Activated FGFR2 signalling as a biomarker for selection of intrahepatic cholangiocarcinoma patients candidate to FGFR targeted therapies.

FGFR inhibitors have been developed to inhibit FGFR activation and signal transduction; notwithstanding, currently the selection of intrahepatic cholangiocarcinoma (iCCA) patients for these drugs only relies on the detection of FGFR2 genetic alterations (GAs) in tumor tissues or circulating tumor DNAs, without concomitant assessment of FGFR2 signalling status. Accordingly, we performed multi-omic analyses of FGFR2 genes and FGFR2 signalling molecules in the tissue samples from 36 iCCA naïve patients. Gain-of-function FGFR2 GAs were detected in 7 patients, including missense mutations (n = 3; p.F276C, p.C382R and p.Y375C), translocations (n = 1) and copy number gain (n = 4; CNV ≥ 4). In contrast, among 29 patients with wild-type FGFR2, 4 cases showed activation of FGFR2 signalling, as they expressed the FGFR2 ligand FGF10 and phosphorylated FGFR2/FRS2α proteins; the remaining 25 cases resulted negative for activated FGFR2 signalling, as they lacked FGFR2 (n = 8) or phosphorylated FRS2α (n = 17) expression. Overall, we found that activation of FGFR2 signalling occurs not only in iCCA naïve patients with FGFR2 GAs, but also in a subgroup carrying wild-type FGFR2. This last finding entails that also this setting of patients could benefit from FGFR targeted therapies, widening indication of these drugs for iCCA patients beyond current approval. Future clinical studies are therefore encouraged to confirm this hypothesis.

FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions.

Fibroblast growth factor (FGF) signalling via FGF receptors (FGFR1-4) orchestrates fetal development and contributes to tissue and whole-body homeostasis, but can also promote tumorigenesis. Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. Erdafitinib is approved for patients with urothelial carcinoma harbouring FGFR2/3 alterations, and futibatinib and pemigatinib are approved for patients with cholangiocarcinoma harbouring FGFR2 fusions and/or rearrangements. Clinical benefit from these agents is in part limited by hyperphosphataemia owing to off-target inhibition of FGFR1 as well as the emergence of resistance mutations in FGFR genes, activation of bypass signalling pathways, concurrent TP53 alterations and possibly epithelial-mesenchymal transition-related isoform switching. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence.

WNT signaling and cancer stemness.

Cancer stemness, defined as the self-renewal and tumor-initiation potential of cancer stem cells (CSCs), is a cancer biology property featuring activation of CSC signaling networks. Canonical WNT signaling through Frizzled and LRP5/6 receptors is transmitted to the ß-catenin-TCF/LEF-dependent transcription machinery to up-regulate MYC, CCND1, LGR5, SNAI1, IFNG, CCL28, CD274 (PD-L1) and other target genes. Canonical WNT signaling causes expansion of rapidly cycling CSCs and modulates both immune surveillance and immune tolerance. In contrast, noncanonical WNT signaling through Frizzled or the ROR1/2 receptors is transmitted to phospholipase C, Rac1 and RhoA to control transcriptional outputs mediated by NFAT, AP-1 and YAP-TEAD, respectively. Noncanonical WNT signaling supports maintenance of slowly cycling, quiescent or dormant CSCs and promotes epithelial-mesenchymal transition via crosstalk with TGFß (transforming growth factor-ß) signaling cascades, while the TGFß signaling network induces immune evasion. The WNT signaling network orchestrates the functions of cancer-associated fibroblasts, endothelial cells and immune cells in the tumor microenvironment and fine-tunes stemness in human cancers, such as breast, colorectal, gastric and lung cancers. Here, WNT-related cancer stemness features, including proliferation/dormancy plasticity, epithelial-mesenchymal plasticity and immune-landscape plasticity, will be discussed. Porcupine inhibitors, ß-catenin protein-protein interaction inhibitors, ß-catenin proteolysis targeting chimeras, ROR1 inhibitors and ROR1-targeted biologics are investigational drugs targeting WNT signaling cascades. Mechanisms of cancer plasticity regulated by the WNT signaling network are promising targets for therapeutic intervention; however, further understanding of context-dependent reprogramming trajectories might be necessary to optimize the clinical benefits of WNT-targeted monotherapy and applied combination therapy for patients with cancer.

Precision medicine for human cancers with Notch signaling dysregulation (Review).

NOTCH1, NOTCH2, NOTCH3 and NOTCH4 are transmembrane receptors that transduce juxtacrine signals of the delta­like canonical Notch ligand (DLL)1, DLL3, DLL4, jagged canonical Notch ligand (JAG)1 and JAG2. Canonical Notch signaling activates the transcription of BMI1 proto­oncogene polycomb ring finger, cyclin D1, CD44, cyclin dependent kinase inhibitor 1A, hes family bHLH transcription factor 1, hes related family bHLH transcription factor with YRPW motif 1, MYC, NOTCH3, RE1 silencing transcription factor and transcription factor 7 in a cellular context­dependent manner, while non­canonical Notch signaling activates NF­κB and Rac family small GTPase 1. Notch signaling is aberrantly activated in breast cancer, non­small­cell lung cancer and hematological malignancies, such as T­cell acute lymphoblastic leukemia and diffuse large B­cell lymphoma. However, Notch signaling is inactivated in small­cell lung cancer and squamous cell carcinomas. Loss­of­function NOTCH1 mutations are early events during esophageal tumorigenesis, whereas gain­of­function NOTCH1 mutations are late events during T­cell leukemogenesis and B­cell lymphomagenesis. Notch signaling cascades crosstalk with fibroblast growth factor and WNT signaling cascades in the tumor microenvironment to maintain cancer stem cells and remodel the tumor microenvironment. The Notch signaling network exerts oncogenic and tumor­suppressive effects in a cancer stage­ or (sub)type­dependent manner. Small­molecule γ­secretase inhibitors (AL101, MRK­560, nirogacestat and others) and antibody­based biologics targeting Notch ligands or receptors [ABT­165, AMG 119, rovalpituzumab tesirine (Rova­T) and others] have been developed as investigational drugs. The DLL3­targeting antibody­drug conjugate (ADC) Rova­T, and DLL3­targeting chimeric antigen receptor­modified T cells (CAR­Ts), AMG 119, are promising anti­cancer therapeutics, as are other ADCs or CAR­Ts targeting tumor necrosis factor receptor superfamily member 17, CD19, CD22, CD30, CD79B, CD205, Claudin 18.2, fibroblast growth factor receptor (FGFR)2, FGFR3, receptor­type tyrosine­protein kinase FLT3, HER2, hepatocyte growth factor receptor, NECTIN4, inactive tyrosine­protein kinase 7, inactive tyrosine­protein kinase transmembrane receptor ROR1 and tumor­associated calcium signal transducer 2. ADCs and CAR­Ts could alter the therapeutic framework for refractory cancers, especially diffuse­type gastric cancer, ovarian cancer and pancreatic cancer with peritoneal dissemination. Phase III clinical trials of Rova­T for patients with small­cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch­related knowledge­base and optimize Notch­targeted therapy for patients with cancer.

Genomic testing, tumor microenvironment and targeted therapy of Hedgehog-related human cancers.

Hedgehog signals are transduced through Patched receptors to the Smoothened (SMO)-SUFU-GLI and SMO-Gi-RhoA signaling cascades. MTOR-S6K1 and MEK-ERK signals are also transduced to GLI activators through post-translational modifications. The GLI transcription network up-regulates target genes, such as BCL2, FOXA2, FOXE1, FOXF1, FOXL1, FOXM1, GLI1, HHIP, PTCH1 and WNT2B, in a cellular context-dependent manner. Aberrant Hedgehog signaling in tumor cells leads to self-renewal, survival, proliferation and invasion. Paracrine Hedgehog signaling in the tumor microenvironment (TME), which harbors cancer-associated fibroblasts, leads to angiogenesis, fibrosis, immune evasion and neuropathic pain. Hedgehog-related genetic alterations occur frequently in basal cell carcinoma (BCC) (85%) and Sonic Hedgehog (SHH)-subgroup medulloblastoma (87%) and less frequently in breast cancer, colorectal cancer, gastric cancer, pancreatic cancer, non-small-cell lung cancer (NSCLC) and ovarian cancer. Among investigational SMO inhibitors, vismodegib and sonidegib are approved for the treatment of patients with BCC, and glasdegib is approved for the treatment of patients with acute myeloid leukemia (AML). Resistance to SMO inhibitors is caused by acquired SMO mutations, SUFU deletions, GLI2 amplification, other by-passing mechanisms of GLI activation and WNT/ß-catenin signaling activation. GLI-DNA-interaction inhibitors (glabrescione B and GANT61), GLI2 destabilizers (arsenic trioxide and pirfenidone) and a GLI-deacetylation inhibitor (4SC-202) were shown to block GLI-dependent transcription and tumorigenesis in preclinical studies. By contrast, SMO inhibitors can remodel the immunosuppressive TME that is dominated by M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells and regulatory T cells, and thus, a Phase I/II clinical trial of the immune checkpoint inhibitor pembrolizumab with or without vismodegib in BCC patients is ongoing.

Fibroblast growth factor receptors as treatment targets in clinical oncology.

FGFRs are receptor tyrosine kinases with a role in several biological processes, such as the regulation of development and tissue repair. However, alterations in FGFRs 1-4, such as amplifications, fusions and mutations, as well as aberrant epigenetic or transcriptional regulation and changes in tumour-stromal interactions in the tumour microenvironment, can lead to the development and/or progression of cancer. Similar to other kinase alterations, such alterations are targetable using small molecules or antibodies, and the benefits of FGFR inhibitors have been demonstrated in clinical trials involving subsets of patients with solid tumours harbouring FGFR alterations. However, the response rates in patients with FGFR alterations were relatively low, and responses in patients without detectable FGFR alterations were also observed. In this Review, the author describes the clinical experience with FGFR inhibitors to date, and highlights key aspects that might lead to improved response rates and/or the avoidance of acquired resistance, including the selection of patients who are most likely to benefit from treatment, and the use of FGFR inhibitors in combination regimens with other agents.

Multi­layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/ß­catenin signaling activation (Review).

ß­catenin/CTNNB1 is an intracellular scaffold protein that interacts with adhesion molecules (E­cadherin/CDH1, N­cadherin/CDH2, VE­cadherin/CDH5 and α­catenins), transmembrane­type mucins (MUC1/CD227 and MUC16/CA125), signaling regulators (APC, AXIN1, AXIN2 and NHERF1/EBP50) and epigenetic or transcriptional regulators (BCL9, BCL9L, CREBBP/CBP, EP300/p300, FOXM1, MED12, SMARCA4/BRG1 and TCF/LEF). Gain­of­function CTTNB1 mutations are detected in bladder cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer and uterine cancer, whereas loss­of­function CTNNB1 mutations are also detected in human cancer. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA and ZNRF3 are representative ß­catenin target genes. ß­catenin signaling is involved in myofibroblast activation and subsequent pulmonary fibrosis, in addition to other types of fibrosis. ß­catenin and NF­κB signaling activation are involved in field cancerization in the stomach associated with Helicobacter pylori (H. pylori) infection and in the liver associated with hepatitis C virus (HCV) infection and other etiologies. ß­catenin­targeted therapeutics are functionally classified into ß­catenin inhibitors targeting upstream regulators (AZ1366, ETC­159, G007­LK, GNF6231, ipafricept, NVP­TNKS656, rosmantuzumab, vantictumab, WNT­C59, WNT974 and XAV939), ß­catenin inhibitors targeting protein­protein interactions (CGP049090, CWP232228, E7386, ICG­001, LF3 and PRI­724), ß­catenin inhibitors targeting epigenetic regulators (PKF118­310), ß­catenin inhibitors targeting mediator complexes (CCT251545 and cortistatin A) and ß­catenin inhibitors targeting transmembrane­type transcriptional outputs, including CD44v6, FZD7 and LGR5. Eradicating H. pylori and HCV is the optimal approach for the first­line prevention of gastric cancer and hepatocellular carcinoma (HCC), respectively. However, ß­catenin inhibitors may be applicable for the prevention of organ fibrosis, second­line HCC prevention and treating ß­catenin­driven cancer. The multi­layered prevention and treatment strategy of ß­catenin­related human diseases is necessary for the practice of personalized medicine and implementation of precision medicine.

Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review).

Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFß/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49). Aberrant canonical and non-canonical WNT signaling in human malignancies, including breast, colorectal, gastric, lung, ovary, pancreatic, prostate and uterine cancers, leukemia and melanoma, are involved in CSC survival, bulk-tumor expansion and invasion/metastasis. WNT signaling-targeted therapeutics, such as anti-FZD1/2/5/7/8 monoclonal antibody (mAb) (vantictumab), anti-LGR5 antibody-drug conjugate (ADC) (mAb-mc-vc-PAB-MMAE), anti-PTK7 ADC (PF-06647020), anti-ROR1 mAb (cirmtuzumab), anti-RSPO3 mAb (rosmantuzumab), small-molecule porcupine inhibitors (ETC-159, WNT-C59 and WNT974), tankyrase inhibitors (AZ1366, G007-LK, NVP-TNKS656 and XAV939) and ß-catenin inhibitors (BC2059, CWP232228, ICG-001 and PRI-724), are in clinical trials or preclinical studies for the treatment of patients with WNT-driven cancers. WNT signaling-targeted therapeutics are applicable for combination therapy with BCR-ABL, EGFR, FLT3, KIT or RET inhibitors to treat a subset of tyrosine kinase-driven cancers because WNT and tyrosine kinase signaling cascades converge to ß-catenin for the maintenance and expansion of CSCs. WNT signaling-targeted therapeutics might also be applicable for combination therapy with immune checkpoint blockers, such as atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab and pembrolizumab, to treat cancers with immune evasion, although the context-dependent effects of WNT signaling on immunity should be carefully assessed. Omics monitoring, such as genome sequencing and transcriptome tests, immunohistochemical analyses on PD-L1 (CD274), PD-1 (PDCD1), ROR1 and nuclear ß-catenin and organoid-based drug screening, is necessary to determine the appropriate WNT signaling-targeted therapeutics for cancer patients.

Molecular genetics and targeted therapy of WNT-related human diseases (Review).

Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/ß-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/ß-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate ß-catenin phosphorylation and ß-catenin-dependent transcription. Germline mutations in WNT signaling molecules cause hereditary colorectal cancer, bone diseases, exudative vitreoretinopathy, intellectual disability syndrome and PCP-related diseases. APC or CTNNB1 mutations in colorectal, endometrial and prostate cancers activate the WNT/ß-catenin signaling cascade. RNF43, ZNRF3, RSPO2 or RSPO3 alterations in breast, colorectal, gastric, pancreatic and other cancers activate the WNT/ß-catenin, WNT/STOP and other WNT signaling cascades. ROR1 upregulation in B-cell leukemia and solid tumors and ROR2 upregulation in melanoma induce invasion, metastasis and therapeutic resistance through Rho-ROCK, Rac-JNK, PI3K-AKT and YAP signaling activation. WNT signaling in cancer, stromal and immune cells dynamically orchestrate immune evasion and antitumor immunity in a cell context-dependent manner. Porcupine (PORCN), RSPO3, WNT2B, FZD5, FZD10, ROR1, tankyrase and ß-catenin are targets of anti-WNT signaling therapy, and ETC-159, LGK974, OMP-18R5 (vantictumab), OMP-54F28 (ipafricept), OMP-131R10 (rosmantuzumab), PRI-724 and UC-961 (cirmtuzumab) are in clinical trials for cancer patients. Different classes of anti-WNT signaling therapeutics are necessary for the treatment of APC/CTNNB1-, RNF43/ZNRF3/RSPO2/RSPO3- and ROR1-types of human cancers. By contrast, Dickkopf-related protein 1 (DKK1), SOST and glycogen synthase kinase 3ß (GSK3ß) are targets of pro-WNT signaling therapy, and anti-DKK1 (BHQ880 and DKN-01) and anti-SOST (blosozumab, BPS804 and romosozumab) monoclonal antibodies are being tested in clinical trials for cancer patients and osteoporotic post-menopausal women. WNT-targeting therapeutics have also been applied as reagents for in vitro stem-cell processing in the field of regenerative medicine.

Prognostic significance of ß-catenin expression in patients with non-small cell lung cancer: a meta-analysis.

BACKGROUND: ß-catenin is a key component of the canonical Wnt pathway, which plays pivotal roles in malignant transformation and cancer progression. Several studies have reported the clinical significance of the expression level of ß-catenin in different subcellular locations. This meta-analysis aimed to assess the prognostic value of ß-catenin expression patterns in patients with non-small cell lung cancer (NSCLC). METHODS: PubMed and Embase databases were searched to identify all articles referring to the association between ß-catenin expression level and outcomes of patients of NSCLC up to November 2016. We included eligible studies to summarize the extracted data in terms of pooled hazard ratios (HRs) and their 95% confidence intervals (95% CIs). RESULTS: A total of 24 studies published between 2000 and 2016 were eligible for this meta-analysis. The total number of patients with NSCLC included was 2,807. Pooled HRs and 95% CIs suggested that positive ß-catenin expression in membrane was associated with higher survival rates (HR: 0.53; 95% CI: 0.32-0.87), whereas ß-catenin expression in cytoplasm and nucleus had unfavorable impacts on survival rates with HR of 1.63 (95% CI: 1.34-1.99) and HR of 3.15 (95% CI: 1.97-5.05), respectively. But, there was no significant association between ß-catenin expression in abnormal pattern with prognosis (HR: 1.38; 95% CI: 0.61-3.15). Publication bias was absent in all of the four outcomes. Sensitivity analysis revealed that the results of this meta-analysis were robust. CONCLUSIONS: Reduced membranous ß-catenin, positive expression of cytoplasmic or nuclear ß-catenin is all correlated with poor prognosis, although we did not identify a significant association between abnormal ß-catenin expression and clinical outcome of NSCLC patients. The meta-analysis suggested that membranous, cytoplasmic and nuclear ß-catenin all could serve as an important prognosticator for patients with NSCLC.

Therapeutics Targeting FGF Signaling Network in Human Diseases.

Fibroblast growth factor (FGF) signaling through its receptors, FGFR1, FGFR2, FGFR3, or FGFR4, regulates cell fate, angiogenesis, immunity, and metabolism. Dysregulated FGF signaling causes human diseases, such as breast cancer, chondrodysplasia, gastric cancer, lung cancer, and X-linked hypophosphatemic rickets. Recombinant FGFs are pro-FGF signaling therapeutics for tissue and/or wound repair, whereas FGF analogs and gene therapy are under development for the treatment of cardiovascular disease, diabetes, and osteoarthritis. FGF traps, anti-FGF/FGFR monoclonal antibodies (mAbs), and small-molecule FGFR inhibitors are anti-FGF signaling therapeutics under development for the treatment of cancer, chondrodysplasia, and rickets. Here, I discuss the benefit-risk and cost-effectiveness issues of precision medicine targeting FGFRs, ALK, EGFR, and FLT3. FGFR-targeted therapy should be optimized for cancer treatment, focusing on genomic tests and recurrence.

Genomic Landscape of Experimental Bladder Cancer in Rodents and Its Application to Human Bladder Cancer: Gene Amplification and Potential Overexpression of Cyp2a5/CYP2A6 Are Associated with the Invasive Phenotype.

Non-muscle invasive (superficial) bladder cancer is a low-grade malignancy with good prognosis, while muscle invasive (invasive) bladder cancer is a high-grade malignancy with poor prognosis. N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) induces superficial bladder cancers with papillary morphology in rats and invasive bladder cancers with infiltrating phenotype in mice. In this study, we analyzed genomic landscapes of rodent BBN-induced bladder cancers using array-based comparative genomic hybridization (array CGH). While no significant copy number alterations were detected in superficial bladder tumors in rats, copy number gains in chromosomal regions 2D-E1, 7qA3, 9F2, and 11C-D were detected in invasive bladder tumors in mice. Amplification of representative genes located on 2D-E1 and 7qA3 chromosomal regions was confirmed by quantitative PCR. Cyp2a22 and Cyp2a5 genes but not Cyp2g1, Cyp2a12, and Rab4b genes on mouse chromosome 7qA3 were amplified in invasive bladder cancers. Although the human ortholog gene of Cyp2a22 has not been confirmed, the mouse Cyp2a5 gene is the ortholog of the human CYP2A6 gene located in chromosomal region 19q13.2, and CYP2A6 was identified by database search as one of the closest human homolog to mouse Cyp2a22. Considering a possibility that this region may be related to mouse 7qA3, we analyzed CYP2A6 copy number and expression in human bladder cancer using cell lines and resected tumor specimens. Although only one of eight cell lines showed more than one copy increase of the CYP2A6 gene, CYP2A6 amplification was detected in six out of 18 primary bladder tumors where it was associated with the invasive phenotype. Immunohistochemical analyses of 118 primary bladder tumors revealed that CYP2A6 protein expression was also higher in invasive tumors, especially in those of the scattered type. Together, these findings indicate that the amplification and overexpression of the CYP2A6 gene are characteristic of human bladder cancers with increased malignancy and that CYP2A6 can be a candidate prognostic biomarker in this type of cancer.

Mechanistic Investigation of Catalyst-Transfer Suzuki-Miyaura Condensation Polymerization of Thiophene-Pyridine Biaryl Monomers with the Aid of Model Reactions.

We have investigated the requirements for efficient Pd-catalyzed Suzuki-Miyaura catalyst-transfer condensation polymerization (Pd-CTCP) reactions of 2-alkoxypropyl-6-(5-bromothiophen-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (12) as a donor-acceptor (D-A) biaryl monomer. As model reactions, we first carried out the Suzuki-Miyaura coupling reaction of X-Py-Th-X' (Th=thiophene, Py=pyridine, X, X'=Br or I) 1 with phenylboronic acid ester 2 by using tBu3 PPd0 as the catalyst. Monosubstitution with a phenyl group at Th-I mainly took place in the reaction of Br-Py-Th-I (1 b) with 2, whereas disubstitution selectively occurred in the reaction of I-Py-Th-Br (1 c) with 2, indicating that the Pd catalyst is intramolecularly transferred from acceptor Py to donor Th. Therefore, we synthesized monomer 12 by introduction of a boronate moiety and bromine into Py and Th, respectively. However, examination of the relationship between monomer conversion and the Mn of the obtained polymer, as well as the matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectra, indicated that Suzuki-Miyaura coupling polymerization of 12 with (o-tolyl)tBu3 PPdBr initiator 13 proceeded in a step-growth polymerization manner through intermolecular transfer of the Pd catalyst. To understand the discrepancy between the model reactions and polymerization reaction, Suzuki-Miyaura coupling reactions of 1 c with thiopheneboronic acid ester instead of 2 were carried out. This resulted in a decrease of the disubstitution product. Therefore, step-growth polymerization appears to be due to intermolecular transfer of the Pd catalyst from Th after reductive elimination of the Th-Pd-Py complex formed by transmetalation of polymer Th-Br with (Pin)B-Py-Th-Br monomer 12 (Pin=pinacol). Catalysts with similar stabilization energies of metal-arene η2 -coordination for D and A monomers may be needed for CTCP reactions of biaryl D-A monomers.

Prognostic value of wingless-type proteins in non-small cell lung cancer patients: a meta-analysis.

BACKGROUND: Wingless-type protein (Wnt) signaling pathway plays a crucial role in the development of human malignancies, such as epithelial-to-mesenchymal transition (EMT) and the maintenance of cancer stem cells (CSCs). Several studies have shown that the expression levels of Wnt proteins, ligands of Wnt signaling pathway, are related to clinical outcomes of non-small cell lung cancer (NSCLC) patients. This meta-analysis aimed to assess the prognostic value of Wnts proteins in patients with NSCLC. METHODS: A multiple electronic literature search was conducted to identify all articles referring to the prognostic value of Wnt proteins in patients of NSCLC up to July 2016. Eligible studies were included in a meta-analysis in order to summarize the extracted data in terms of pooled hazard ratios (HRs) and their 95% confidence intervals (95% CIs). RESULTS: Ten studies published between 2005 and 2015 were eligible for this meta-analysis. The total number of patients included was 1,805. The combined HR for all eligible studies evaluating the overall survival (OS) of NSCLC patients with positive Wnt expression was 1.60 (95% CI: 1.39-1.84). The subgroup analysis showed both Wnt1 and Wnt5a are associated with clinical outcome of NSCLC patients. CONCLUSIONS: Overexpression of Wnt proteins, as well as Wnt1 or Wnt5a alone, was markedly associated with adverse OS in lung cancer patients, suggesting that Wnts may act as a prognostic marker among NSCLCs.

FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review).

Fibroblast growth factor (FGF)2, FGF4, FGF7 and FGF20 are representative paracrine FGFs binding to heparan-sulfate proteoglycan and fibroblast growth factor receptors (FGFRs), whereas FGF19, FGF21 and FGF23 are endocrine FGFs binding to Klotho and FGFRs. FGFR1 is relatively frequently amplified and overexpressed in breast and lung cancer, and FGFR2 in gastric cancer. BCR-FGFR1, CNTRL-FGFR1, CUX1-FGFR1, FGFR1OP-FGFR1, MYO18A-FGFR1 and ZMYM2-FGFR1 fusions in myeloproliferative neoplasms are non-receptor-type FGFR kinases, whereas FGFR1-TACC1, FGFR2-AFF3, FGFR2-BICC1, FGFR2-PPHLN1, FGFR3-BAIAP2L1 and FGFR3-TACC3 fusions in solid tumors are transmembrane-type FGFRs with C-terminal alterations. AZD4547, BGJ398 (infigratinib), Debio-1347 and dovitinib are FGFR1/2/3 inhibitors; BLU9931 is a selective FGFR4 inhibitor; FIIN-2, JNJ-42756493, LY2874455 and ponatinib are pan-FGFR inhibitors. AZD4547, dovitinib and ponatinib are multi-kinase inhibitors targeting FGFRs, colony stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF)R2, and others. The tumor microenvironment consists of cancer cells and stromal/immune cells, such as cancer-associated fibroblasts (CAFs), endothelial cells, M2-type tumor-associating macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs) and regulatory T cells. FGFR inhibitors elicit antitumor effects directly on cancer cells, as well as indirectly through the blockade of paracrine signaling. The dual inhibition of FGF and CSF1 or VEGF signaling is expected to enhance the antitumor effects through the targeting of immune evasion and angiogenesis in the tumor microenvironment. Combination therapy using tyrosine kinase inhibitors (FGFR or CSF1R inhibitors) and immune checkpoint blockers (anti-PD-1 or anti-CTLA-4 monoclonal antibodies) may be a promising choice for cancer patients. The inhibition of FGF19-FGFR4 signaling is associated with a risk of liver toxicity, whereas the activation of FGF23-FGFR4 signaling is associated with a risk of heart toxicity. Endocrine FGF signaling affects the pathophysiology of cancer patients who are prescribed FGFR inhibitors. Whole-genome sequencing is necessary for the detection of promoter/enhancer alterations of FGFR genes and rare alterations of other genes causing FGFR overexpression. To sustain the health care system in an aging society, a benefit-cost analysis should be performed with a focus on disease-free survival and the total medical cost before implementing genome-based precision medicine for cancer patients.