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Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors.

ABSTRACT: Molecular-targeted therapies have demonstrated disappointing results against most advanced solid cancers. This may largey be attributed to irrational drug use against unselected cancers. We investigated the efficacy of dual MEK-PI3K drug therapy against KRAS mutated mucin 2 (MUC2)-secreting LS174T cells and patient-derived ex vivo and in vivo models of KRAS mutated mucinous colon/appendix cancers. These tumors demonstrate unique phenotypic and genotypic features that likely predict sensitivity to this targeted co-therapy. Co-treatment with MEK inhibitor (trametinib) and PI3K inhibitor (pictilisib)-induced synergistic cytotoxicity and intrinsic mitochondrial-mediated apoptosis in LS174T cells and tumor explants in vitro. Dual drug therapy also induced endoplasmic reticulum stress (ERS)-associated proteins (GRP78/BiP, ATF4, and CHOP). However, CHOP knock-down assays demonstrated that mitochondrial-mediated apoptosis in LS174T cells was not ERS-dependent. Dual drug therapy also significantly decreased MUC2 expression, MUC2 post-translational modification (palmitoylation) and secretion in LS174T cells, suggesting a simultaneous cytotoxic and mucin suppressive mechanism of action. We also demonstrated effective mucinous tumor growth suppression in ex vivo epithelial organoid (colonoid) cultures and in in vivo intraperitoneal patient-derived xenograft models derived from mucinous colon/appendix cancer. These promising preclinical data support a role for dual MEK-PI3K inhibitor therapy in mucinous colon/appendix cancers. We postulate that mucinous KRAS mutated cancers are especially vulnerable to this co-treatment based on their unique phenotypic and genotypic characteristics.

SUBMITTER: Dilly A

PROVIDER: S-EPMC7050077 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors.

Dilly Ashokkumar A Honick Brendon D BD Lee Yong J YJ Bartlett David L DL Choudry Haroon A HA

Cancer medicine 20200120 5

Molecular-targeted therapies have demonstrated disappointing results against most advanced solid cancers. This may largey be attributed to irrational drug use against unselected cancers. We investigated the efficacy of dual MEK-PI3K drug therapy against KRAS mutated mucin 2 (MUC2)-secreting LS174T cells and patient-derived ex vivo and in vivo models of KRAS mutated mucinous colon/appendix cancers. These tumors demonstrate unique phenotypic and genotypic features that likely predict sensitivity t ...[more]

PMID: 31958897

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Project description:Contemporary treatment of node-positive (N+) colon cancer consists of adjuvant chemotherapy; however, randomized data supporting this practice were derived from lesions T2 or greater. Minimal data exist regarding the use and need for adjuvant chemotherapy in T1N+ disease.The aim of this study was to determine treatment trends and the effects of adjuvant chemotherapy on T1N+ colon cancers by using the National Cancer Database.This was a retrospective study. Baseline demographics, tumor, and cancer treatment characteristics were compared. Groups were matched on the propensity to receive chemotherapy. Adjusted long-term survival stratified by chemotherapy use was compared by using the Kaplan-Meier method with the log-rank test. Predictors of not receiving chemotherapy were identified by using a multivariable logistic regression model.Data were collected from the National Cancer Database, which collects cancer data from over 1500 cancer centers.We identified patients from 1998 to 2006 with T1N+ disease, excluding those with metastatic disease or previous cancer. Patients were stratified based on whether or not they received chemotherapy.The primary outcome measure of this study was long-term survival.Three thousand one hundred thirty-seven patients had T1N+ disease; 70.6% (n = 2216) received chemotherapy, and utilization significantly increased from 1998 to 2011 (p < 0.001). Unadjusted analysis revealed that patients treated with chemotherapy were statistically younger and healthier, and had shorter postoperative lengths of stay (all p < 0.001). Unadjusted 5-year survival was higher in patients receiving chemotherapy (87.9% vs 63.0% in patients with no chemotherapy; p < 0.001) and this persisted after propensity matching with (83.4% and 63.0% in patients with or without chemotherapy; p < 0.001). Only age (OR, 0.29; p < 0.001) predicted not receiving chemotherapy.Limitations include potential selection bias as well as the inability to compare disease-free survival/recurrence.Adjuvant chemotherapy appears to significantly improve long-term survival in patients receiving chemotherapy in T1N+ disease. Thus, the use of chemotherapy in T1N+ disease is justified and provides a highly significant survival benefit.

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Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors.

Publications

Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors.

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