國家衛生研究院 NHRI:Item 3990099045/12218

NHRI > Institute of Biotechnology and Pharmaceutical Research > Shau-Hua Ueng > Conference Papers/Meeting Abstract > Item 3990099045/12218

Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/12218

Title:	Use of integrated genomic analyses in patient-derived tumor model to discover new clinical indications for the multikinase inhibitor drug candidate, DBPR216
Authors:	Kuo, CC;Jiaang, WT;Ou, JJ;Chen, CT;Hsu, SC;Shih, C;Lin, LM;Sun, M;Wang, YH;Huang, ZT;Chang, JY;Ueng, SH
Contributors:	Institute of Biotechnology and Pharmaceutical Research;National Institute of Infectious Diseases and Vaccinology
Abstract:	Developing realistic preclinical models using clinical samples that reflect complex tumor biology is critical to advancing cancer research. Patient-derived preclinical tumor models are the optimal tool for understanding drug action patterns and resistance mechanisms. In order to improve the capability of drug R&D in our institute (NHRI-IBPR), we have generated several patient-derived xenograft (PDX) models and characterized the genomic signature and responsiveness to standard-of-care (SOC) therapy. DBPR216, an orally bioavailable multikinase inhibitor, showed potent effect for treatment of gastrointestinal stromal tumors (GISTs) and acute myeloid leukemia (AML) through targeting of c-KIT and FLT-3, respectively. In order to further discover other indications of DBPR216 for clinical application, we investigated the anti-tumor effect of DBPR216 in several in-house PDX models. Among them, we found that DBPR216 was effectively to suppress PDX tumor growth in the immuno-deficient mice in two colorectal adenocarcinoma PDX models, C008 and C015. These PDX models showed similar genomic features with original tumor samples from patients when test using targeted sequencing of cancer related genes. To further identify if DBPR216 is superior to other kinase inhibitors and SOC therapy, we used in vitro PDX cell proliferation assay to quickly examine the anti-tumor effect of DBPR216 compared to a panel of therapeutic drugs. The result demonstrated that DBPR216 appeared to be superior in potency to kinase inhibitors (Regorafenib, Afatinib, Sunitinib, and Imatinib) and SOC therapy (Irinotecan, 5-FU, and Oxaliplatin). Combining the kinase profiling of DBPR216 and mutational analysis of C008 and C015 PDX models, we proposed that DDR2, FLT1, PDGFRα, PDGFRβ, RET, and SRC may be the potential targets of DBPR216 in these PDX models, and need further elucidation. Taken together, we found that DBPR216 exhibits potent anticancer effect against colorectal cancer and may bring the better opportunity than Regorafenib, a therapeutic agent for metastatic colorectal cancer in clinical. DBPR216 is now under preclinical development for further IND submission.
Date:	2019-07
Relation:	Cancer Research. 2019 Jul;79(13, Suppl.):Abstract number 4626.
Link to:	http://dx.doi.org/10.1158/1538-7445.Am2019-4626
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0008-5472&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000488279404499
Appears in Collections:	[Shau-Hua Ueng] Conference Papers/Meeting Abstract [Chuan Shih(2014-2017)] Conference Papers/Meeting Abstract [Shu-Ching Hsu] Conference Papers/Meeting Abstract [Weir-Torn Jiaang] Conference Papers/Meeting Abstract [Ching-Chuan Kuo] Conference Papers/Meeting Abstract [Chiung-Tong Chen] Conference Papers/Meeting Abstract

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