Paediatric strategy forum for medicinal product development of PI3-K, mTOR, AKT and GSK3β inhibitors in children and adolescents with cancer

Abstract

Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.

Keywords: AKT and GSK3β Inhibitors; Cancer therapeutics; Combinations; Diffuse midline glioma; Drug development; MTOR; PI3-K; Paediatric oncology; Paediatric strategy forum.

Figure 1.. Schematic overview of the PI3K/AKT/mTOR pathway

Activation of tyrosine kinase receptors (TKR) results in the activation/recruitment of phosphatidylinositol 3-kinase (PI3K) to the cell membrane, which in turn phosphorylates phosphatidylinositol-4,5-biphosphonate (PIP2) to phosphatidylinositol-3,4,5-biphosphonate (PIP3). PIP3 interacts with and activates AKT which in turn phosphorylates and inhibits glycogen synthase kinase-3 beta (GSK3B) leading to cell cycle progression and alterations in protein and glycogen synthesis. Similarly, activated AKT inhibits FOXO1 and tuberous sclerosis complex 2 (TSC2). In turn, inhibition of TSC2 leads to activation of the mammalian target of rapamycin complex 1 (mTORC1). All of these signalling pathways result in increased cell proliferation, growth, and survival. The mammalian target of rapamycin complex 2 (mTORC2) can also activate AKT. The tumour suppressor phosphatase and TENsin homolog (PTEN) inactivates PIP3 back to PIP2. Created with BioRender.com.