Chemoprevention in familial adenomatous polyposis: past, present and future

Abstract

Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome characterized by colorectal adenomas and a near 100% lifetime risk of colorectal cancer (CRC). Prophylactic colectomy, usually by age 40, is the gold-standard therapy to mitigate this risk. However, colectomy is associated with morbidity and fails to prevent extra-colonic disease manifestations, including gastric polyposis, duodenal polyposis and cancer, thyroid cancer, and desmoid disease. Substantial research has investigated chemoprevention medications in an aim to prevent disease progression, postponing the need for colectomy and temporizing the development of extracolonic disease. An ideal chemoprevention agent should have a biologically plausible mechanism of action, be safe and easily tolerated over a prolonged treatment period, and produce a durable and clinically meaningful effect. To date, no chemoprevention agent tested has fulfilled these criteria. New agents targeting novel pathways in FAP are needed. Substantial preclinical literature exists linking the molecular target of rapamycin (mTOR) pathway to FAP. A single case report of rapamycin, an mTOR inhibitor, used as chemoprevention in FAP patients exists, but no formal clinical studies have been conducted. Here, we review the prior literature on chemoprevention in FAP, discuss the rationale for rapamycin in FAP, and outline a proposed clinical trial testing rapamycin as a chemoprevention agent in patients with FAP.

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

“…In familial adenomatous polyposis (FAP), chemoprevention strategies using combined cyclo-oxygenase and epidermal growth factor inhibitors show promise in clinical trials, but they are not in routine clinical use ( 22–24 ). Case reports have described clinical benefit from mammalian target of rapamycin (mTOR) inhibitors in JPI ( 25 , 26 ), PHTS ( 27 ) and FAP ( 23 ), but their efficacy has not previously been demonstrated in controlled studies.…”

Pharmacogenetic Review: Germline Genetic Variants Possessing Increased Cancer Risk With Clinically Actionable Therapeutic Relationships

“…Known primarily as critical enzymes in the eicosanoid pathway, Cyclooxygenase-1 (COX-1) and COX-2 complete the two catalytic steps required for the conversion of arachidonic acid into prostaglandin H2. Aspirin covalently and irreversibly binds to COX-1 and COX-2, while other NSAIDs reversibly inhibit these enzymes preventing the downstream signal from inducing inflammation, fever, and prothrombotic events ( Kemp Bohan et al, 2020 ). Also found to contribute a role in cell cycle progression, increased COX-2 expression resulting from upregulation of the Wnt/B-catenin signaling pathway as a key contributing factor in the formation of gastrointestinal polyps.…”

The prognostic and clinicopathological roles of microsatellite instability, PD-L1 expression and tumor-infiltrating leukocytes in familial adenomatous polyposis

“…FAP is an autosomal dominant hereditary colorectal disease with poor prognosis, which is associated with chromosomal instability (CIN) caused by germline APC mutation [1,2]. Surgery is an effective therapy for FAP patients with colonic disorders, and regular chemotherapy has been shown to benefit FAP patients with postoperative pathological diagnosis of adenocarcinoma [5e7].…”