mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion

Abstract

Background Ultrarare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor, type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype then deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. Methods A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mTOR inhibition (adverse events, disease progression, time to colectomy, and mortality) in patients with JPI. Results Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (Everolimus n = 2 or Sirolimus n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio 0.27, 95% CI 0.07–0.954, p = 0.042) and resulted in significant improvements in serum albumin level (mean increase 16.3 g/L, p = 0.0003) and hemoglobin (mean increase 2.68 g/dL, p = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Conclusion Early therapy with mTOR inhibitors offers effective, pathway-specific, personalized treatment for patients with JPI. Inhibition of the PI3K-AKT–mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome.

Polygenic Infantile Juvenile Polyposis Syndrome Managed With Sirolimus and Endoscopic Polypectomy

“…This allowed for reduction in GI blood and protein loss, optimization of weight gain with successful weaning off PN while avoiding bowel resection. This is consistent with recently published data on patients with infantile JPS [ 5 ]. Even still, until this point, a full narrative account of a patient with infantile JPS, treated with sirolimus without need for bowel resection, had not been published.…”

“…Compared to its less severe counterpart of JPS, infantile JPS occurs much earlier in life with more severe disease manifestations. A study of 25 JPS patients noted that those presenting in infancy had higher polyp burden, greater risk of PLE and higher need for colectomy compared to those presenting after 1 year of age (relative risk (RR) for colectomy = 2.16, 95% confidence interval (CI) = 1.02 - 5.34, P = 0.03) [ 5 ].…”

“…Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disease associated with hamartomatous growths that can occur throughout the gastrointestinal (GI) tract of affected children [ 1 , 2 ]. Infantile JPS is a more aggressive form that arises during the first year of life, and is thought to be caused by deletion of the PTEN and/or BMPR1A genes [ 3 - 5 ]. Without intervention, infantile JPS is often associated with detrimental health sequelae such as protein losing enteropathy (PLE), blood loss, malabsorption, malnutrition, and intussusception.…”

Sirolimus treatment of a PTEN hamartoma tumor syndrome presenting with melena

“…32,33 Regarding the efficacy of sirolimus on GIS findings in patients, successful results in decreasing the number and size of polyps have been demonstrated not only for PTEN point mutations but also for intragenic PTEN deletions and larger deletions encompassing both PTEN and BMRP1A. 26,[34][35][36][37] In another recent interventional study by Komiya et al 11 , a 56-day course of sirolimus treatment was well tolerated in patients with PHTS and was associated with some evidence of improvement in symptoms, skin and GI lesions, cerebellar function, and decreased mTOR signaling. Thus, mTOR inhibitor treatment was initiated in the present study, as a role of sirolimus was shown in several studies in patients with PHTS.…”

Tumor predisposition: what's the skin got to do with it?

“…Pathogenic variants in PTEN cause constitutive activation of AKT and subsequent upregulation of mTOR signaling, explaining the overgrowth and cancer predisposition associated with PHTS. For patients with JPI, mTOR inhibitors can reduce enteropathy, intestinal bleeding, and colectomy rate [57 ▪ ]. A pilot study showed that sirolimus in patients with Cowden syndrome improved symptoms, skin and gastrointestinal lesions, cerebellar function, and decreased mTOR signaling [58].…”