更新于：2024-11-01

MNK x VEGFR

更新于：2024-11-01

基本信息

关联

项与 MNK x VEGFR 相关的药物

JDB-153

靶点

MNK x VEGFR

作用机制

MNK抑制剂 [+1]

在研机构

上海嘉葆药银医药科技有限公司

原研机构

上海嘉葆药银医药科技有限公司

在研适应症

晚期恶性实体瘤 [+2]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 MNK x VEGFR 相关的临床试验

CTR20221468 / Not yet recruiting临床1期

评价JDB153单药治疗晚期实体瘤患者安全性、有效性及药代动力学特征的开放、单中心、I期临床研究

评估JDB153在晚期实体瘤（结直肠癌，胃癌等）患者中的安全性和耐受性；确定最大耐受剂量（MTD）、剂量限制性毒性（DLT），以及II期临床推荐剂量（RP2D）。

开始日期-

申办/合作机构

上海嘉葆药银医药科技有限公司

CTR20241038 / Not yet recruiting临床1期

评价JDB153片在中国健康成人受试者中的随机、两周期、双交叉食物影响研究

评估JDB153 在中国健康成人受试者中空腹或高脂餐后单次给药的PK特征；评估JDB153 在中国健康成人受试者中空腹或高脂餐后单次给药的安全性和耐受性。

开始日期-

申办/合作机构

上海嘉葆药银医药科技有限公司

100 项与 MNK x VEGFR 相关的临床结果

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100 项与 MNK x VEGFR 相关的转化医学

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0 项与 MNK x VEGFR 相关的专利（医药）

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项与 MNK x VEGFR 相关的文献（医药）

2021-04-01·Molecular Cancer Therapeutics2区 · 医学

ONC201 Shows Potent Anticancer Activity Against Medullary Thyroid Cancer via Transcriptional Inhibition of RET, VEGFR2, and IGFBP2

2区 · 医学

Article

作者: Gagel, Robert F. ; Bagheri-Yarmand, Rozita ; Martinez, Jade A. ; Sherman, Steven I. ; Williams, Michelle D. ; Shiny Jebaraj, Yaashmin ; Ye, Lei ; Tarapore, Rohinton S. ; Allen, Joshua E. ; Ma, Junsheng ; Dadu, Ramona

AbstractGain-of-function point mutations in the receptor tyrosine kinase RET, a driver oncogene in medullary thyroid carcinoma (MTC), prevent apoptosis through inhibition of ATF4, a critical transcriptional regulator of endoplasmic reticulum stress. However, the critical regulatory mechanisms driving RET-dependent oncogenesis remain elusive, and there is a clinical need to identify a transcriptional RET inhibitor. Here, we found that RET depletion decreased IGFBP2 and VEGFR2 mRNA and protein expression in MTC cells. IGFBP2 knockdown decreased cell survival and migration of MTC cells. In patients, IGFBP2 expression increased in metastatic MTC, and high IGFBP2 associated with poor overall survival. VEGFR2 protein levels were positively associated with RET expression in primary tumors, and VEGF-mediated increased cell viability was RET dependent. The small-molecule ONC201 treatment of MTC cells caused apoptotic cell death, decreased transcription of RET, VEGFR2, IGFBP2, increased mRNA levels of ATF4, and ATF4 target genes including DDIT3, BBC3, DUSP8, MKNK2, KLF9, LZTFL1, and SESN2. Moreover, IGFBP2 depletion increased ONC201-induced cell death. ONC201 inhibited tumor growth at a well-tolerated dose of 120 mg/kg/week administered by oral gavage and decreased MTC xenograft cell proliferation and angiogenesis. The protein levels of RET, IGFBP2, and VEGFR2 were decreased in ONC201-treated xenografts. Our study uncovered a novel ONC201 mechanism of action through regulation of RET and its targets, VEGFR2 and IGFBP2; this mechanism could be translated into the clinic and represent a promising strategy for the treatment of all patients with MTC, including those with TKI-refractory disease and other cancer with RET abnormalities.

2017-01-01·World Journal of Stem Cells3区 · 医学

Next-generation sequencing traces human induced pluripotent stem cell lines clonally generated from heterogeneous cancer tissue

3区 · 医学

Article

作者: Ishikawa, Tetsuya

AIMTo investigate genotype variation among induced pluripotent stem cell (iPSC) lines that were clonally generated from heterogeneous colon cancer tissues using next-generation sequencing.METHODSHuman iPSC lines were clonally established by selecting independent single colonies expanded from heterogeneous primary cells of S-shaped colon cancer tissues by retroviral gene transfer (OCT3/4, SOX2, and KLF4). The ten iPSC lines, their starting cancer tissues, and the matched adjacent non-cancerous tissues were analyzed using next-generation sequencing and bioinformatics analysis using the human reference genome hg19. Non-synonymous single-nucleotide variants (SNVs) (missense, nonsense, and read-through) were identified within the target region of 612 genes related to cancer and the human kinome. All SNVs were annotated using dbSNP135, CCDS, RefSeq, GENCODE, and 1000 Genomes. The SNVs of the iPSC lines were compared with the genotypes of the cancerous and non-cancerous tissues. The putative genotypes were validated using allelic depth and genotype quality. For final confirmation, mutated genotypes were manually curated using the Integrative Genomics Viewer.RESULTSIn eight of the ten iPSC lines, one or two non-synonymous SNVs in EIF2AK2, TTN, ULK4, TSSK1B, FLT4, STK19, STK31, TRRAP, WNK1, PLK1 or PIK3R5 were identified as novel SNVs and were not identical to the genotypes found in the cancer and non-cancerous tissues. This result suggests that the SNVs were de novo or pre-existing mutations that originated from minor populations, such as multifocal pre-cancer (stem) cells or pre-metastatic cancer cells from multiple, different clonal evolutions, present within the heterogeneous cancer tissue. The genotypes of all ten iPSC lines were different from the mutated ERBB2 and MKNK2 genotypes of the cancer tissues and were identical to those of the non-cancerous tissues and that found in the human reference genome hg19. Furthermore, two of the ten iPSC lines did not have any confirmed mutated genotypes, despite being derived from cancerous tissue. These results suggest that the traceability and preference of the starting single cells being derived from pre-cancer (stem) cells, stroma cells such as cancer-associated fibroblasts, and immune cells that co-existed in the tissues along with the mature cancer cells.CONCLUSIONThe genotypes of iPSC lines derived from heterogeneous cancer tissues can provide information on the type of starting cell that the iPSC line was generated from.