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

• Published in: European journal of cancer (1990) Vol. 207; p. 114145
• Main Authors: Pearson, Andrew DJ, DuBois, Steven G., Macy, Margaret E., de Rojas, Teresa, Donoghue, Martha, Weiner, Susan, Knoderer, Holly, Bernardi, Ronald, Buenger, Vickie, Canaud, Guillaume, Cantley, Lewis, Chung, John, Fox, Elizabeth, Friend, John, Glade-Bender, Julia, Gorbatchevsky, Igor, Gore, Lia, Gupta, Abha, Hawkins, Douglas S., Juric, Dejan, Lang, Leigh Anna, Leach, Danielle, Liaw, Danny, Lesa, Giovanni, Ligas, Franca, Lindberg, Gavin, Lindberg, Wendy, Ludwinski, Donna, Marshall, Lynley, Mazar, Andrew, McDonough, Joe, Nysom, Karsten, Ours, Christopher, Pappo, Alberto, Parsons, D.William, Rosenfeld, Amy, Scobie, Nicole, Smith, Malcolm, Taylor, Danielle, Weigel, Brenda, Weinstein, Amy, Karres, Dominik, Vassal, Gilles
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2024
• Subjects: Adolescent; AKT and GSK3β Inhibitors; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer therapeutics; Child; Combinations; Diffuse midline glioma; Drug development; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - metabolism; Humans; MTOR; MTOR Inhibitors - pharmacology; MTOR Inhibitors - therapeutic use; Neoplasms - drug therapy; Neoplasms - genetics; Paediatric oncology; Paediatric strategy forum; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Phosphoinositide-3 Kinase Inhibitors - therapeutic use; PI3-K; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - antagonists & inhibitors; PI3-K; Cancer therapeutics; AKT and GSK3β Inhibitors; Combinations; Paediatric oncology; Paediatric strategy forum; Drug development; Diffuse midline glioma; MTOR
• ISSN: 0959-8049; 1879-0852; 1879-0852
• DOI: 10.1016/j.ejca.2024.114145

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. •PI3-K pathway mutations are rare in paediatrics, with the highest frequency in DMG.•New trials of mTOR inhibitors should be supported by strong biological rationale.•Toxicities and lack of activity have been major barriers to clinical translation.•New mutation-specific inhibitors in combination, may greatly increase activity.•Evaluating mutation-specific, CNS penetrant, inhibitors in DMG is a priority.