Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model

Secombe, Kate R.; Ball, Imogen A.; Shirren, Joseph; Wignall, Anthony; Finnie, John; Keefe, Dorothy; Avogadri-Connors, Francesca; Olek, Elizabeth; Martin, David; Moran, Susan; Bowen, Joanne M.

doi:10.1007/s00280-018-3756-8

Cited by 17 publications

(21 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bile acid malabsorption (BAM) has been widely implicated in the development of diarrhea, including diarrhea caused by the tyrosine kinase inhibitor neratinib (35) and in patients with GI-GvHD(36), increasing colonic secretion of water and electrolytes and the induction of propagated contractions (37). We identi ed changes in plasma bile acids and ileal gene expression following melphalan, indicative of BAM.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Host Microbiome Dictates Infection Risk after Chemotherapy Revealing New Avenues for Antibiotic Stewardship in Oncology

Wardill¹,

Mooij²,

Ferreira³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Mucosal barrier injury (MBI) is a recognized risk factor for blood stream infection (BSI) in people undergoing chemotherapy, permitting expansion and translocation of enteric pathobionts; a phenomenon now clinically referred to as MBI-associated laboratory-confirmed BSI. Although recognized to originate from endogenous gastrointestinal sources, MBI-associated BSI continue to be treated with antibiotics; a counterintuitive approach that may increase infection risk by depletion of the host microbiome. While this point has been argued in numerous clinical studies and opinion pieces, there are few data describing mechanistic strategies to decrease MBI-associated BSI, reflecting a lack of translationally robust preclinical models. Here, we report on a new translational model of MBI caused by the chemotherapeutic drug, melphalan. We aimed to identify candidate pathways to strengthen the mucosal barrier and prevent infection, prompting new antibiotic stewardship initiatives. Results: Melphalan caused dose-dependent, systemic toxicity characterized by severe neutropenia, self-limiting intestinal injury, inflammation and biphasic fever, all of which were clinically and molecularly consistent with the dynamics of melphalan conditioning. The fecal microbiome following melphalan was depleted in richness and commensal taxa, impairing colonization resistance and the microbial metabolome and prompting expansion of enteric pathogens. Breakdown of the intestinal barrier was initiated by melphalan and exacerbated by mucotoxic bile acids.Conclusions: MBI-associated BSI is simply a form of collateral damage resulting from breakdown of the gastrointestinal microenvironment and self-perpetuating injury. Efforts to intervene early in these sequelae are therefore of great clinical significance to restrict antibiotic use and mitigate their detrimental consequences on treatment outcomes and antibiotic resistance. Our data support interventions targeting the host microbiome and metabolome due to its ubiquitous control of inflammation, mucosal injury, bile acid transformation; all of which contribute to infection risk in cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Bile acid sequestrants (colesevelam) may offer bene ts in both the prevention of acute diarrhea (caused by motility/secretory mechanisms) as well as the prevention of MBI-LCBI. Coleveselam has already been deemed safe in oncology cohorts and has demonstrated clinical e cacy in treatment neratinib-induced diarrhea (35,44).…”

Section: Discussionmentioning

confidence: 99%

Host Microbiome Dictates Infection Risk after Chemotherapy Revealing New Avenues for Antibiotic Stewardship in Oncology

Wardill¹,

Mooij²,

Ferreira³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…This caught our interest because the dose-limiting sequela for neratinib is diarrhea, and MST3 and MST4 play important roles in regulating the integrity of the epithelial brush boarder in the gut. 182 , 183 Because we did not know what effects would be observed, we agnostically examined the activities of multiple MAP4K enzymes, as well as associated chaperone/docking proteins following neratinib exposure. As MAP4K/MAP3K enzymes are expressed in carcinoma cells which express high levels of ERBB family receptors as well as in blood cancer cells that express none or very low levels of that receptor family, we performed studies in both tumor cell types.…”

Section: Using Our Understanding Of Autophagy and Cell Signaling To Tmentioning

confidence: 99%

Cell Signaling and Translational Developmental Therapeutics

Dent

2022

Comprehensive Pharmacology

View full text Add to dashboard Cite

“…65 Due to the high levels of morbidity associated with neratinibinduced diarrhea, potential mechanisms that could contribute to the incidence were considered, and inflammatory, secretory, or bile acid absorption mechanisms were identified ( Figure 1 ). [66][67][68][69][70] Diarrhea Management Strategies . The CONTROL study was designed with mechanism-based anti-diarrheal interventions to reduce the incidence, severity, and duration of treatment-related diarrhea with neratinib in the extended adjuvant setting.…”

Section: Neratinib For Patients With Her2-positive Breast Cancermentioning

confidence: 99%

Optimal Strategies for Successful Initiation of Neratinib in Patients with HER2-Positive Breast Cancer

Jackisch

Barcenas

Bartsch

et al. 2021

Clinical Breast Cancer

View full text Add to dashboard Cite

Neratinib is an irreversible, pan-human epidermal growth factor inhibitor that has shown efficacy across human epidermal growth factor receptor 2 (HER2)-positive breast cancer settings. Neratinib is indicated for use as extended adjuvant therapy for HER2-positive early-stage breast cancer or, in combination with capecitabine, in the treatment of HER2positive metastatic breast cancer. The primary tolerability concern with neratinib is diarrhea, and severe diarrhea early in treatment can lead to a substantial proportion of patients discontinuing neratinib, which may lead to reduced or nonexistent efficacy. In order to establish a set of treatment recommendations for use of neratinib, on May 12, 2020, an expert panel of oncologists and gastroenterologists met virtually to discuss the role of neratinib in the treatment of patients with HER2-positive breast cancer. The panel reviewed the current data on neratinib, including efficacy across settings and diarrhea management strategies. Based on these data and their clinical experience, the panelists developed a set of recommendations to guide selection of patients for neratinib, implement weekly dose escalation at initiation of therapy, and prophylactically manage diarrhea.

show abstract

Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model

Cited by 17 publications

References 36 publications

Host Microbiome Dictates Infection Risk after Chemotherapy Revealing New Avenues for Antibiotic Stewardship in Oncology

Host Microbiome Dictates Infection Risk after Chemotherapy Revealing New Avenues for Antibiotic Stewardship in Oncology

Cell Signaling and Translational Developmental Therapeutics

Optimal Strategies for Successful Initiation of Neratinib in Patients with HER2-Positive Breast Cancer

Contact Info

Product

Resources

About