This study is a single-arm, open-label trial to clarify the safety and efficacy of the combined treatment of lenvatinib and VIC-1911 in patients with advanced liver cancer.

开始日期2024-08-01

申办/合作机构-

NCT05718882 / RecruitingN/AIIT

Safety and Efficacy of Lenvatinib Combined With VIC-1911 in the Treatment of Lenvatinib-unresponsive or Lenvatinib-resistant Hepatocellular Carcinoma

This is a prospective clinical study aiming to test the safety and efficacy of lenvatinib in combination with Aurora kinase A inhibitor VIC-1911 in participate with lenvatinib-unresponsive or lenvatinib-resistant hepatocellular carcinoma(HCC).

开始日期2023-07-01

申办/合作机构

上海交通大学医学院附属仁济医院

100 项与 Aurora A x NTRK 相关的临床结果

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100 项与 Aurora A x NTRK 相关的转化医学

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0 项与 Aurora A x NTRK 相关的专利（医药）

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项与 Aurora A x NTRK 相关的文献（医药）

2021-11-01·European Journal of Medicinal Chemistry1区 · 医学

Design and synthesis of novel orally selective and type II pan-TRK inhibitors to overcome mutations by property-driven optimization

1区 · 医学

Article

作者: Chen-Lung Huang ; Wen-Hsing Lin ; Mu-Chun Li ; Chiung-Tong Chen ; Yu-Chieh Su ; Pei-Chen Wang ; Teng-Kuang Yeh ; Chu-Min Fan ; Hsing-Pang Hsieh ; Ling Chang ; Pei-Yi Chen ; Chun-Hsien Chiu ; Ching-Ping Chen

Rare oncogenic NTRK gene fusions result in uncontrolled TRK signaling leading to various adult and pediatric solid tumors. Based on the architecture of our multi-targeted clinical candidate BPR1K871 (10), we designed and synthesized a series of quinazoline compounds as selective and orally bioavailable type II TRK inhibitors. Property-driven and lead optimization strategies informed by structure-activity relationship studies led to the identification of 39, which showed higher (about 15-fold) selectivity for TRKA over AURA and AURB, as well as potent cellular activity (IC₅₀ = 56.4 nM) against the KM12 human colorectal cancer cell line. 39 also displayed good AUC and oral bioavailability (F = 27%), excellent in vivo efficacy (TGI = 64%) in a KM12 xenograft model, and broad-spectrum anti-TRK mutant potency (IC₅₀ = 3.74-151.4 nM), especially in the double-mutant TRKA enzymatic assays. 39 is therefore proposed for further development as a next-generation, selective, and orally-administered type II TRK inhibitor.

2021-06-01·Investigational New Drugs3区 · 医学

TAS-119, a novel selective Aurora A and TRK inhibitor, exhibits antitumor efficacy in preclinical models with deregulated activation of the Myc, β-Catenin, and TRK pathways

3区 · 医学

Article

作者: Suzuki, Takamasa ; Sugimoto, Tetsuya ; Ito, Kimihiro ; Hirai, Hiroshi ; Masuko, Norio ; Fukushima, Hiroto ; Uto, Yoshihiro ; Mizuarai, Shinji ; Miura, Akihiro ; Hashimoto, Akihiro ; Sootome, Hiroshi ; Takahashi, Hidekazu ; Mitsuya, Morihiro ; Fujita, Naoya

Aurora kinase A, a mitotic kinase that is overexpressed in various cancers, is a promising cancer drug target. Here, we performed preclinical characterization of TAS-119, a novel, orally active, and highly selective inhibitor of Aurora A. TAS-119 showed strong inhibitory effect against Aurora A, with an IC₅₀ value of 1.04 nmol/L. The compound was highly selective for Aurora A compared with 301 other protein kinases, including Aurora kinase B. TAS-119 induced the inhibition of Aurora A and accumulation of mitotic cells in vitro and in vivo. It suppressed the growth of various cancer cell lines harboring MYC family amplification and CTNNB1 mutation in vitro. In a xenograft model of human lung cancer cells harboring MYC amplification and CTNNB1 mutation, TAS-119 showed a strong antitumor activity at well-tolerated doses. TAS-119 induced N-Myc degradation and inhibited downstream transcriptional targets in MYCN-amplified neuroblastoma cell lines. It also demonstrated inhibitory effect against tropomyosin receptor kinase (TRK)A, TRKB, and TRKC, with an IC₅₀ value of 1.46, 1.53, and 1.47 nmol/L, respectively. TAS-119 inhibited TRK-fusion protein activity and exhibited robust growth inhibition of tumor cells via a deregulated TRK pathway in vitro and in vivo. Our study indicates the potential of TAS-119 as an anticancer drug, especially for patients harboring MYC amplification, CTNNB1 mutation, and NTRK fusion.

2018-07-01·Minerva Urologica e Nefrologica3区 · 医学

Biological effect of neoadjuvant androgen-deprivation therapy assessed on specimens from radical prostatectomy: a systematic review

3区 · 医学

Review

作者: Grisanti, Salvatore ; Berruti, Alfredo ; Furlan, Maria ; Triggiani, Luca ; Veccia, Alessandro ; Palumbo, Carlotta ; Magrini, Stefano ; Simeone, Claudio ; Antonelli, Alessandro ; Zamboni, Stefania

INTRODUCTIONAndrogen-deprivation therapy (ADT) administered in neoadjuvant setting before radical prostatectomy (RP) represents an ideal in vivo human model to test the efficacy of hormonal treatments in prostate cancer (PCa). This review summarizes the findings from published studies specifically focused on the biological effects of ADT assessed on specimens from RP. The aim is to provide a base of knowledge that might be used to design future studies on neoadjuvant therapy for PCa.EVIDENCE ACQUISITIONA systematic review of the literature was performed according to the PRISMA statements. Search protocol identified published studies including a detailed analysis on specimen from RP to assess the biological effects of neoadjuvant ADT. In November 2017, Medline, Embase, and Scopus databases were searched using the terms "neoadjuvant" AND ("hormone therapy" OR "androgen deprivation therapy") AND "prostate cancer" in the "Title/Abstract" fields. Effects of ADT were classified according to four pathways - suppression of cellular proliferation, induction of apoptosis, alteration of immune response and onset of hormonal refractoriness - and relative markers of response were identified.EVIDENCE SYNTHESISFrom 1856 papers initially retrieved, 19 studies were finally selected and included into the present review. ADT was constituted by luteinizing hormone-releasing hormone (LH-RH) agonist alone in two, peripheral anti-androgen alone in one, both in 10, abiraterone acetate in one, unspecified in five. According to the above-mentioned four pathways, the following markers of response were identified: transcription of the oncogene TMPRSS2:ERG, translation of Aurora-A, coding of β1C integrin gene, translation of Ki-67, expression of nerve growth factors TrkA and p75NGFR, anti-angiogenic activity and micro-vessel density were involved into suppression of proliferation; mRNA transcription of bcl-2, expression of cleaved caspase-3 and translation of insulin growth factor binding protein 3, into induction of apoptosis; expression of IL-7 gene, programmed death-ligand 1, and increase of intra-prostatic T-cell population were related to alteration of immune response; finally, expression of heat shock protein 27 and de-differentiation of PCa to neuroendocrine cells, influenced the onset of hormonal refractoriness.CONCLUSIONSDespite a potential high interest, unexpectedly, only 19 heterogeneous studies investigated the effects of ADT through the analysis of specimens from RP. The present review summarizes the available evidences on this topic showing that ADT interferes on PCa at different levels that can be investigated by specific biological markers.