Clinical Development of c-MET Inhibition in Hepatocellular Carcinoma.
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ABSTRACT:
SUBMITTER: Lee JJX
PROVIDER: S-EPMC5548260 | biostudies-literature | 2015 Oct
REPOSITORIES: biostudies-literature
Publications
Clinical Development of c-MET Inhibition in Hepatocellular Carcinoma.
Lee Joycelyn J X JJX Chan Jack J JJ Choo Su Pin SP
Diseases (Basel, Switzerland) 20151028 4
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death. In patients with advanced or unresectable HCC, there are few treatment options. Conventional chemotherapy has limited benefits. Sorafenib, a multi-kinase inhibitor, improves survival, but options for patients intolerant of or progressing on sorafenib are limited. There has been much interest in recent years in molecular therapeutic targets and drug development for HCC. One of the more promising molecular targets in HCC ...[more]
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Project description:Backgroundc-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF), plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with activated HGF/c-Met signaling have a significantly worse prognosis. Targeted therapies using c-Met tyrosine kinase inhibitors are currently in clinical trials for HCC, although receptor tyrosine kinase inhibition in other cancers has demonstrated early success. Unfortunately, therapeutic effect is frequently not durable due to acquired resistance.MethodsWe utilized the human MHCC97-H c-Met positive (c-Met+) HCC cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knockdown (MHCC97-H c-Met KD cells) were generated using a c-Met shRNA vector with puromycin selection and stably transfected scrambled shRNA as a control. Gene expression profiling was conducted, and protein expression was analyzed to characterize MHCC97-H cells after blockade of the c-Met oncogene. A high-throughput siRNA screen was performed to find putative compensatory survival proteins, which could drive HCC growth in the absence of c-Met. Findings from this screen were validated through subsequent analyses.ResultsWe have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. MHCC97-H c-Met KD cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling and siRNA screening against 873 kinases and phosphatases, we identified ErbB3 and TGF-? as compensatory survival factors that are upregulated after c-Met inhibition. Suppressing these factors in c-Met KD MHCC97-H cells suppresses tumor growth in vitro. In addition, we found that the PI3K/Akt signaling pathway serves as a negative feedback signal responsible for the ErbB3 upregulation after c-Met inhibition. Furthermore, in vitro studies demonstrate that combination therapy with PHA665752 and Gefitinib (an EGFR inhibitor) significantly reduced cell viability and increased apoptosis compared with either PHA665752 or Gefitinib treatment alone.Conclusionc-Met inhibition monotherapy is not sufficient to eliminate c-Met+ HCC tumor growth. Inhibition of both c-Met and EGFR oncogenic pathways provides superior suppression of HCC tumor growth. Thus, combination of c-Met and EGFR inhibition may represent a superior therapeutic regimen for c-Met+ HCC.
| S-EPMC4441360 | biostudies-literature
Project description:There is no available effective systemic treatment for patients with advanced hepatocellular carcinoma (HCC) who are intolerant of sorafenib or who have disease that has progressed on sorafenib. In Phase I and II studies, tivantinib (ARQ 197), an oral inhibitor of MET, demonstrated promising antitumor activity in patients with HCC, both as monotherapy and in combination with sorafenib. A randomized Phase II trial in second-line HCC showed improved overall survival (hazard ratio: 0.38; p = 0.01) in patients with MET-high tumors, as demonstrated by immunohistochemistry, treated with tivantinib versus placebo. Here we present the treatment rationale and study design of the METIV-HCC Phase III study. This randomized, double-blind study will investigate tivantinib monotherapy as second-line treatment in patients with advanced, pretreated, MET-high HCC. Approximately 303 patients will be randomized 2:1 to tivantinib or placebo for the purpose of analyzing the primary end point. Tivantinib will be dosed at 120 mg twice daily, and treatment will continue until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. The primary end point of this study is overall survival, while secondary end points include progression-free survival and safety. All patients will be tested for biomarkers. If the primary objective is achieved, this study will provide the first effective therapy for a biologically selected patient population in HCC.
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Project description:Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. Activation of the AKT/mTOR cascade is one of the most frequent events along hepatocarcinogenesis. mTOR is a serine/threonine kinase and presents in two distinct complexes: mTORC1 and mTORC2. While mTORC1 has been extensively studied in HCC, the functional contribution of mTORC2 during hepatocarcinogenesis has not been well characterized, especially in vivo. Pten expression is one of the major mechanisms leading to the aberrant activation of the AKT/mTOR signaling. Here, we show that concomitant downregulation of Pten and upregulation of c-Met occurs in a subset of human HCC, mainly characterized by poor prognosis. Using CRISPR-based gene editing in combination with hydrodynamic injection, Pten was deleted in a subset of mouse hepatocytes (sgPten). We found that loss of Pten synergizes with overexpression of c-Met to promote HCC development in mice (sgPten/c-Met). At the molecular level, sgPten/c-Met liver tumor tissues display increased AKT and mTOR signaling. Using Rictor conditional knockout mice, we demonstrate that sgPten/c-Met-driven HCC development strictly depends on an intact mTORC2 complex. Our findings therefore support the critical role of mTORC2 in hepatocarcinogenesis. sgPten/c-Met mouse model represents a novel valuable system that can be used for the development of targeted therapy against this deadly malignancy.
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Project description:Fibrolamellar hepatocellular carcinoma(FLC) is a rare form of cancer that affects primarily adolescentsand young adults. FLC tumors are typically associated with an intrachromosomal deletion resulting in expression of a fusion protein between the chaperone DNAJ1B and the protein kinase PKA. FLC ischallenging to study because of its rarity and limited pre-clinical models. Here, we developed a novel transgenic mouse model of FLC. In this model, DNAJ1B-PKA expression in the liver of mouse embryos results in perinatal lethalityassociated with liver developmental defects, while DNAJ1B-PKA expression in the liver of adult mice initiates tumors resembling FLC at low penetrance. Some of these tumors can be serially propagated in 3D cultures and in allografts, including in syngeneic hosts. One such model shows growth inhibition upon treatment with the CDK4/6 inhibitor palbociclib. New pre-clinical models of FLC will provide novel insights into the biology of this rare cancerand may help identify novel therapeutic strategies.
2024-06-03 | GSE249325 | GEO
Project description:Rationale: Hyperactivation of HGF/MET signaling pathway is a critical driver in liver tumorigenesis. Cytochrome P450 1A2 (CYP1A2) was significantly down-regulated in hepatocellular carcinoma (HCC). However, little is explored about its tumor suppressive role in HCC. In this study, we examined the functional mechanisms and clinical implication of CYP1A2 in HCC. Methods: The clinical impact of CYP1A2 was evaluated in HCC patients in Hong Kong cohort. The biological functions of CYP1A2 were investigated in vitro and in vivo. A series of biochemical experiments including Western blot assay, immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, and Co-immunoprecipitation assay were conducted. Results: CYP1A2 expression was prominently silenced in HCC tumor tissues and the high expression of CYP1A2 was significantly correlated with lower AFP level, less vascular invasion, and better tumor-free survival in local cohort of HCC patients. The overexpression of CYP1A2 inhibited HCC cell viability and clonogenicity, reduced cell migration and invasion abilities in vitro, and suppressed tumorigenicity in vivo, whereas CYP1A2 knockdown exhibited the opposite effects. CYP1A2 significantly hindered HGF/MET signaling and Matrix metalloproteinases (MMPs) expression in HCC cells. Mechanically, CYP1A2 decreased HGF level and diminished HIF-1α expression, both of which are recognized as key regulators of MET activation. As the transcriptional activator of MET, HIF-1α was identified as a binding partner of CYP1A2. Direct binding of CYP1A2 with HIF-1α induced ubiquitin-mediated degradation of HIF-1α, inhibiting HIF-1α-mediated transcriptions. Conclusions: In conclusion, our results have identified CYP1A2 as a novel antagonist of HGF/MET signaling, and CYP1A2 may serve as an independent new biomarker for the prognosis of HCC patients.
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Project description:BackgroundClear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer. Small molecule VEGFR inhibitors are widely used but are not curative and various resistance mechanisms such as activation of the MET pathway have been described. Dual MET/VEGFR2 inhibitors have recently shown clinical benefit but limited preclinical data evaluates their effects in ccRCC.MethodsAn interrogation of the Cancer Genome Atlas (TCGA) dataset was performed to evaluate oncogenic alterations in the MET/VEGFR2 pathway. We evaluated the in vitro effects of Cabozantinib, a dual MET/VEGFR2 inhibitor, using a panel of ccRCC cell lines. Drug effects of cell viability and proliferation, migration, cell scatter, anchorage independent growth, and downstream MET/VEGFR2 signaling pathways were assessed.ResultsTwelve percent of TCGA cases had possible MET/HGF oncogenic alterations with co-occurrence noted (p<0.001). MET/HGF altered cases had worse overall survival (p=0.044). Cabozantinib was a potent inhibitor of MET and VEGFR2 in vitro in our cell line panel. PI3K, MAPK and mTOR pathways were also suppressed by cabozantinib, however the effects on cell viability in vitro were modest. At nanomolar concentrations of cabozantinib, HGF-stimulated migration, invasion, cellular scattering and soft agar colony formation were inhibited.ConclusionsWe provide further preclinical rationale for dual MET/VEGFR2 inhibition in ccRCC. While the MET pathway is implicated in VEGFR resistance, dual inhibitors may have direct anti-tumor effects in a patient subset with evidence of MET pathway involvement. Cabozantinib is a potent dual MET/VEGFR2 inhibitor, significantly inhibits cell migration and invasion in vitro and likely has anti-angiogenic effects similar to other VEGFR tyrosine kinase inhibitors. Future work involving in vivo models will be useful to better define mechanisms of potential anti-tumor activity.
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Project description:The current standard treatment option for advanced hepatocellular carcinoma (HCC) is sorafenib, but its clinical benefit is modest. In spite of many attempts, few drugs can provide any significant improvement of survival as the first- or second-line therapy of choice in phase III randomized controlled trials. Recently, the subgroup analysis of a phase II randomized controlled trial has shown that tivantinib, a selective MET inhibitor, can significantly improve the overall survival in patients with MET-positive advanced HCC after the failure or intolerance of a prior systemic therapy. These findings enlighten the role of MET inhibitors in the treatment of advanced HCC. In this paper, we review all ongoing and completed clinical trials regarding this topic. As for the first-line therapy of advanced HCC, INC280 and foretinib are being evaluated in 2 phase II single-arm trials; and MSC2156119J and golvatinib plus sorafenib are being compared with sorafenib alone in 2 phase II randomized controlled trials. As for the second-line therapy of advanced HCC, tivantinib and cabozantinib are being compared with placebo in 2 phase III randomized controlled trials.
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Project description:Hepatocellular carcinoma (HCC) is a major malignancy of cancer-related mortality worldwide. Metastasis-associated in colon cancer-1 (MACC1) was suggested as a marker for vascular invasive HCC. This study investigated the MACC1 single-nucleotide polymorphisms (SNPs) to evaluate HCC susceptibility and clinicopathological characteristics. In this study, real-time polymerase chain reaction was applied to analyze five SNPs of MACC1 rs1990172, rs975263, rs3095007, rs4721888, and rs3735615 in 378 patients with HCC and 1199 cancer-free controls. The results showed that in 151 HCC patients among smokers who carried MACC1 rs1990172 "CA + AA" variants had a lower risk of developing a large tumor (odds ratio [OR] = 0.375, p = 0.026), more advanced clinical stage ([OR] = 0.390, p=0.032), and vascular invasion ([OR] = 0.198, p = 0.034). In 137 HCC patients among drinkers who carried MACC1 rs4721888 "GC + CC" variants had a higher risk to develop vascular invasion ([OR] = 3.780, p = 0.009). Further analyses revealed a statistical significance of aberrant AST/ALT ratio in HCC patients with MACC1 rs975263 "AG+GG" variants before adjustment of age and alcohol drinking. In conclusion, our results suggested that the MACC1 SNPs rs1990172, rs4721888, and rs975263 are involved in HCC progression and clinical characteristics. MACC1 polymorphisms may serve as a marker or a predictor to evaluate HCC progression and prognosis.
| S-EPMC6995387 | biostudies-literature
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