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|Ref Type||Journal Article|
|Authors||Scott AJ, Arcaroli JJ, Bagby SM, Yahn R, Huber KM, Serkova NJ, Nguyen A, Kim J, Thorburn A, Vogel J, Quackenbush KS, Capasso A, Schreiber A, Blatchford P, Klauck PJ, Pitts TM, Eckhardt SG, Messersmith WA|
|Title||Cabozantinib Exhibits Potent Antitumor Activity in Colorectal Cancer Patient-Derived Tumor Xenograft Models via Autophagy and Signaling Mechanisms.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Antiangiogenic therapy used in treatment of metastatic colorectal cancer (mCRC) inevitably succumbs to treatment resistance. Upregulation of MET may play an essential role to acquired anti-VEGF resistance. We previously reported that cabozantinib (XL184), an inhibitor of receptor tyrosine kinases (RTK) including MET, AXL, and VEGFR2, had potent antitumor effects in mCRC patient-derived tumor explant models. In this study, we examined the mechanisms of cabozantinib sensitivity, using regorafenib as a control. The tumor growth inhibition index (TGII) was used to compare treatment effects of cabozantinib 30 mg/kg daily versus regorafenib 10 mg/kg daily for a maximum of 28 days in 10 PDX mouse models. In vivo angiogenesis and glucose uptake were assessed using dynamic contrast-enhanced (DCE)-MRI and [18F]-FDG-PET imaging, respectively. RNA-Seq, RTK assay, and immunoblotting analysis were used to evaluate gene pathway regulation in vivo and in vitro Analysis of TGII demonstrated significant antitumor effects with cabozantinib compared with regorafenib (average TGII 3.202 vs. 48.48, respectively; P = 0.007). Cabozantinib significantly reduced vascularity and glucose uptake compared with baseline. Gene pathway analysis showed that cabozantinib significantly decreased protein activity involved in glycolysis and upregulated proteins involved in autophagy compared with control, whereas regorafenib did not. The combination of two separate antiautophagy agents, SBI-0206965 and chloroquine, plus cabozantinib increased apoptosis in vitro Cabozantinib demonstrated significant antitumor activity, reduction in tumor vascularity, increased autophagy, and altered cell metabolism compared with regorafenib. Our findings support further evaluation of cabozantinib and combinational approaches targeting autophagy in colorectal cancer. Mol Cancer Ther; 17(10); 2112-22. ©2018 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||colorectal cancer||not applicable||Cabozantinib + SBI-0206965||Preclinical - Cell culture||Actionable||In a preclinical study, Cometriq (Cabometyx, cabozantinib) treatment in combination with SBI-0206965 enhanced apoptosis in colorectal cancer cells in culture (PMID: 30026382).||30026382|
|Unknown unknown||colorectal cancer||not applicable||Cabozantinib + Chloroquine||Preclinical - Cell culture||Actionable||In a preclinical study, Cometriq (Cabometyx, cabozantinib) treatment in combination with Chloroquine enhanced apoptosis in a colorectal cancer cell line in culture (PMID: 30026382).||30026382|
|Unknown unknown||colorectal cancer||no benefit||Regorafenib + SBI-0206965||Preclinical - Cell culture||Actionable||In a preclinical study, Stivarga (regorafenib) treatment in combination with SBI-0206965 did not enhance apoptosis over Stivarga (regorafenib alone in a colorectal cancer cell line in culture (PMID: 30026382).||30026382|
|Unknown unknown||colorectal cancer||not applicable||Cabozantinib||Preclinical - Pdx||Actionable||In a preclinical study, Cometriq (Cabometyx, cabozantinib) treatment inhibited activation of PI3K/AKT/MTOR signaling pathway, reduced phosphorylation of Met, Ret, and Axl, and induced autophagy in colorectal cancer cells in culture, and decreased tumor vascularity, reduced tumor growth, and induced regression in patient-derived xenograft (PDX) models (PMID: 30026382).||30026382|
|Unknown unknown||colorectal cancer||no benefit||Crizotinib + SBI-0206965||Preclinical - Cell culture||Actionable||In a preclinical study, Xalkori (crizotinib) treatment in combination with SBI-0206965 did not enhance apoptosis over Xalkori (crizotinib) alone in colorectal cancer cells in culture (PMID: 30026382).||30026382|