c-Met Expression Research Articles

22P Hepatocyte growth factor (HGF) and c-Met expression in metastatic endometrial cancer

HGF/c-Met is one of the signaling pathways that determine the invasiveness and metastatic potential of various cancers, however, its significance for the progression of endometrial cancer (EC) remains not entirely clear. The aim of this study was to investigate HGF and c-Met expression in tumours of EC patients in relation to the presence of metastasis.

Immunohistochemical expression of HGF and cMET in meningiomas

Abstract Background Meningiomas are the most common intracranial neoplasm together with gliomas; but unlike gliomas they are still graded according to their histopathological picture. Many growth factors and tyrosine kinase receptors have been studied in meningiomas in an attempt for prognostic stratification of patients, also to find a suitable targeted therapy for meningiomas. Aim of the study To correlate the immunohistochemical expression of HGF and cMET with the different WHO grades of meningioma in addition to brain invasion. Materials and methods This study included 60 cases of meningiomas (WHO grade I, n = 30 and WHO grade II & III, n = 30), brain invasion was present in 14 cases. Results HGF, cMET & HGF/cMET co-expression were positive in 60.0%, 65.0% and 58.3% respectively of the cases; WHO grade I meningioma showed positivity in 30.0%, 33.3% and 30.0% of the cases respectively in contrast with 90.0%, 96.7% and 86.7% of the cases of WHO grades II & III meningiomas respectively. The relation was statistically highly significant (p- value: <0.001). As regards cases with brain invasion the expression of HGF, cMET and HGF/cMET co-expression was found in 92.9%, 100.0% and 92.9% respectively in comparison with 50.0%, 54.3% and 47.8% in the rest of the cases of meningiomas respectively; the relation was statistically significant (p- value: 0.004). Conclusion The results suggest that HGF/cMET pathway may play a role in the progression of meningiomas from WHO grade I to higher grades II & III.

OA15.04 Telisotuzumab Vedotin (teliso-v) Monotherapy in Patients With Previously Treated c-Met+ Advanced Non-Small Cell Lung Cancer

Teliso-V is an anti-c-Met antibody conjugated with a tubulin inhibitor MMAE. The aim of this phase 2 trial (NCT03539536) is to explore safety and efficacy of teliso-V in cohorts (based on histopathology and EGFR mutation) and subgroups (based on c-Met expression) of patients with c-Met+ advanced NSCLC (stage 1), followed by expansion into an appropriately selected population for further evaluation of safety and efficacy (stage 2). Abstract previously submitted to, but not yet presented at AACR 2021.

P47.03 Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met+ Advanced Non-Small Cell Lung Cancer: Stage 2

Telisotuzumab vedotin (Teliso-V) is an anti-c-Met antibody conjugated with a tubulin inhibitor, monomethylauristatin E. The c-Met receptor tyrosine kinase is the cell surface receptor for hepatocyte growth factor (HGF) encoded for by the MET proto-oncogene. c-Met overexpression occurs in various solid tumors, including non-small cell lung cancer (NSCLC), and the aberrant activation of the c-Met/HGF axis contributes to tumor progression, angiogenesis, invasive growth, metastasis, and resistance to therapies. Following encouraging evidence of anti-tumor activity in a Phase 1 study (Strickler et al. J Clin Oncol 2018;36:3298–3306), a Phase 2 study was initiated to explore the safety and efficacy of Teliso-V monotherapy in 3 cohorts (based on histopathology and epidermal growth factor receptor [EGFR] mutation) and 5 subgroups (based on c-Met expression) of patients with c-Met+ advanced NSCLC (study Stage 1), followed by expansion into an appropriately selected population based on study Stage 1 results for further evaluation of safety and efficacy (study Stage 2). This Phase 2, non-randomized, single-arm, adaptive study (NCT03539536) is enrolling patients aged ≥18 years with Eastern Cooperative Oncology Group performance status ≤1 and locally advanced or metastatic c-Met+ NSCLC who have received 1–2 prior lines of therapy (including systemic chemotherapy, immunotherapy, and targeted therapy, if eligible). Based on data from study Stage 1 (Camidge et al. AACR 2021), the cohort of patients with non-squamous EGFR wild type c-Met+ NSCLC met prespecified criteria to transition to the study Stage 2 single-arm expansion cohort. Study Stage 2 enrollment commenced in February 2021 and is ongoing; up to approximately 160 patients will be enrolled in study Stage 2. c-Met status is determined centrally by immunohistochemistry. The primary endpoint is overall response rate per independent central review (based on Response Evaluation Criteria in Solid Tumors version 1.1). Secondary endpoints are duration of response, disease control rate, progression-free survival, and overall survival. Quality of life will be evaluated as an exploratory efficacy endpoint and safety and tolerability will be assessed. Pharmacokinetic and biomarker samples will also be collected for analysis. Teliso-V is administered as a 30±10 min intravenous infusion at a dose of 1.9 mg/kg every 2 weeks until disease progression or study discontinuation criteria are met. ▪▪▪ ▪▪▪

Long Noncoding RNA LINC00839 Promotes the Malignant Progression of Osteosarcoma by Competitively Binding to MicroRNA-454-3p and Consequently Increasing c-Met Expression [Retraction

[This retracts the article DOI: 10.2147/CMAR.S269774.].

Upregulation of Linc00284 Promotes Lung Cancer Progression by Regulating the miR-205-3p/c-Met Axis.

Lung cancer (LC) is a malignant tumor with the highest incidence and mortality rates worldwide. Linc00284, a long non-coding RNA, is a newly discovered regulator of LC. This study aimed to explore the role of Linc00284 in LC progression. Gene expression levels were detected by RT-qPCR and/or western blot analysis. Cell migratory and invasive capabilities were measured by wound healing and transwell assays. Subcutaneous xenograft models were constructed to examine tumor growth of LC cells. Data showed that Linc00284 was significantly upregulated in LC tissues compared to adjacent normal lung tissues and predicted poor prognosis in patients with LC. In vitro, Linc00284 was highly expressed in LC cells and was mainly localized in the cytoplasm. Mechanistically, Linc00284 directly bound to miR-205-3p, leading to the upregulation of c-Met expression. A significant negative correlation was observed between Linc00284 and miR-205-3p expression levels, and the Linc00284 level was positively correlated with the c-Met expression. Linc00284/miR-205-3p/c-Met regulatory axis promotes LC cell proliferation, migration, and invasion. Furthermore, the in vivo results indicated that Linc00284 knockdown markedly suppressed tumor growth. Taken together, these data suggest that Linc00284 facilitates LC progression by targeting the miR-205-3p/c-Met axis, which may be a potential target for LC treatment.

MP40-05 c-MET RECEPTOR-TARGETED FLUORESCENCE ON THE ROAD TO IMAGE-GUIDED SURGERY IN PENILE SQUAMOUS CELL CARCINOMA PATIENTS

You have accessJournal of UrologyPenile & Testicular Cancer I (MP40)1 Sep 2021MP40-05 c-MET RECEPTOR-TARGETED FLUORESCENCE ON THE ROAD TO IMAGE-GUIDED SURGERY IN PENILE SQUAMOUS CELL CARCINOMA PATIENTS Hielke de Vries, Elise Bekers, Matthias van Oosterom, Baris Karakullukcu, Henk van der Poel, Fijs van Leeuwen, Tessa Buckle, and Oscar Brouwer Hielke de VriesHielke de Vries More articles by this author , Elise BekersElise Bekers More articles by this author , Matthias van OosteromMatthias van Oosterom More articles by this author , Baris KarakullukcuBaris Karakullukcu More articles by this author , Henk van der PoelHenk van der Poel More articles by this author , Fijs van LeeuwenFijs van Leeuwen More articles by this author , Tessa BuckleTessa Buckle More articles by this author , and Oscar BrouwerOscar Brouwer More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002055.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In penile squamous cell carcinoma (pSCC), primary surgery aims to obtain oncologically safe margins while minimizing mutilation. Surgical guidance provided by receptor-specific tracers could potentially improve margin detection and reduce unnecessary excision of healthy tissue. Here, we present the first results of a prospective feasibility study for real-time intraoperative visualization of pSCC using a fluorescent c-MET receptor targeting tracer (EMI-137). METHODS: EMI-137 tracer performance was initially assessed ex vivo (N=10) via incubation of freshly excised pSCC in a solution containing EMI-137 (500 nM). The in vivo potential of c-MET targeting and intraoperative tumour visualization was assessed after intravenous administration of EMI-137 in five pSCC patients scheduled for surgical resection using a Cy5 fluorescence camera. Fluorescence imaging results were related to standard pathological tumour evaluation and c-MET immunohistochemistry. Three of the five in vivo patients also underwent a sentinel node resection after local administration of the hybrid tracer ICG-99mTc-nanocolloid, which could be imaged using a near-infrared fluorescence camera. RESULTS: No tracer-related adverse events were encountered. Both ex vivo and in vivo, EMI-137 enabled c-MET based tumour visualization in all patients. Histopathological analyses showed that all pSCC's expressed c-MET, with expression levels of ≥70% in 14/15 patients. Moreover, the highest c-MET expression levels were seen on the outside rim of the tumours, and a visual correlation was found between c-MET expression and fluorescence signal intensity. No complications were encountered when combining primary tumour targeting with lymphatic mapping. As such, simultaneous use of Cy5 and ICG in the same patient proved to be feasible. CONCLUSIONS: Fluorescence imaging of c-MET receptor-expressing pSCC tumours after intravenous injection of EMI-137 was shown to be feasible and can be combined with fluorescence-based lymphatic mapping. This combination is unique and paves the way towards further development of this surgical guidance approach. Source of Funding: This research was financially supported by a Netherlands Organization for Scientific Research TTW-VICI grant (Grant No. TTW 16141). EMI-137 was provided by Edinburgh Molecular Imaging (EMI), KARL STORZ provided the Cy5 fluorescence camera, and the FIS-00 near-infrared fluorescence camera was made available by Hamamatsu photonics © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e716-e716 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hielke de Vries More articles by this author Elise Bekers More articles by this author Matthias van Oosterom More articles by this author Baris Karakullukcu More articles by this author Henk van der Poel More articles by this author Fijs van Leeuwen More articles by this author Tessa Buckle More articles by this author Oscar Brouwer More articles by this author Expand All Advertisement Loading ...

The protective effects of hepatocyte growth factor on the intestinal mucosal atrophy induced by total parenteral nutrition in a rat model

PurposeTotal parental nutrition (TPN) causes gastrointestinal mucosal atrophy. The present study investigated the effects of hepatocyte growth factor (HGF) on the intestinal mucosal atrophy induced by TPN.MethodsRats underwent jugular vein catheterization and were divided into four groups: oral feeding (OF), TPN alone (TPN), TPN plus low-dose HGF (0.3 mg/kg/day; TPNLH), and TPN plus high-dose HGF (1.0 mg/kg/day; TPNHH). On day 7, rats were euthanized, and the small intestine was harvested and evaluated histologically. The expression of c-MET, a receptor of HGF, and nutrition transporter protein were evaluated using quantitative polymerase chain reaction.ResultsThe jejunal villus height (VH) and absorptive mucosal surface area in the TPNHH group were significantly higher than in the TPN group (p < 0.05). The VH in the ileum showed the same trend only in the TPNHH group, albeit without statistical significance. The crypt cell proliferation rate (CCPR) of the jejunum in both HGF-treated groups was significantly higher than in the TPN group (p < 0.01). The expression of c-MET and transporter protein in all TPN-treated groups was decreased compared with that in the OF group.ConclusionHGF attenuated TPN-associated intestinal mucosal atrophy by increasing the villus height, which was associated with an increase in CCPR.

PrPC Regulates the Cancer Stem Cell Properties via Interaction With c-Met in Colorectal Cancer Cells.

Studies have reported that the expression of c-Met and PrPC improves tumor progression. However, not much is known about their relationship. We hypothesized that c-Met and PrPC interact with each other, and enhance cancer stem cell (CSC) characteristics. Magnetic activated cell sorting was used to examine the interaction between c-Met and PrPC The effects of the interaction on downstream signals, stem cell marker expression, and sphere formation of colorectal cancer (CRC) cells were investigated. We demonstrated the increased expression and binding levels of c-Met and PrPC in CRC cells compared to normal colon epithelial cells. We revealed that the c-Met and PrPC interaction induced the ERK activation and Oct4 upregulation. The inhibition of c-Met by crizotinib reduced ERK activation and Oct4 expression and suppressed CSC properties. c-Met and PrPC interact with each other, and targeting c-Met using crizotinib could be a powerful strategy for CRC therapy.

P4-13 cMET promotes metastasis and epithelial-mesenchymal transition in colorectal carcinoma via repressing RKIP

Colorectal cancer (CRC) ranks among the most frequent malignancies globally and is associated with high metastasis incidence. Today, it is becoming more prevalent among Asian populations, especially in the Chinese. There is increasing evidence that c-mesenchymal-epithelial transition factor (cMET) plays an important role in malignant progression, and its overexpression is closely linked with poor survival and enhanced resistance to drug therapy, hence abnormal cMET is viewed as a signature event in CRC. As a metastasis suppressor, loss of raf kinase inhibitory protein (RKIP) has been reported in many of cancer types. Both of them may serve to regulate CRC initiation and progression. It is therefore necessary to address the interaction between cMET/ERK signal axis and RKIP. In this study, expression of cMET and RKIP in CRC tissues and cell lines were determined, and their crosstalk and potential biological effects were explored using. Immunofluorescence staining and Chromatin immunoprecipitation. Our results showed cMET was inversely correlated with RKIP. Both cMET upregulation and RKIP downregulation implied poor clinical outcomes. Moreover, the MAPK/ERK signal pathway was involved in the regulation of cMET and RKIP. Overexpression of cMET promoted epithelial mesenchymal transition (EMT), invasion, migration and chemoresistance of tumor cells, whereas the impact could be efficiently impeded by increased RKIP. Notably, shRNA-mediated cMET knockdown dramatically suppressed cell proliferation, although no influence of RKIP on cell growth was observed in CRC. Altogether, cMET overexpression may contribute to tumor progression by inhibiting anti-oncogene RKIP, which provides preclinical justification for targeting RKIP to treat cMET-induced metastasis in CRC.

Abstract 926: BYON3521, a novel effective and safe c-Met targeting antibody-drug conjugate

Abstract c-Met, the cell-surface receptor for HGF/SF which is widely overexpressed in various solid cancer types, is an attractive target for the development of antibody-based therapeutics. However, the apparently delicate balance between anti-tumor activity and target mediated-toxicities proved to be quite a challenge. As a result, there are currently no c-Met targeting antibodies or antibody-drug conjugates (ADCs) on the market. We developed BYON3521, a novel site-specifically conjugated, duocarmycin-based ADC, comprising a humanized, cysteine-engineered IgG1 monoclonal antibody with low pM binding affinity towards both human and cynomolgus c-Met. In vitro studies showed that BYON3521 internalizes efficiently upon c-Met binding, and induces both target- as well as bystander-mediated cell killing. BYON3521 showed good potency and full efficacy in MET-amplified and high c-Met-expressing cancer cell lines; in moderate and in low c-Met-expressing cancer cell lines partial efficacy was observed. PK/PD studies and a mouse clinical trial in patient-derived xenograft models showed significant anti-tumor activity of BYON3521 upon single dose administration in multiple tumor types. BYON3521 showed responses in non-MET-amplified tumors with low, moderate and high c-Met expression, with partial and complete tumor remission seen in several models with moderate c-Met expression. In the repeat-dose GLP safety assessment in cynomolgus monkeys BYON3521 was well tolerated. In all, BYON3521 was deemed a safe ADC with potential for clinical benefit in patients. Preparations are ongoing to start clinical Phase I in 2021. Citation Format: Patrick Groothuis, Danielle Jacobs, Inge Hermens, Desiree Damming, Ellen Mattaar, Myrthe Rouwette, Monique van der Vleuten, Aloys Sesink, Fred Dijcks, Ruud Coumans, Marion Blomenrohr, Ruud Ubink, Miranda van der Lee, Wim H.A. Dokter. BYON3521, a novel effective and safe c-Met targeting antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 926.

Abstract CT179: Telisotuzumab vedotin (teliso-v) monotherapy in patients with previously treated c-Met+ advanced non-small cell lung cancer

Abstract Background: Teliso-V is an anti-c-Met antibody conjugated with a tubulin inhibitor MMAE. The aim of this phase 2 trial (NCT03539536) is to explore safety and efficacy of teliso-V in cohorts (based on histopathology and EGFR mutation) and subgroups (based on c-Met expression) of patients with c-Met+ advanced NSCLC (stage 1), followed by expansion into an appropriately selected population for further evaluation of safety and efficacy (stage 2).Methods: Patients had ECOG ≤ 1 with 1-2 prior lines of therapy including cytotoxic chemotherapy, immunotherapy and targeted therapy. c-Met status was determined centrally by IHC (SP44 antibody). Membrane staining ≥ 25% 3+ or ≥ 75% 1+ was considered positive for non-squamous and squamous, respectively. Teliso-V dose was 1.9 mg/kg Q2W. Primary endpoint was objective response rate (ORR) per central review in patients with ≥ 12 weeks follow-up. Secondary endpoints were duration of response, disease control rate, PFS and OS.Results: ORR was 35.1% in the non-squamous EGFR WT cohort (53.8% in c-Met high group and 25.0% in c-Met intermediate group; Table), but was modest in the squamous and EGFR Mu cohorts. G3 or higher AEs occurred in 50/113 (44%) patients, with most common (≥ 2%) being malignant neoplasm progression (6.2%), pneumonia (5.3%), hyponatremia (4.4%), anemia (2.7%), dyspnea (2.7%), fatigue (2.7%), increased GGT (2.7%), peripheral sensory neuropathy (2.7%), and pneumonitis (2.7%). G5 AEs investigators considered possibly related to teliso-V were sudden death, dyspnea, and pneumonitis (1 event each). Conclusions: ORR in non-squamous EGFR WT NSCLC was encouraging with a tolerable safety profile, and this cohort met prespecified criteria to transition to stage 2. In this cohort, ORR was highest in the c-Met high group, though also clinically meaningful in the intermediate group. Enrollment into the squamous cohort was stopped. Enrollment into the EGFR MU cohort will continue until the next interim analysis. NSCLC GroupN(Total=88)Confirmed ResponsesORR(95% CI)NSQ EGFR WT371335.1% (20,53)c-Met high (≥ 50% positive, 3+ staining)13753.8% (25, 81)c-Met int(25-49%, 3+ staining)24625.0% (10,47)NSQ EGFR MU30413.3% (4,31)c-Met high (≥ 50%, 3+ staining)22418.2% (5, 40)c-Met int (25-49%, 3+ staining)800 (-,-)SQUAMOUS(≥ 75%, 1+ staining)21314.3% (3, 36) Citation Format: D. Ross Camidge, Fedor Moiseenko, Irfan Cicin, Hidehito Horinouchi, Elena Filippova, Jair Bar, Shun Lu, Pascale Tomasini, Christopher Ocampo, Danielle Sullivan, David Maag, Jonathan W. Goldman. Telisotuzumab vedotin (teliso-v) monotherapy in patients with previously treated c-Met+ advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT179.

Abstract 2496: CD82 regulation of c-Met in metastatic prostate cells

Abstract Metastatic prostate cancer is the second leading cause of cancer deaths among men in the U.S. Metastasis involves regulators, which involve complex cell signaling processes and our current knowledge on how prostate cancer metastasis develops is still under investigation. If these regulators can be identified and the mechanisms fully elucidated, they can be potential targets for oncologic treatment. CD82 (KAI1), a tetraspanin first identified as a metastasis tumor suppressor in prostate cells is one such regulator involved in the metastatic process. Currently, CD82 downregulation is not only observed in prostate but also in a variety of many invasive epithelial tumors which include tumors of the gastric, colon, cervix, breast, skin, bladder, lung, pancreas, liver, and thyroid. CD82 has been well documented as an inhibitor of cell motility and invasion in cancer cells, with varied inhibitory mechanisms. By introducing CD82 in metastatic cell lines (PC3) that do not express CD82, we have shown CD82 to regulate c-Met, a growth factor receptor, a protooncogene that is over expressed and or over activated in prostate tumors. Overactivation of c-Met promotes cell proliferation, migration and invasion. However, it is still not well understood how exactly CD82 regulates c-Met. Using metastatic prostate cell lines (PC3) and comparing them with PC3 clones generated to express CD82, we are using immunofluorescence, immunoprecipitation, flow cytometry, and western blot techniques to analyze the exact mechanism by which CD82 regulates c-Met. Preliminary data indicate CD82 does not colocalize with CD82, nor does it downregulate c-Met expression on the cell surface. However, CD82 expression seems to cause varied distribution of c-Met in the cell and is currently being investigated. Preliminary indications are that CD151, another tetraspanin may be involved in this regulation. CD151 is a known tumor promoter and has been shown to associate with c-Met. Currently, our lab is exploring the redistribution pattern of c-Met upon CD82 expression as a regulatory mechanism, in addition to exploring the CD82 and CD151 expression dynamics as part of or as alternate mechanism to c-Met regulation. The results observed will provide insights into the role CD82 plays in c-Met regulation as well as it may overall play in tumor progression and metastasis in prostate cancer. Notably, the results may also shed more light on CD82 regulation in other tumors where CD82 downregulation is observed. Citation Format: Suganthi Sridhar, Emily Brandes, Patrick Aller, Eddie Barrie. CD82 regulation of c-Met in metastatic prostate cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2496.

Abstract 952: The bispecific antibody MCLA-129 impairs NSCLC tumor growth by targeting EGFR and c-MET, inhibiting ligand-induced signaling and promoting ADCC and ADCP

Abstract MCLA-129 is an ADCC-enhanced common light chain bispecific human IgG1 Biclonics® antibody specifically targeting the receptor tyrosine kinases EGFR and c-MET. It inhibits activation and downstream signaling of EGFR and c-MET induced by their respective ligands EGF and HGF and promotes elimination of tumor cells via Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cell-Mediated Phagocytosis (ADCP). MCLA-129 was developed to overcome c-MET signaling-dependent EGFR TKI-resistance mechanisms and was identified during an unbiased screening campaign with a focus on inhibition of ligand-induced proliferation and migration of cancer cells. Selectivity of MCLA-129 for tumor cells is achieved by simultaneously targeting both EGFR and c-MET. MCLA-129 blocks EGF and HGF binding to EGFR and c-MET, respectively, and consequently inhibits their ligand-induced phosphorylation. MCLA-129 was shown to bind critical residues on EGFR and c-MET for EGF and HGF ligand binding. GlymaxX® low fucose glycoengineering technology was used to enhance the mononuclear cell ADCC activity of the bispecific antibody. MCLA-129 demonstrated potent dose-dependent ADCC and ADCP against all NSCLC cell lines tested, which positively correlated with the EGFR and c-MET expression levels on the target cells. Significant inhibition of tumor growth of NCI-H1975EGFR L858R, T790M and HCC827/ER1EGFR del (E746, A750), c-MET amplified NSCLC cell line derived tumors was observed following MCLA-129 treatment. MCLA-129 can overcome HGF-mediated EGFR-TKI resistance, as demonstrated by testing a non-ADCC enhanced version of this antibody in a panel of NSCLC cell lines in vitro and orthotopic tumors in vivo showing that it inhibits EGFR and c-MET activity. Significant tumor regression was observed following treatment of immunodeficient xenograft NSG-hHGFki mice bearing orthotopic tumors established from HCC827EGFR del (E746, A750) cells. In addition, in an acquired erlotinib EGFR TKI resistance model, treatment of mice harboring tumors as big as &amp;gt;500 mm3 led to significant reduction of tumor size which persisted after the treatment period. Taken together these data demonstrate that MCLA-129 is a potent inhibitor of tumor growth applying various mechanisms of action, including inhibition of c-MET and EGFR signaling, ADCC and ADCP. MCLA-129 holds promise as a potential treatment for patients with NSCLC and other cancers, and warrants clinical evaluation. Citation Format: David J. de Gorter, Alexandre Deshiere, Martijn van Rosmalen, Christian Wohn, Berina Eppink, Tristan Gallenne, Rinse Klooster, Li Mao, Wenxin Xu, Liang Deng, Qingyu Shu, Wei Liu, John de Kruif, Mario Di Matteo, Massimiliano Mazzone, Mark Throsby, Cecile A. Geuijen. The bispecific antibody MCLA-129 impairs NSCLC tumor growth by targeting EGFR and c-MET, inhibiting ligand-induced signaling and promoting ADCC and ADCP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 952.

Higher cMET dependence of sacral compared to clival chordoma cells: contributing to a better understanding of cMET in chordoma

Chordomas are rare slow growing, malignant bone tumors of the axial skeleton with no approved medical treatment. As the majority of chordomas express cMET and its ligand, HGF, and crosstalks between EGFR and MET-signaling exist, we aimed to explore cMET activity in chordoma cell lines and clinical samples. We investigated nine chordoma patients and four chordoma cell lines for cMET expression. Two clival and two sacral chordoma cell lines were tested for chromosomal abnormalities of the MET gene locus; we studied the influence of HGF on the autocrine secretion and migration behavior, as well as protein expression and phosphorylation. Two MET/ALK inhibitors were investigated for their effects on cell viability, cell cycle, cyclin alterations, apoptosis, and downstream signaling pathways. Moderate and strong expression of membrane and cytoplasmic cMET in chordoma patients and cell lines used, as well as concentration-dependent increase in phospho cMET expression after HGF stimulation in all four chordoma cell lines was shown. U-CH2, MUG-Chor1, and UM-Chor1 are polysomic for MET. Chordoma cell lines secreted EGF, VEGF, IL-6, and MMP9 upon HGF-stimulation. Sacral cell lines showed a distinct HGF-induced migration. Both inhibitors dose-dependently inhibited cell growth, induce apoptosis and cell-cycle arrest, and suppress downstream pathways. Heterogeneous responses obtained in our in vitro setting indicate that cMET inhibitors alone or in combination with other drugs might particularly benefit patients with sacral chordomas.

CMet agonistic antibody prevents acute kidney injury to chronic kidney disease transition by suppressing Smurf1 and activating Smad7.

We aimed to investigate the role of cMet agonistic antibody (cMet Ab) in preventing kidney fibrosis during acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Additionally, we explored the effect of cMet Ab on TGF-β1/Smad pathway during the pathogenesis of kidney fibrosis. A unilateral ischemia-reperfusion injury (UIRI) mouse model was established to induce AKI-to-CKD transition. Furthermore, we incubated human proximal tubular epithelial cells (hPTECs) under hypoxic conditions as in vitro model of kidney fibrosis. We analyzed the soluble plasma cMet level in patients with AKI requiring dialysis. Patients who did not recover kidney function and progressed to CKD presented a higher increase in the cMet level. The kidneys of mice treated with cMet Ab showed fewer contractions and weighed more than the controls. The mice in the cMet Ab-treated group showed reduced fibrosis and significantly decreased expression of fibronectin and α-smooth muscle actin. cMet Ab treatment decreased inflammatory markers (MCP-1, TNF-α, and IL-1β) expression, reduced Smurf1 and Smad2/3 level, and increased Smad7 expressions. cMet Ab treatment increased cMet expression and reduced the hypoxia-induced increase in collagen-1 and ICAM-1 expression, thereby reducing apoptosis in the in vitro cell model. After cMet Ab treatment, hypoxia-induced expression of Smurf1, Smad2/3, and TGF-β1 was reduced, and suppressed Smad7 was activated. Down-regulation of Smurf1 resulted in suppression of hypoxia-induced fibronectin expression, whereas treatment with cMet Ab showed synergistic effects. cMet Ab can successfully prevent fibrosis response in UIRI models of kidney fibrosis by decreasing inflammatory response and inhibiting the TGF-β1/Smad pathway.

Circulating Levels of the Interferon-γ-Regulated Chemokines CXCL10/CXCL11, IL-6 and HGF Predict Outcome in Metastatic Renal Cell Carcinoma Patients Treated with Antiangiogenic Therapy.

Simple SummaryWe have studied blood levels of cytokines/chemokines in patients with metastatic renal cell carcinoma treated with sunitinib or pazopanib, with the goal of identifying biomarkers that can predict efficacy and survival. We have found that high levels of CXCL10, CXCL11, HGF and IL-6 before treatment associate with poor prognosis in these patients. Moreover, these factors are correlated in patients with renal carcinoma, suggesting a coordinated expression and secretion. We have developed a prognostic signature including these factors that predicts very accurately prognosis. Our results may help defining better the group of renal cell carcinoma patients who may benefit from sunitinib/pazopanib.Sunitinib and pazopanib are standard first-line treatments for patients with metastatic renal cell carcinoma (mRCC). Nonetheless, as the number of treatment options increases, there is a need to identify biomarkers that can predict drug efficacy and toxicity. In this prospective study we evaluated a set of biomarkers that had been previously identified within a secretory signature in mRCC patients. This set includes tumor expression of c-Met and serum levels of HGF, IL-6, IL-8, CXCL9, CXCL10 and CXCL11. Our cohort included 60 patients with mRCC from 10 different Spanish hospitals who received sunitinib (n = 51), pazopanib (n = 4) or both (n = 5). Levels of biomarkers were studied in relation to response rate, progression-free survival (PFS) and overall survival (OS). High tumor expression of c-Met and high basal serum levels of HGF, IL-6, CXCL11 and CXCL10 were significantly associated with reduced PFS and/or OS. In multivariable Cox regression analysis, CXCL11 was identified as an independent biomarker predictive of shorter PFS and OS, and HGF was an independent predictor of reduced PFS. Correlation analyses using our cohort of patients and patients from TCGA showed that HGF levels were significantly correlated with those of IL-6, CXCL11 and CXCL10. Bioinformatic protein–protein network analysis revealed a significant interaction between these proteins, all this suggesting a coordinated expression and secretion. We also developed a prognostic index that considers this group of biomarkers, where high values in mRCC patients can predict higher risk of relapse (HR 5.28 [2.32–12.0], p < 0.0001). In conclusion, high plasma HGF, CXCL11, CXCL10 and IL-6 levels are associated with worse outcome in mRCC patients treated with sunitinib or pazopanib. Our findings also suggest that these factors may constitute a secretory cluster that acts coordinately to promote tumor growth and resistance to antiangiogenic therapy.

Combined BRM270 and endostatin inhibit relapse of NSCLC while suppressing lung cancer stem cell proliferation induced by endostatin

Endostatin (ES, ENDO) has been reported to suppress the growth of tumors while inducing the proliferation of lung cancer stem cells (LCSCs), causing a poor prognosis for lung cancer. In this study, we aimed to clarify whether BRM270 can inhibit the proliferation of cancer stem cells (CSCs). Endostatin + BRM270 showed anti-tumor effects by reducing tumor volume and increasing survival. Administration of BRM270 reduced the number of aldehyde dehydrogenase-positive (ALDH+) cells and the level of ALDH1A1 expression in tumors by increasing the level of miR-128 while decreasing the levels of BMI-1, ABCC-5, E2F3, and c-MET. The luciferase activity of miR-128 promoter was increased by an increasing concentration of BRM270. In addition, BMI-1, ABCC-5, E2F3, and c-MET were identified as candidate targets of miR-128, and the overexpression of miR-128 significantly reduced mRNA/protein levels of BMI-1, ABCC-5, E2F3, and c-MET in A549 and H460 cells. Administration of BRM270 inhibited the expression of BMI-1, ABCC-5, E2F3, and c-MET in a dose-dependent manner. In this study, we showed for the first time that the combined administration of endostatin and BRM270 achieved anti-tumor effects while suppressing the proliferation of stem cells.

Pulmonary metastasectomy in renal cell carcinoma: Predictive and prognostic elements from paired histopathological analysis of primary tumors and respective metastases

Objective: To identify histopathological and immunophenotypical features with potential predictive or prognostic value in patients undergoing pulmonary metastasectomy from renal cell carcinoma (RCC). Methods: We retrospectively collected all consecutive patients undergoing pulmonary metastasectomy from RCC after prior nephrectomy. Paired samples of primary tumors and corresponding pulmonary metastases were analyzed, revising histopathological features and testing C-MET, mTOR, and PD-L1 by immunohistochemistry. Results: A total of 25 patients were included. Median overall survival (mOS) from metastasectomy was 5.5 years (95% CI = 1.9–9.1). The laterality of metastases had a significant predictive value, with median relapse-free survival (mRFS) from metastasectomy not reached (NR) at mean follow-up (FU) of 60.8 months for left lung involvement, mRFS of 52.9 months (95% CI = 0–145.5) for the right lung and 6.4 months (95% CI = 1.7–11) for bilateral metastases ( p = 0.028). Primary RCC with positive expression of mTOR had higher mOS after metastasectomy than negative cases ( p &lt; 0.001), NR at mean FU of 4.3 years versus mOS of 2 years (95% CI = 0.7–3.3), respectively. PD-L1 positivity on intra-tumor (TILs) and peri-tumor (RILs) infiltrating lymphocytes of metastases was related to higher OS, NR versus 2 years (95% CI = 1.2–2.7, p = 0.003), and NR versus 1.4 years (95% CI = 0.2–2.6, p = 0.012), respectively. The shorter was the surgical interval, the more probably the metastases had high c-MET expression (&gt;70%) ( p = 0.007) and PD-L1 expression &gt;10% on TILs ( p = 0.024). Conclusions: mTOR positivity on primary RCC could be a favorable prognostic factor to select patients for pulmonary metastasectomy. The positive impact of PD-L1 expression on immune cells is opposite to the well-known negative prognostic value of PD-L1 on tumor cells in RCC.

Oncogenic long intervening noncoding RNA Linc00284 promotes c-Met expression by sponging miR-27a in colorectal cancer

Emerging evidences suggest that long noncoding RNA (lncRNA) plays a vital role in tumorigenesis and cancer progression. Here, the aim of this study is to investigate the biological function of long intervening noncoding RNA Linc00284 in colorectal cancer (CRC). The expression levels of Linc00284, miR-27a and c-Met were evaluated by qPCR and/or Western blotting. Immunohistochemistry was used to detect the expression of Ki67 and Phh3 in tumor tissues. The interaction between Linc00284, miR-27a and c-Met was validated by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Cell function experiments, including CCK-8, wound-healing and transwell invasion assays, were conducted. The in vivo studies were performed with the subcutaneous tumor xenograft mouse models. Our findings reveal that Linc00284 is upregulated in CRC tissues and colorectal cancer cell lines HCT116 and SW480 in comparison with corresponding para-carcinoma tissues and human fetal colonic mucosa cells FHC. High expression of Linc00284 in tumor tissues is associated with tumor metastasis and predicts a poor clinical outcome in CRC patients. Serum Linc00284 is increased, while miR-27a is decreased in CRC patients compared to healthy controls. ROC curve analysis indicates that serum Linc00284 and miR-27a produce the area under the curve (AUC) value of at 0.8151 and 0.7316 in patients with colorectal cancer compared to healthy individuals, respectively. Additionally, results in vitro and in vivo experiments suggest that Linc00284 silencing significantly suppresses CRC cell proliferation and/or invasion. Mechanistically, Linc00284 promotes c-Met expression by acting as miR-27a sponge, leading to the activation of downstream signaling pathways, thereby causing malignant phenotypes of CRC cells. Taken together, Linc00284 exhibits oncogenic function and the disturbance of Linc00284/miR-27a/c-Met regulatory axis contributes to CRC progression, providing new insight into the pathogenesis of colorectal cancer. Importantly, the expression levels of serum Linc00284 and miR-27a may serve as clinical biomarkers for CRC diagnosis.