Joint estimation of compartment-specific T2 relaxation and tumor microstructure using multi-TE IMPULSED MRI.

PURPOSE: This study aims to assess how T2 heterogeneity biases IMPULSED-derived metrics of tissue microstructure in solid tumors and evaluate the potential of estimating multi-compartmental T2 and microstructural parameters simultaneously. METHODS: This study quantifies the impact of T2 relaxation on IMPULSED-derived microstructural parameters using computer simulations and in vivo multi-TE IMPULSED MRI in five tumor models, including brain, breast, prostate, melanoma, and colon cancer. A comprehensive T2 + IMPULSED method was developed to fit multi-compartmental T2 and microstructural parameters simultaneously. A Bayesian model selection approach was carried out voxel-wisely to determine if the T2 heterogeneity needs to be included in IMPULSED MRI in cancer. RESULTS: Simulations suggest that T2 heterogeneity has a minor effect on the estimation of d in tissues with intermediate or high cell density, but significantly biases the estimation of v in $$ {v}_{in} $$ with low cell density. For the in vivo animal experiments, all IMPULSED metrics except v in $$ {v}_{in} $$ are statistically independent on TE. For B16 tumors, the IMPULSED-derived v in $$ {v}_{in} $$ exhibited a notable increase with longer TEs. For MDA-MB-231 tumors, IMPULSED-derived v in $$ {v}_{in} $$ showed a significant increase with increasing TEs. The T2 + IMPULSED-derived T 2 in $$ {T}_2^{in} $$ of all five tumor models are consistently smaller than T 2 ex $$ {T}_2^{ex} $$ . CONCLUSIONS: The findings from this study highlight two key observations: (i) TE has a negligible impact on IMPULSED-derived cell sizes, and (ii) the TE-dependence of IMPULSED-derived intracellular volume fractions used in T2 + IMPULSED modeling to estimate T 2 in $$ {T}_2^{in} $$ and T 2 ex $$ {T}_2^{ex} $$ . These insights contribute to the ongoing development and refinement of non-invasive MRI techniques for measuring cell sizes.

Targeting c-Met in Cancer Therapy: Unravelling Structure-Activity Relationships and Docking Insights for Enhanced Anticancer Drug Design.

The c-Met receptor, a pivotal player in oncogenesis and tumor progression, has become a compelling target for anticancer drug development. This review explores the intricate landscape of Structure-Activity Relationship [SAR] studies and molecular binding analyses performed on c-Met inhibitors. Through a comprehensive examination of various chemical scaffolds and modifications, SAR investigations have elucidated critical molecular features essential for the potent inhibition of c-Met activity. Additionally, molecular docking studies have provided invaluable insights into how c-Met inhibitors interact with their target receptor, facilitating the rational design of novel compounds with enhanced efficacy and selectivity. This review highlights key findings from recent SAR and docking studies, particularly focusing on the structural determinants that govern inhibition potency and selectivity. Furthermore, the integration of computational methodologies with experimental approaches has accelerated the discovery and optimization of c-Met inhibitors, fostering the advancement of promising candidates for clinical applications. Overall, this review underscores the pivotal role of SAR and molecular docking studies in advancing our understanding of c-Met inhibition and guiding the rational design of next-generation anticancer agents targeting this pathway.

Targeting the MET gene: unveiling therapeutic opportunities in immunotherapy within the tumor immune microenvironment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) represents the most prevalent histological subtype of lung cancer. Within this disease, the MET gene emerges as a critical therapeutic target, exhibiting various forms of dysregulation. Although MET tyrosine kinase inhibitors, HGF/c-MET targeting antibodies, and antibody-drug conjugates constitute the primary treatment modalities for patients with MET-altered NSCLC, numerous questions remain regarding their optimal application. The advent of immunotherapy holds promise for enhancing therapeutic outcomes in patients with MET-altered NSCLC. MET mutations can reshape the tumor immune microenvironment of NSCLC by reducing tumor immunogenicity, inducing exhaustion in immune-activated cells, and promoting immune evasion, which are crucial for modulating treatment responses. Furthermore, we emphasize the promising synergy of immunotherapy with emerging treatments and the challenges and opportunities in refining these approaches to improve patient outcomes.

Met-Flow analyses of the metabolic heterogeneity associated with different stages of cord blood-derived hematopoietic cell differentiation.

Background: The differentiation of hematopoietic cells is significantly affected by cell metabolic activity. However, despite increasing interest in this field, there has been no comprehensive investigation of the metabolic functions of human hematopoietic cells during specific phases of differentiation. Thus, this study was conducted to develop a method for comparing hematopoietic cell lineage differentiation based on the metabolic functions of the cell. The metabolic activity of human umbilical cord-derived hematopoietic cells was examined during various phases of differentiation, specifically, hematopoietic stem cells (HSCs), hematopoietic progenitor cells, and differentiated blood cells. This approach was used to develop comprehensive metabolic maps corresponding to the different stages. Results: HSCs were found to have robust fatty acid (FA) synthesis, FA oxidation, pentose phosphate pathway (PPP) activity, and glucose uptake, shown by their significantly higher expression of ACAC, CPT1A, G6PD, and GLUT1 as compared to differentiated pluripotent progenitor cells, common myeloid progenitors, megakaryocyte erythroid progenitors, lympho-myeloid primed progenitors, and granulocyte-macrophage progenitor cell populations. In monocytic differentiation, higher levels of ACAC, ASS1, ATP5A, CPT1A, G6PD, GLUT1, IDH2, PRDX2, and HK1 protein expression were evident in classical and intermediate monocytes relative to non-classical monocytes, consistent with high anabolic and catabolic levels. Compared with myelocytes and mature cells, the meta-myelocyte and pro-myelocyte populations of granulocytes show significantly elevated levels of ACAC, ASS1, ATP5A, CPT1A, G6PD, IDH2, PRDX2, and HK. In contrast to naïve and regulatory B cells, pro-B cells had higher levels of oxidative phosphorylation, while regulatory B cells showed greater PPP activity, glucose uptake, and tricarboxylic acid cycle activity. The analyses of T cells also indicated significantly higher ACAC, ASS1, ATP5A, CPT1A, G6PD, GLUT1, IDH2, PRDX2, and HK1 expression levels in CD4+ populations compared with CD8+ populations. Conclusions: The results provide comprehensive analytical methods and reference values for future systematic studies into the metabolic functions of various cord blood-derived hematopoietic cell populations in different pathological or physiological conditions. These findings could also contribute to research on the connection between cellular metabolism and cancer or aging.

LINC00161 upregulated by M2-like tumor-associated macrophages promotes hepatocellular carcinoma progression by methylating HACE1 promoters.

M2-like tumor-associated macrophages (M2-TAM) played an essential part in hepatocellular carcinoma (HCC) progression. Long intergenic noncoding RNA 00161 (LINC00161), is a long non-coding RNA, that was related to HCC development. However, the relationship between LINC00161 and TAM remains indistinct. HCC cells were cocultured with an M2-like conditioned medium (M2-CM). cell counting kit-8 (CCK-8), plate cloning, cell scratch, and transwell assay evaluated cell biological activities of HCC cells. The interactions among molecules were analyzed by chromatin immunoprecipitation (CHIP), dual-luciferase reporter, and RNA immunoprecipitation (RIP). The methylation status of HECT domain and ankyrin repeat-containing, E3 ubiquitin protein ligase 1 (HACE1) was evaluated using methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP). The xenograft model was established in vivo using subcutaneous nude mice. Histological analyses were performed using hematoxylin-eosin (HE) staining. The expression of molecules was determined using immunohistochemistry (IHC), western blot and quantitative real-time PCR (qPCR). LINC00161 expression was promoted in HCC. LINC00161 knockdown significantly reduced HCC cell proliferation, migration, and invasion. Additionally, M2-TAM stimulated LINC00161 transcription and expression in HCC cells by secreting hepatocyte growth factor (HGF) to activate the Met/NFκB pathway. LINC00161 suppressed HACE1 expression, and knockdown of LINC00161 decreased the methylation on the HACE1 promoter. Meanwhile, a binding relationship between the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and HACE1 was observed. LINC00161 overexpression increased the binding of EZH2 on the HACE1 promoter region. Furthermore, LINC00161 knockdown suppressed tumor growth in vivo and induced HACE1 expression by inhibiting its methylation. LINC00161, induced by M2-TAM, played a pivotal role in contributing to HCC development by recruiting EZH2 to promote the methylation of HACE1. This underscores the significant involvement of LINC00161 in mediating the progression of HCC.

ALK-tyrosine kinase inhibitor intrinsic resistance due to de novo MET-amplification in metastatic ALK-rearranged non-small cell lung cancer effectively treated by alectinib-crizotinib combination-case report.

Background: Most patients with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) experience prolonged response to second-generation (2G) ALK-tyrosine kinase inhibitors (TKIs). Herein, we present a case of metastatic ALK+ NSCLC rapidly progressing on first-line treatment due to de novo amplification of the mesenchymal-epithelial transition factor (MET) gene, which is a still elusive and underrecognized mechanism of primary resistance to ALK-TKIs. Case Description: A 43-year-old, female diagnosed with T4N3M1c NSCLC harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variant 1 (EML4-ALK v.1) and TP53 co-mutation, displayed only mixed response after three months and highly symptomatic progression after 6 months of first-line brigatinib treatment. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis on re-biopsies from a new liver metastasis revealed overexpression of MET receptor (3+ in 80% of tumor cells) and heterogeneously increased MET gene copy number (CN) in tumor cells, including 20% with MET clusters (corresponds to ≥15 gene copies, thus exact CN uncountable by FISH) and the other 80% with median MET CN of 8.3, both changes indicating high-level MET-amplification. DNA and RNA next-generation sequencing (NGS) displayed preserved ALK fusion and TP53 co-mutation, but no additional genomic alterations, nor MET-amplification. Therefore, we retrospectively investigated the diagnostic biopsy from the primary tumor in the left lung with IHC and FISH revealing the presence of increased MET receptor expression (2+ in 100% of tumor cells) and MET-amplification (median MET CN of 6.1), which otherwise was not detected by NGS. Thus, given the well-documented efficacy of alectinib towards EML4-ALK v.1, combined second-line treatment with alectinib and the MET-TKI, crizotinib, was implemented resulting in very pronounced objective response, significantly improved quality of life, and no adverse events so far during the ongoing treatment (6 months). Conclusions: The combination of alectinib and crizotinib may be a feasible and effective treatment for ALK+ NSCLC with de novo MET-amplification. The latter may represent a mechanism of intrinsic ALK-TKI resistance and its recognition by FISH, in NGS-negative cases, may be considered before initiating first-line treatment. This recognition is clinically important as combined therapy with ALK-TKI and MET-inhibitor should be the preferred first-line treatment.

The Clinicopathological and Prognostic Significance of the Expression of PD-L1 and MET Genes in Breast Cancer: Potential Therapeutic Targets.

INTRODUCTION: The heterogeneity of breast cancer requires exploring novel prognostic biomarkers as well as therapeutic targets for the treatment of the disease. METHODS: The METABRIC dataset was used to describe the gene expression of the programmed death-ligand 1 (PD-L1) and the hepatocyte growth factor receptor (MET) and their association with the tumor clinicopathologic characteristics and overall survival in breast cancer. RESULTS: The expression of the PD-L1 and MET genes correlated positively with the Nottingham Prognostic Index (NPI) (p=0.003 and p < 0.001, respectively). The expression of the two genes correlated inversely with luminal A and luminal B tumors (r= - 0.089, p= 0.021 and r= - 0.116, p= 0.013, respectively). The PD-L1 mRNA levels were significantly higher in hormone receptor-negative and HER2-positive tumors. MET mRNA expression levels were significantly higher in hormone receptor-negative, HER2-enriched, and non-luminal breast cancers. The PD-L1/MET double-high expression was associated with younger age of patients at diagnosis, higher NPI scores, larger tumors, advanced stage, high-grade, hormone receptor-negativity, HER2-positivity, and non-luminal tumors. None of the genes or their double expression status was significantly associated with overall survival in this analysis. CONCLUSION: The expression of the PD-L1 and MET genes is remarkably associated with worse tumor clinicopathologic features and poor prognosis in patients with breast cancer. Further investigations using combination drug regimens targeting PD-L1 and MET are important, particularly in breast tumors expressing high levels of both proteins.

Unveiling LGR5: Prostate cancer's hidden stem cell and treatment target.

Prostate cancer poses a significant risk to the well-being and way of life of countless men, with an increased likelihood of relapse recorded following modern treatment. This highlights the need for innovative approaches, specifically targeting LGR5. This systematic review aims to establish a connection between LGR5 and the various signaling pathways involved in the progression of prostate cancer. LGR5, a gene targeted by Wnt signaling, encodes a receptor protein that serves as a prognostic biomarker for stem cells and indicates the presence of cancer stem cells in colorectal and gastrointestinal cancers. The functions of LGR5 include processes such as cell proliferation, differentiation, and signaling pathways. Any modifications to the LGR5 gene, whether caused by mutations or mechanical stimuli, can lead to the development of treatment-resistant stem cell cancers. This review examines the molecular mechanisms associated with LGR5 and emphasizes methodologies aimed at targeting LGR5 to enhance understanding and promote the development of LGR5-specific therapies.

Case report: Germline CHEK2 mutation is associated with a giant cell glioblastoma.

Giant cell glioblastoma often exhibits genome instability and is frequently associated with mutations in genes involved in DNA repair pathways including TP53 and DNA mismatch repair genes. Several germline mutations have been identified in giant cell glioblastoma, including mutations of MSH1 and MSH2, TP53, and POLE. We have documented a case of a germline mutation in CHEK2, another gene crucial to DNA repair, in a patient with giant cell glioblastoma. The CHEK2 mutation was inherited from the patient's father, who had a history of gastric cancer and renal cell carcinoma. In addition to the germline CHEK2 mutation, the giant cell glioblastoma exhibited a genome-wide loss of heterozygosity, a characteristic observed in a subset of giant cell glioblastomas. Additional mutations detected in the tumor included TP53, PTEN, and a PTPRZ1-MET fusion. This represents the first reported case of a CHEK2 germline mutation in giant cell glioblastoma, further supporting the significance of impaired DNA repair mechanisms in the development of this disease.

Exceptional sustained long-term complete response to Tepotinib in a MET-amplified advanced intrahepatic biliary tract cancer failing Durvalumab plus Cisplatin and Gemcitabine.

BACKGROUND: Biliary tract cancers (BTCs) are a diverse group of malignancies with varied genetic backgrounds. The prevalence of intrahepatic cholangiocarcinoma (iCC) is increasing, particularly in Western countries. Despite advancements in treatments, the prognosis for BTC remains poor. Recent molecular profiling has revealed that up to 40% of iCC cases have targetable genetic alterations. MET amplification, although rare, presents a significant target for therapy. CASE PRESENTATION: A 25-year-old female with a history of ulcerative colitis presented with shoulder pain and a positron emission tomography-computed tomography (PET-CT) scan revealed an enlarged liver and multiple metastases. Histopathological analysis diagnosed poorly differentiated adenocarcinoma. First-line therapy with Cisplatin, Gemcitabine, and Durvalumab resulted in disease progression. Molecular profiling identified a TP53 mutation and MET amplification. Based on these findings, Tepotinib was initiated. Tepotinib treatment led to a significant reduction in tumor size and normalization of CA 19-9 levels within 2 months, achieving a complete metabolic remission lasting up to 17 months. The treatment was well tolerated with minimal side effects. DISCUSSION: MET-amplified BTCs are exceedingly rare, and evidence for targeted treatment is limited. This case demonstrates the efficacy of Tepotinib in a young patient with MET-amplified iCC, showing a long-term response and suggesting a potential new standard treatment option for this molecularly defined entity. This case also highlights the aggressive nature of MET-amplified tumors and the need for targeted second-line therapies. CONCLUSION: Tepotinib showed remarkable efficacy in treating MET-amplified intrahepatic cholangiocarcinoma, underscoring the importance of molecular profiling in BTCs and suggesting a potential new therapeutic approach for this rare cancer subtype.

Decision regret analysis in early URSL vs medical expulsive therapy 1 for ureteric calculi ≤ 1cm.

BACKGROUND: The study assesses the decisional regret following Shared Decision-making (SDM) in patients selecting either early ureteroscopic lithotripsy (URSL) or medical expulsive therapy (MET) for ureteric stones ≤ 1 cm, with the aim to evaluate their decisional Conflict, satisfaction, and regret regarding their opted treatment choices. METHODS: Adults aged more than 18 years with one stone up to 1 cm in either ureter were included. After SDM, the patients were allocated into their opted group viz. URSL or MET. Patients in each group were reassessed at "treatment completion". Cambridge Ureteric Stone PROM (CUSP) questionnaire for HRQoL, Decision Regret Scale and the OPTION scale (SDM) were filled at treatment completion. FINDINGS: 111 patients opted for MET, while 396 patients opted for early URSL. Mean stone size was larger in URSL group (7.16 ± 1.63 mm vs. 5.50 ± 1.89; p < 0.001). Decisional conflict was higher in patients opting for URSL (77.3% vs. 57.7%; p < 0.001). Stone-free rate at four weeks was higher in URSL group (87.1%vs68.5%, p < 0.001). Decisional regret was higher in patients opting for MET (33.24 ± 30.89 vs. 17.26 ± 12.92; p = 0.002). Anxiety, was higher in patients opting for MET (6.94 ± 1.89 vs. 5.85 ± 1.54; p < 0.001). Urinary symptoms and interference in patients' travel plans and work-related activities were more in URSL group (6.21 ± 1.57 vs. 5.59 ± 1.46; p < 0.001 and 6.56 ± 1.59 vs. 6.05 ± 1.72; p < 0.001 respectively). INTERPRETATION: After SDM, decisional regret is higher in patients opting for MET mainly due protracted treatment duration with increased pain and anxiety during the treatment course and the need for additional procedure for attaining stone clearance and the. Despite higher decisional conflict, a larger proportion of patients opt for early URSL with the aim of avoiding anxiety and achieving early stone clearance.

c-Met inhibitor upregulates E-cadherin, which is lost in portal vein tumor thrombus of hepatocellular carcinoma.

AIM: Portal vein tumor thrombus (PVTT) in hepatocellular carcinoma (HCC) is an essential therapeutic and prognostic factor. E-cadherin plays a crucial role in adhesive properties and intercellular interaction in various cancer tissues, including HCC, but the expression profile and functional contribution of E-cadherin in PVTT remain unknown. This study aimed to analyze the expression of E-cadherin in the main tumor tissue and PVTT tissue of HCC, and evaluate the functional roles of E-cadherin in PVTT formation. METHODS: A retrospective analysis was performed using the medical records of patients who underwent liver resection for HCC with PVTT, analyzing tissue specimens from 1995 to 2016. E-cadherin expression is evaluated using immunohistochemistry and western blot. The study also uses a c-Met inhibitor to explore its impact on E-cadherin expression in vitro and in vivo using cell lines and a tumor xenograft mouse model. RESULTS: The results revealed a reduced E-cadherin expression in PVTT tissue than in the main tumor tissue. The inhibition of c-Met activation, frequently detected in HCC, upregulated E-cadherin expression in HCC cell lines. Furthermore, treatment with c-Met inhibitors induced changes in epithelial morphology, and inhibited migration and invasion of HCC cell lines. CONCLUSIONS: This study demonstrates the downregulation of E-cadherin in PVTT, and underscores the potential of c-Met inhibition in upregulating E-cadherin and inhibiting metastatic behavior. Understanding the significance of E-cadherin and c-Met in HCC progression provides a foundation for future clinical investigations into the therapeutic effects of c-Met inhibitors on PVTT in HCC patients.

Exploration of efficacy of the first-line treatment for advanced non-small cell lung cancer with primary MET-amplification: Retrospective evaluation of 36 cases.

BACKGROUND: There are few clinical data on targeted therapy for primary mesenchymal-epidermal transforming factor amplification (METamp), unlike METamp secondary to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). First-line treatment options for patients with primary METamp NSCLC remain unclear, and in particular, the efficacy of immune checkpoint inhibitors (ICIs) in these patients is controversial. METHODS: We retrospectively included primary METamp patients who had received at least one line of systemic anticancer therapy, diagnosed at Zhejiang Cancer Hospital from June 2018 to June 2023, and analyzed the efficacies of different treatment patterns for these patients. We also evaluated the potential relationship between the tumor immune microenvironment (TIME) and the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) axis in primary METamp NSCLC patients. High-level METamp was defined as gene copy number (GCN) ≥ 10 [1]. The clinical outcomes included objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS). RESULTS: We screened 2016 NSCLC patients and detected 36 primary METamp, resulting in a prevalence of 1.79 %. Among the patients, the average MET GCN was 4.6, the overall ORR was 50.0 %, DCR was 77.8 %, mPFS was 5.8 months and mOS was 11.7 months. We categorized the first-line treatments that patients received as: immuno-chemotherapy (CI-group), antiangio-chemotherapy (CA-group), chemotherapy (C-group) and MET-TKIs therapy (TKI-group). The ORR of CI-group, CA-group, C-group and TKI-group was 64.3 %, 16.7 %, 33.4 % and 71.4 %, respectively. And the DCR of this four groups was 100 %, 50 %, 66.7 % and 71.4 %, respectively. CI-group achieved longer mPFS and mOS than other groups, respectively (mPFS: 8.63 vs 3.73 vs 3.53 vs 5.50 months, P = 0.021; mOS: 15.10 vs 11.73 vs 9.93 vs 13.93 months, P = 0.023). The mPFS was longer in the PD-L1-positive group than in the PD-L1 negative group (P = 0.046) and PD-L1 positivity was an independent prognostic indicator for PFS (P = 0.005). In addition, the disease remission effect was significantly lower in Foxp3-positive expressors than in negative expressors (ORR: 33.3 % vs 75.0 %, P = 0.024). CONCLUSIONS: Immuno-chemotherapy is a first-line optional treatment strategy in addition to targeted therapy for NSCLC patients with primary METamp. Foxp3-negative expression better predicts the near-term efficacy of immunotherapy.

Design, synthesis and biological evaluation of thienopyridine derivatives as c-Met kinase inhibitors.

With cabozantinib as the precursor, a novel small molecule inhibitors of c-Met kinase with thieno [2,3-b] pyridine as the scaffold were designed, synthesized and evaluated for their biological activity against A549, Hela and MCF-7 cell lines. The in vitro activities of 16 compounds were tested by MTT method with cabozantinib as control drug. Most compounds had moderate to strong inhibitory activities on cells. Among them, compound 10 had the strongest inhibitory activity, which was superior to the lead compound cabozantinib. Its IC50 values for A549, Hela and MCF-7 cells were 0.005, 2.833 and 13.581 µM, respectively. The colony formation assay demonstrated that compound 10 significantly inhibited the colony formation of A549 cells and suppressed their growth in a concentration-dependent manner. The wound healing assay showed that compound 10 could effectively inhibit the migration of cancer cells compared to a blank control group. The AO/EB assay demonstrated that compound 10 possesses the capability to effectively trigger apoptosis in a concentration-dependent manner. The elementary structure-activity relationship, molecular docking and pharmacokinetics studies revealed the significance of thieno [2,3-b] pyridine derivatives in anti-tumor activity.

Genomic signature for oligometastatic disease in non-small cell lung cancer patients with brain metastases.

Purpose/objectives: Biomarkers for extracranial oligometastatic disease remain elusive and few studies have attempted to correlate genomic data to the presence of true oligometastatic disease. Methods: Patients with non-small cell lung cancer (NSCLC) and brain metastases were identified in our departmental database. Electronic medical records were used to identify patients for whom liquid biopsy-based comprehensive genomic profiling (Guardant Health) was available. Extracranial oligometastatic disease was defined as patients having ≤5 non-brain metastases without diffuse involvement of a single organ. Widespread disease was any spread beyond oligometastatic. Fisher's exact tests were used to screen for mutations statistically associated (p<0.1) with either oligometastatic or widespread extracranial disease. A risk score for the likelihood of oligometastatic disease was generated and correlated to the likelihood of having oligometastatic disease vs widespread disease. For oligometastatic patients, a competing risk analysis was done to assess for cumulative incidence of oligometastatic progression. Cox regression was used to determine association between oligometastatic risk score and oligoprogression. Results: 130 patients met study criteria and were included in the analysis. 51 patients (39%) had extracranial oligometastatic disease. Genetic mutations included in the Guardant panel that were associated (p<0.1) with the presence of oligometastatic disease included ATM, JAK2, MAP2K2, and NTRK1, while ARID1A and CCNE1 were associated with widespread disease. Patients with a positive, neutral and negative risk score for oligometastatic disease had a 78%, 41% and 11.5% likelihood of having oligometastatic disease, respectively (p<0.0001). Overall survival for patients with positive, neutral and negative risk scores for oligometastatic disease was 86% vs 82% vs 64% at 6 months (p=0.2). Oligometastatic risk score was significantly associated with the likelihood of oligoprogression based on the Wald chi-square test. Patients with positive, neutral and negative risk scores for oligometastatic disease had a cumulative incidence of oligometastatic progression of 77% vs 35% vs 33% at 6 months (p=0.03). Conclusions: Elucidation of a genomic signature for extracranial oligometastatic disease derived from non-invasive liquid biopsy appears feasible for NSCLC patients. Patients with this signature exhibited higher rates of early oligoprogression. External validation could lead to a biomarker that has the potential to direct local therapies in oligometastatic patients.

Combined inhibition of MET and VEGF enhances therapeutic efficacy of EGFR TKIs in EGFR-mutant non-small cell lung cancer with concomitant aberrant MET activation.

BACKGROUND: Aberrant activation of mesenchymal epithelial transition (MET) has been considered to mediate primary and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). However, mechanisms underlying this process are not wholly clear and the effective therapeutic strategy remains to be determined. METHODS: The gefitinib-resistant NSCLC cell lines were induced by concentration increase method in vitro. Western blot and qPCR were used to investigate the relationship between MET and vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway. Double luciferase reporter gene and co-immunoprecipitation were used to further reveal the regulation mechanism between MET and VEGF/VEGFR2. The effect of combined inhibition of MET and VEGF/VEGFR2 signaling pathway on the therapeutic sensitivity of EGFR-TKI in gefitinib resistant cell lines with MET aberration was verified ex vivo and in vivo. RESULTS: We successfully obtained two gefitinib-resistant NSCLC cell lines with EGFR mutation and abnormal activation of MET. We observed that MET formed a positive feedback loop with the VEGF/VEGFR2 signaling, leading to persistent downstream signaling activation. Specifically, MET up-regulated VEGFR2 expression in a MAPK/ERK/ETS1-dependent manner, while VEGF promoted physical interaction between VEGFR2 and MET, thereby facilitating MET phosphorylation. A MET inhibitor, crizotinib, combined with an anti-VEGF antibody, bevacizumab, enhanced the sensitivity of NSCLC cells to gefitinib and synergistically inhibited the activation of downstream signaling in vitro. Dual inhibition of MET and VEGF combined with EGFR TKIs markedly restrained tumor growth in both human NSCLC xenograft models and in an EGFR/MET co-altered case. CONCLUSIONS: Our work reveals a positive feedback loop between MET and VEGF/VEGFR2, resulting in continuous downstream signal activation. Combined inhibition of MET and VEGF/VEGFR2 signaling pathway may be beneficial for reversing EGFR TKIs resistance.

Landscape of C-MET overexpression in non-small cell lung cancer: a large-scale study of clinicomolecular features and prognosis based on Chinese data.

Background: Real-world data on C-MET protein overexpression in non-small cell lung cancer (NSCLC) patients, particularly among the Asian Chinese population, are limited. Objectives: This study aimed to evaluate the clinicomolecular characteristics and prognosis of C-MET overexpression in Chinese NSCLC patients, focusing on those with positive C-MET overexpression (immunohistochemistry (IHC) 3+). Design: A retrospective and observational study. Methods: Data were collected from NSCLC patients diagnosed at the First Affiliated Hospital of Guangzhou Medical University between November 2006 and April 2021. We identified C-MET overexpression using IHC and C-MET overexpression positivity was defined as IHC 3+ with ⩾50% tumor cells. Additionally, patient genotypes were collected for subgroup analysis. Results: Data from 9785 NSCLC patients were collected. C-MET (-) accounted for 5% (503/9785), C-MET (+) for 27% (2654/9785), C-MET (++) for 36% (3464/9785), and C-MET (+++) for 32% (3164/9785). Genetic testing was available for 4326 patients. Wild-type was observed in 37% (1591 cases), with epidermal growth factor receptor (EGFR) abnormalities being the most common at 49% (2127 cases). Positive C-MET overexpression correlated significantly with women (p < 0.001), early-stage (p = 0.003), adenocarcinoma (p < 0.001), and driver mutations (p < 0.001). Patients with anaplastic lymphoma kinase (ALK) alterations had a higher occurrence of C-MET overexpression positivity (57.1%). Positive C-MET overexpression was significantly associated with EGFR (p < 0.001), ALK (p < 0.001), and KRAS alterations (p = 0.024). Compared to C-MET overexpression (IHC 0), C-MET overexpression (IHC 2+) (hazard ratio (HR) = 0.455, p < 0.001) and C-MET overexpression (IHC 3+) (HR = 0.569, p < 0.001) were correlated with better overall survival in overall NSCLC patients, especially for C-MET overexpression (IHC 2+). Conclusion: Our study elucidates the clinicomolecular characteristics and prognosis of C-MET overexpression in NSCLC patients, particularly those with positive C-MET overexpression (IHC 3+). This provides insight into the prevalence of C-MET overexpression in Chinese NSCLC patients and offers a basis for considering C-MET overexpression as a prognostic and predictive marker in NSCLC.

Functional interaction between receptor tyrosine kinase MET and ETS transcription factors promotes prostate cancer progression.

Prostate cancer, the most common malignancy in men, has a relatively favourable prognosis. However, when it spreads to the bone, the survival rate drops dramatically. The development of bone metastases leaves patients with aggressive prostate cancer, the leading cause of death in men. Moreover, bone metastases are incurable and very painful. Hepatocyte growth factor receptor (MET) and fusion of genes encoding E26 transformation-specific (ETS) transcription factors are both involved in the progression of the disease. ETS gene fusions, in particular, have the ability to induce the migratory and invasive properties of prostate cancer cells, whereas MET receptor, through its signalling cascades, is able to activate transcription factor expression. MET signalling and ETS gene fusions are intimately linked to high-grade prostate cancer. However, the collaboration of these factors in prostate cancer progression has not yet been investigated. Here, we show, using cell models of advanced prostate cancer, that ETS translocation variant 1 (ETV1) and transcriptional regulator ERG (ERG) transcription factors (members of the ETS family) promote tumour properties, and that activation of MET signalling enhances these effects. By using a specific MET tyrosine kinase inhibitor in a humanised hepatocyte growth factor (HGF) mouse model, we also establish that MET activity is required for ETV1/ERG-mediated tumour growth. Finally, by performing a comparative transcriptomic analysis, we identify target genes that could play a relevant role in these cellular processes. Thus, our results demonstrate for the first time in prostate cancer models a functional interaction between ETS transcription factors (ETV1 and ERG) and MET signalling that confers more aggressive properties and highlight a molecular signature characteristic of this combined action.

Incidence and Temporal Patterns of Differentiated Thyroid Carcinoma in Children and Adolescents in Germany: A Pooled Analysis Based on Data from the German Malignant Endocrine Tumor Registry and the German Childhood Cancer Registry.

Introduction: The increasing incidence of differentiated thyroid carcinoma (DTC) in children and adolescents has become a growing concern. This study provides the first extensive assessment of incidence patterns and temporal trends of pediatric DTC in Germany, using the best available data from the German Malignant Endocrine Tumor (MET) Registry and the German Childhood Cancer Registry (GCCR) covering a period of 25 years. Patients and Methods: We conducted a register-based incidence and time series analysis, identifying all children and adolescents diagnosed with DTC at ages 0-17 years between 1997 and 2021 in Germany, as recorded in the German MET Registry and/or the GCCR. Age-specific and age-standardized incidence rates (ASR) over time, average annual percentage changes (AAPC), and cross-tabulations were used to evaluate incidence and temporal patterns. Results: We identified 469 DTC cases, including 85.7% papillary thyroid cancer and 9.4% follicular thyroid cancer. The average ASR for the period 1997-2021 was 1.16 per million, with higher rates in females compared with males (1.64 vs. 0.72 per million, respectively). Incidence rates increased with increasing age. The overall ASR increased from 0.84 per million in 1997-2001 to 1.48 per million in 2017-2021, with an AAPC of 3.46% [confidence interval or CI: 2.12-4.83]. The increase was most pronounced in adolescents aged 15-17 years (AAPC: 6.79% [CI: 4.43-9.19]). The proportion of incidentalomas rose from 5% in 1997-2001 to 26% in 2017-2021, yet we observed no marked shift in tumor size between symptomatic and incidental cases. Conclusions: Our study revealed a significant increase in pediatric DTC incidence in Germany, most pronounced among adolescents. The observation of an increasing incidence mirrors global trends and presents a complex public health challenge. While improved detection likely contributes to this trend, the stable tumor size distribution suggests that other factors are also in play. The rising detection of incidentalomas suggests enhanced diagnostic practices unrelated to symptoms of thyroid neoplasia. These findings highlight the need to carefully evaluate diagnostic and screening practices in pediatric populations.