In a review article published in February 2014 issue of Nature Reviews Drug Discovery, David A Fruman of the Department of Molecular Biology & Biochemistry, and Institute for Immunology, University of California, Irvine, USA, reviews key challenges and opportunities for the clinical development of inhibitors targeting the PI3K/AKT/mTOR pathway. The authors anticipate that through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realise the potential of this promising class of targeted anti-cancer agents.
Opportunities for the clinical development of these inhibitors
The signalling network defined by PI3K, AKT and mTOR controls most hallmarks of cancer, including cell cycle, survival, metabolism, motility and genomic instability. The pathway also contributes to cancer-promoting aspects of the tumour environment, such as angiogenesis and inflammatory cell recruitment. Cancer genetic studies suggest that the PI3K pathway is the most frequently altered pathway in human tumours: the PIK3CA gene is the second most frequently mutated oncogene, and PTEN is among the most frequently mutated tumour suppressor genes.
The strong genetic evidence, in addition to the druggability of various components in the network, provided the original rationale and enthusiasm for targeting PI3K/AKT/mTOR signalling in oncology. The targeting of this signalling network was seen as an opportunity to combat tumour complexity and genomic heterogeneity through a central, common oncogenic driver that is fundamental to all cancer cells. However, counterbalancing this opportunity is the challenge of targeting enzymes that are also active and have crucial roles in normal cells and tissues.
There are six general classes of agents in clinical trials targeting the PI3K/AKT/mTOR network: pan-class I PI3K inhibitors, isoform-selective PI3K inhibitors, rapamycin analogues (rapalogues), active-site mTOR inhibitors, pan PI3K/mTOR inhibitors and AKT inhibitors.
However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy.
Key challenges to their development
In their article, the authors illustrate the PI3K/AKT/mTOR signalling network by providing the complexity, crosstalk and feedback aspects. In addition they feature clinical trial results and associated challenges, elaborate on pan PI3K versus isoform-selective inhibition, single-node versus pan PI3K and mTOR inhibition, rapalogues versus mTOR kinase inhibition, tolerability and alternative targets, and describe emerging rational combination strategies.
At the end of the article, the authors envision four key strategies that will, in their opinion, maximise the potential of PI3K/AKT/mTOR inhibitors in oncology: biomarker identification through next-generation sequencing, putting initial emphasis on haematological malignancies, harnessing immune effects, and performing combination trials.
They conclude that despite many challenges, measurable advances have been made in the clinic. Rapalogues are useful in some advanced cancers and as adjuvants to hormone therapy in breast cancer. Inhibitors of PI3Kδ are on track for FDA approval in certain B cell malignancies. Other agents are advancing through development. Nevertheless, early hopes have been tempered by the realisation that targeting the PI3K/AKT/mTOR pathway alone will not be a cure-all for diverse cancers.
Previous experiences with successful drug development in oncology show the importance of:
- Targeting genetic drivers in selected patient populations
- Understanding the biology of crosstalk and feedback to use effective combinations
- Stimulating an immune environment that favours tumour eradication
The investigators believe that thoughtful application of these principles will light the path towards effective clinical use of PI3K/AKT/mTOR inhibitors.
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