PIK3CA-related overgrowth: silver bullets from the cancer arsenal?
Authors: Ralitsa R. Madsen, Robert K. Semple
Journal: Trends in Molecular Medicine (2022)

Mutations that activate growth factor signaling often drive cancer growth. Many also arise in isolation, causing developmental growth disorders. PIK3CA, that encodes a catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is a cardinal example of this paradigm. Recent exciting progress towards the key goal of cancer drug repurposing for PIK3CA-driven overgrowth is discussed. Mutations that activate growth factor signaling often drive cancer growth. Many also arise in isolation, causing developmental growth disorders. PIK3CA, that encodes a catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is a cardinal example of this paradigm. Recent exciting progress towards the key goal of cancer drug repurposing for PIK3CA-driven overgrowth is discussed. In 1986 Rudolf Happle hypothesized that McCune–Albright Syndrome (MAS), a rare disease featuring asymmetric bony overgrowth, activated hormone signaling, and irregular skin pigmentation, might be caused by a postzygotic mutation that is lethal in the germline. He was quickly proved right. GNAS, the gene encoding the activatory G protein Gαs, was sequenced that same year, and, 3 years later, activating GNAS mutations were found in hormone-secreting tumors, and in mosaic form in MAS 5 years after Happle's speculation [1.Weinstein L.S. et al.Activating mutations of the stimulatory G protein in the McCune–Albright syndrome.N. Engl. J. Med. 1991; 325: 1688-1695Crossref PubMed Scopus (1369) Google Scholar]. Nearly 20 years later, massively parallel DNA sequencing of human tissues began a rush of discoveries of other postzygotic mutations in developmental disorders. This continues today. Many such mutations are known cancer drivers, and act by activating oncogenic signaling pathways, including PI3K/AKT/mTOR and RAS/MAPK. Thus, a paradigm has emerged whereby growth-promoting mutations that contribute to tumor growth also often cause non-cancerous asymmetric overgrowth when they arise in isolation during development. Mutations activating the PI3K pathway cause a particularly wide range of growth disorders that prominently affect blood and lymph vessels, fat, bones, brain, and muscle [2.Madsen R.R. et al.Cancer-associated PIK3CA mutations in overgrowth disorders.Trends Mol. Med. 2018; 24: 856-870Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar]. The PIK3CA gene, encoding the p110α catalytic subunit of PI3Kα, is most commonly mutated, and the term 'PIK3CA-related overgrowth spectrum' (PROS) has been coined to encompass the resulting conditions. Owing to mosaicism, the clinical manifestation of PROS is protean, and is determined by the developmental timing of the mutation, the cell lineage affected, and poorly understood molecular differences among PIK3CA variants [2.Madsen R.R. et al.Cancer-associated PIK3CA mutations in overgrowth disorders.Trends Mol. Med. 2018; 24: 856-870Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar]. At its most severe, PROS can be life-threatening as a result of vascular complications, the compressive effects of overgrown tissue, and/or neurological abnormalities. PIK3CA is also among the most frequently mutated genes in adult cancers, and the mutational spectrum in PROS and cancer is similar [2.Madsen R.R. et al.Cancer-associated PIK3CA mutations in overgrowth disorders.Trends Mol. Med. 2018; 24: 856-870Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar] (Figure 1). Consequently, years of development of PI3K inhibitors for cancer meant that potential targeted therapies for PROS were already 'on the shelf' when the causal mutations were discovered. Such therapies ranged from sirolimus and other mTOR inhibitors, already in clinical use, to emerging p110α-specific inhibitors in clinical trials. Subsequent studies have begun to realize this early potential, but have also illustrated the challenges of cancer drug repurposing in complex developmental disease. Sirolimus shows modest benefits, mostly in lymphatic overgrowth [3.Parker V.E.R. et al.Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum.Genet. Med. 2019; 21: 1189-1198Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar]. As an mTORC1 inhibitor, sirolimus not only inhibits signaling downstream from PI3K but also disrupts the negative feedback that serves to keep PI3K signaling in check in health, thereby attenuating its inhibitory action on the pathway. The PI3Kα inhibitor taselisib, which can induce degradation of mutant p110α as well as inhibiting it, seemed a better prospect; however, despite early evidence of benefits, a Phase IB/IIA trial was halted owing to serious side effects attributed to concomitant taselisib targeting of PI3Kδ and thus immune dysregulation [4.Luu M. et al.Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel–Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study.Genet. Med. 2021; 23: 2433-2442Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. At present, the best hope for PROS is alpelisib/Piqray®, a selective PI3Kα inhibitor, which was recently licensed in combination with hormone therapy for a subset of PIK3CA-mutated breast cancers. In PROS, a major benefit of alpelisib was reported initially in two people with life-threatening disease, and significant but lesser benefits were described in 17 further patients [5.Venot Q. et al.Targeted therapy in patients with PIK3CA-related overgrowth syndrome.Nature. 2018; 558: 540-546Crossref PubMed Scopus (209) Google Scholar]. Because this index study was unregistered, no endpoints nor adverse events were prespecified. Subsequently, alpelisib has been made available in a managed access program for life-threatening PROS in which patients were enrolled in a registered study. Initial results demonstrated that 38% of 32 patients studied showed reduction of 'target lesion' volume, and wider beneficial effects were seen for a raft of other outcome measures, at the cost of 39% alpelisib-related adverse events [6.Canaud G. et al.EPIK-P1: retrospective chart review study of patients (pts) with PIK3CA-related overgrowth spectrum (PROS) who have received alpelisib (ALP) as part of a compassionate use programme.Dev. Therapeut. 2021; 32: S1297Google Scholar]. This consolidates initial positive findings, but leaves room for much-needed further work. An international multicenter, randomized controlled trial (RCT) (EPIK P2)i is now also underway. Designing RCTs for PROS is difficult given its heterogeneity, especially as overgrowth is not sharply anatomically demarcated, as in cancer. Which patients and which types of overgrowth are mostly likely to respond is still poorly defined, and no specific biomarkers have been validated. The time-window in which intervention is most effective is also unknown. PROS usually manifests at birth and progresses during childhood, and early intervention therefore seems desirable. However, drug development pathways, especially when targeting adult cancers, often neglect childhood. EPIK-P2 will provide the best evidence so far regarding some of the unanswered questions, but it excludes children below 2 years old, and preliminary results are not expected until 2024. In the interim, each increase in clinical experience is of value. In a recent report in the Journal of Experimental Medicine, Morin and colleagues offer such an increment [7.Morin G. et al.Treatment of two infants with PIK3CA-related overgrowth spectrum by alpelisib.J. Exp. Med. 2022; 219e20212148Crossref PubMed Scopus (2) Google Scholar]. They report treatment of two children under 1 year old with a low dose of alpelisib. The first, a 9-month-old girl, had severe mixed lymphatic and venous malformations and overgrowth. She had recurrent skin infections, a common consequence of fragile superficial vascular malformations, complicated by septic shock and deep venous thrombosis. Over 1 year, alpelisib treatment led to rapid improvement in vascular malformations and overgrowth. Antibiotics and anticoagulation were stopped, and growth trajectory and serum IGF-1 were normalized, likely due to indirect effects of reduced systemic illness. The second child was an 8-month-old boy with a different manifestation of PROS, including asymmetric brain overgrowth with venous malformations, limb enlargement, and skin capillary malformation. On alpelisib, discoloration of capillary malformation and muscle tone improved, and neurodevelopment was said to resume a normal trajectory. However, no objective change was reported in brain imaging or electrical activity, in keeping with the inability of alpelisib to cross the blood–brain barrier. These findings suggest significant benefits of alpelisib, especially in the first case, in keeping with further recent case reports of alpelisib treatment in children (e.g., [8.Garreta Fontelles G. et al.Alpelisib to treat CLOVES syndrome, a member of the PIK3CA-related overgrowth syndrome spectrum.Br. J. Clin. Pharmacol. 2022; (Published online February 10, 2022)https://doi.org/10.1111/bcp.15270Crossref PubMed Scopus (1) Google Scholar]). No adverse events were reported in any case. Importantly, pharmacokinetic studies were undertaken in the Morin et al. report, the first in any age group with PROS [7.Morin G. et al.Treatment of two infants with PIK3CA-related overgrowth spectrum by alpelisib.J. Exp. Med. 2022; 219e20212148Crossref PubMed Scopus (2) Google Scholar], and the evidence supports a potentially longer half-life of alpelisib in young children. Maximal concentrations at the low dose used were below those reported at a well-tolerated adult dose. Taken together, these studies leave the field in an encouraging but uneasy interim state. There is clear evidence of benefit from alpelisib in PROS, but the precise extent of benefit, the age and PROS subtypes where benefit is greatest, and the adverse event profile have not yet been reported in RCTs, the traditional basis for clinical approval. In an era of rapid information dissemination and highly motivated patient advocacy groups, there is widespread awareness of encouraging preliminary data, driving many to seek access to promising drugs before definitive data are available, with implications for RCT recruitment. There has also been increasing interest in the evolving methodology of registry-based studies embedded in real-world clinical practice [9.Karanatsios B. et al.Defining key design elements of registry-based randomised controlled trials: a scoping review.Trials. 2020; 21: 552Crossref PubMed Scopus (8) Google Scholar]. These offer major cost savings and potentially greater generalizability and external validity than RCTs, and this may be of particular value in a highly heterogeneous disease such as PROS. One downside of alpelisib is its equipotency against mutant and wild-type PI3Kα, leading to disruption of homeostatic processes that depend on this isoform. Cancer trials have confirmed the expected on-target toxicity on blood glucose of alpelisib at the maximum tolerated dose. Although EPIK P2 will provide a more definitive view of the side effects of alpelisib in PROS, reports so far suggest that these are tolerable at the low doses used in PROS. Encouragingly, the continued search for better PI3K inhibitors for cancer therapy may offer a solution should alpelisib fail to benefit some PROS patients because of toxicities. Of particular long-term promise is the recent development of PI3Kα mutant-selective inhibitors [10.Vanhaesebroeck B. et al.Precision targeting of mutant PI3Kalpha in cancer by selective degradation.Cancer Discov. 2022; 12: 20-22Crossref PubMed Scopus (1) Google Scholar]. The new opportunities thrown up by discovery of multiple mosaic genetic growth disorders demand nimbleness and adaptability from preclinical scientists, pharmaceutical companies, physicians and regulators. Pharma should be aware of the possibility to mitigate risk by repurposing cancer drugs in mosaic disorders, often in children, and configure their development pipelines accordingly. If new drugs with suitable toxicity data can be formulated for children, then the corresponding development of registries and adaptive trial methodology will provide an easier conduit for future trials of drugs in the cancer PI3K pipeline. Allied to better preclinical, human-relevant, and mutant-specific disease models, this will provide a roadmap for the delivery of genomically informed precision medicine in a wide range of diseases which until recently have entirely lacked disease-modifying therapies. The gauntlet is down, and if it can be grasped the future is bright. R.K.S. and R.R.M. are supported by fellowships from the Wellcome Trust (grants 210752/Z/18/Z and 220464/Z/20/Z ). R.K.S. has received consulting fees from Novartis and is an investigator in the Novartis-sponsored EPIK-P2 Trial. R.K.S. and R.R.M. have both received research funding from the CLOVES Syndrome Community. ihttps://clinicaltrials.gov/ct2/show/NCT04589650