as anticancer therapeutics has also been explored. Phospholipase D inhibitors have been shown to block invasive migration of human breast cancer lines and enhance the sensitivity of tumor cells towards radiotherapy.…”