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

Abstract

Ultra-rare 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 than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. 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% confidence interval = 0.07-0.954, P = 0.042) and resulted in significant improvements in the 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. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase-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.

Graphical Abstract

Figure 1

Case identification and characterization of JPI patients. (A) Strategies used to identify JPI patients with PTEN and BMPR1A deletions. (B) Age of onset of gastrointestinal symptoms for each included case (black dots). Patients presenting at 12 months of age or younger (below gray dotted line) had more severe phenotype. (C) Percentage of included cases with selected phenotypic features of PHTS and gastrointestinal complications (error bars show 95% confidence interval).

Figure 2

The effect of mTOR inhibitor therapy on time to colectomy in patients with JPI resulting from PTEN and BMPR1A deletion. Survival analyses showing time to colectomy from first onset of gastrointestinal symptoms in patients who received mTOR inhibitor (‘mTOR inhibitor’) and those who did not (‘conventional treatment’). Ticks indicate end point of patients who did not have colectomy. Dots indicate point mTOR inhibitor initiated. P-values calculated by Mantel Cox Log rank analysis. (A) All patients included. (B) Limited to patients presenting at 1 year of age or under. (C) Limited to patients presenting over 1 year of age.

Figure 3

The effect of mTOR inhibitor therapy on hemoglobin and serum albumin concentration. (A, D) variation of serum albumin (A) or hemoglobin (D) concentration by time. Each participant initiated mTOR inhibitor therapy at t = 0. (B, E) A scatter plot comparing minimum serum albumin (B) and hemoglobin (E) concentration before and 3 months and onward on mTOR inhibitor treatment and comparing mean concentrations before and at three time points after initiation of mTOR inhibitor. Paired T-test performed to determine P-values. (C, F) Mean serum albumin (C) and hemoglobin (F) concentrations before and after initiating mTOR inhibitor therapy for each treated patient (error bars show standard deviation). Welch’s T-test performed to determine P-value. MTI = mTOR-inhibitor, # = patient number, ^*P < 0.05, ^**P < 0.01, ^***P < 0.001.

Figure 4

Endoscopic images showing decrease in polyp burden in patient with JPI treated with mTOR inhibitor. Endoscopic images of small intestine showing polyp progression from pre-sirolimus (A), 2 weeks of sirolimus (B) and 4 weeks of sirolimus (C).

Figure 5

Signaling of the PTEN–PI3K and the BMPR1A pathway. A diagram of the PI3K and BMP/SMAD signaling pathways. BMP binding to BMPR complex causes BMPR1A activation and SMAD phosphorylation, nuclear translocation and transcription of SMAD target genes. BMPR1A signaling intersects with Wnt signaling by blocking ß-catenin activation and preventing Wnt target gene expression. PTEN controls the levels of PIP₃, a key mediator of the PI3K–AKT–mTOR signaling pathway that regulates cell proliferation and survival. The complex intersection of signaling pathways at multiple levels of cell cycle control explains the synergistic defect caused by loss of BMPR1A and PTEN in chromosome 10 microdeletions. Therapeutic interference with this dysregulated signaling can be achieved via inhibition of several kinases that mediate the PI3K signaling pathway (including mTOR, AKT or PI3K inhibitors).