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Journal of Translational Medicine Oct 2022Liver carcinoma generally presents as an immunosuppressive microenvironment that promotes tumor evasion. The intercellular crosstalk of immune cells significantly...
BACKGROUND
Liver carcinoma generally presents as an immunosuppressive microenvironment that promotes tumor evasion. The intercellular crosstalk of immune cells significantly influences the construction of an immunosuppressive microenvironment. This study aimed to investigate the important interactions between immune cells and their targeting drugs in liver carcinoma, by using single-cell and bulk transcriptomic data.
METHODS
Single-cell and bulk transcriptomic data were retrieved from Gene Expression Omnibus (GSE159977, GSE136103, and GSE125449) and The Cancer Genome Atlas (TGCA-LIHC), respectively. Quality control, dimension reduction, clustering, and annotation were performed according to the Scanpy workflow based on Python. Cell-cell interactions were explored using the CellPhone database and CellChat. Trajectory analysis was executed using a partition-based graph abstraction method. The transcriptomic factors (TFs) were predicted using single-cell regulatory network inference and clustering (SCENIC). The target genes from TFs were used to establish a related score based on the TCGA cohort; this score was subsequently validated by survival, gene set enrichment, and immune cell infiltration analyses. Drug prediction was performed based on the Cancer Therapeutics Response Portal and PRISM Repurposing datasets.
RESULTS
Thirty-one patients at four different states, including health, hepatitis, cirrhosis, and cancer, were enrolled in this study. After dimension reduction and clustering, twenty-two clusters were identified. Cell-cell interaction analyses indicated that macrophage-naive CD4 + T cell interaction significantly affect cancerous state. In brief, macrophages interact with naive CD4 + T cells via different pathways in different states. The results of SCENIC indicated that macrophages present in cancer cells were similar to those present during cirrhosis. A macrophage-naive CD4 + T cell (MNT) score was generated by the SCENIC-derived target genes. Based on the MNT score, five relevant drugs (inhibitor of polo-like kinase 1, inhibitor of kinesin family member 11, dabrafenib, ispinesib, and epothilone-b) were predicted.
CONCLUSIONS
This study reveals the crucial role of macrophage-naive CD4 + T cell interaction in the immunosuppressive microenvironment of liver carcinoma. Tumor-associated macrophages may be derived from cirrhosis and can initiate liver carcinoma. Predictive drugs that target the macrophage-naive CD4 + T cell interaction may help to improve the immunosuppressive microenvironment and prevent immune evasion. The relevant mechanisms need to be further validated in experiments and cohort studies.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Communication; Epothilones; Humans; Kinesins; Liver Cirrhosis; Liver Neoplasms; Macrophages; T-Lymphocytes; Transcriptome; Tumor Microenvironment
PubMed: 36221095
DOI: 10.1186/s12967-022-03675-2 -
Cancers Dec 2021Constitutive activation of FLT3 by ITD mutations is one of the most common genetic aberrations in AML, present in ~1/3 of cases. Patients harboring -ITD display worse...
Constitutive activation of FLT3 by ITD mutations is one of the most common genetic aberrations in AML, present in ~1/3 of cases. Patients harboring -ITD display worse clinical outcomes. The integration and advancement of FLT3 TKI in AML treatment provided significant therapeutic improvement. However, due to the emergence of resistance mechanisms, -ITD AML remains a clinical challenge. We performed an unbiased drug screen to identify 18 compounds as particularly efficacious against -ITD AML. Among these, we characterized two investigational compounds, WS6 and ispinesib, and two approved drugs, ponatinib and cabozantinib, in depth. We found that WS6, although not yet investigated in oncology, shows a similar mechanism and potency as ponatinib and cabozantinib. Interestingly, ispinesib and cabozantinib prevent activation of AXL, a key driver and mechanism of drug resistance in -ITD AML patients. We further investigated synergies between the selected compounds and found that combination treatment with ispinesib and cabozantinib or ponatinib shows high synergy in -ITD AML cell lines and patient samples. Together, we suggest WS6, ispinesib, ponatinib and cabozantinib as novel options for targeting -ITD AML. Whether combinatorial tyrosine kinase and kinesin spindle blockade is effective in eradicating neoplastic (stem) cells in -ITD AML remains to be determined in clinical trials.
PubMed: 34944800
DOI: 10.3390/cancers13246181 -
Cancer Research Dec 2017This review describes the pivotal roles of cell-cycle and checkpoint regulators and discusses development of specific cell-cycle inhibitors for therapeutic use for... (Review)
Review
This review describes the pivotal roles of cell-cycle and checkpoint regulators and discusses development of specific cell-cycle inhibitors for therapeutic use for pediatric cancer. The mechanism of action as well as the safety and tolerability of drugs in pediatric patients, including compounds that target CDK4/CDK6 (palbociclib, ribociclib, and abemaciclib), aurora kinases (AT9283 and MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib), and tubulin (taxanes, vinca alkaloids), are presented. The design of mechanism-based combinations that exploit the cross-talk of signals activated by cell-cycle arrest, as well as pediatric-focused drug development, are critical for the advancement of drugs for rare childhood diseases. .
Topics: Aurora Kinases; Cell Cycle; Cell Cycle Checkpoints; Cell Cycle Proteins; Child; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Humans; Kinesins; Neoplasms; Nuclear Proteins; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Tubulin
PubMed: 29097609
DOI: 10.1158/0008-5472.CAN-17-2066 -
Clinical Cancer Research : An Official... Jan 2010Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein, a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle...
PURPOSE
Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein, a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have shown a 9% response rate in patients with locally advanced or metastatic breast cancer and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities, or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer, we explored the activity of ispinesib alone and in combination with several therapies approved for the treatment of breast cancer.
EXPERIMENTAL DESIGN
We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo and tested the ability of ispinesib to enhance the antitumor activity of approved therapies.
RESULTS
In vitro, ispinesib displayed broad antiproliferative activity against a panel of 53 breast cell lines. In vivo, ispinesib produced regressions in each of five breast cancer models and tumor-free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the antitumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine and exhibited activity comparable with paclitaxel and ixabepilone.
CONCLUSIONS
These findings support further clinical exploration of kinesin spindle protein inhibitors for the treatment of breast cancer.
Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Kinesins; Mice; Mice, Nude; Mice, SCID; Quinazolines; Xenograft Model Antitumor Assays
PubMed: 20068098
DOI: 10.1158/1078-0432.CCR-09-1498 -
Cell Reports Jun 2022Inhibitors of the mitotic kinesin Kif11 are anti-mitotics that, unlike vinca alkaloids or taxanes, do not disrupt microtubules and are not neurotoxic. However,...
Inhibitors of the mitotic kinesin Kif11 are anti-mitotics that, unlike vinca alkaloids or taxanes, do not disrupt microtubules and are not neurotoxic. However, development of resistance has limited their clinical utility. While resistance to Kif11 inhibitors in other cell types is due to mechanisms that prevent these drugs from disrupting mitosis, we find that in glioblastoma (GBM), resistance to the Kif11 inhibitor ispinesib works instead through suppression of apoptosis driven by activation of STAT3. This form of resistance requires dual phosphorylation of STAT3 residues Y705 and S727, mediated by SRC and epidermal growth factor receptor (EGFR), respectively. Simultaneously inhibiting SRC and EGFR reverses this resistance, and combined targeting of these two kinases in vivo with clinically available inhibitors is synergistic and significantly prolongs survival in ispinesib-treated GBM-bearing mice. We thus identify a translationally actionable approach to overcoming Kif11 inhibitor resistance that may work to block STAT3-driven resistance against other anti-cancer therapies as well.
Topics: Animals; Antimitotic Agents; Cell Line, Tumor; ErbB Receptors; Glioblastoma; Kinesins; Mice; STAT3 Transcription Factor; Signal Transduction
PubMed: 35732128
DOI: 10.1016/j.celrep.2022.110991 -
Cancer Science Nov 2021Screening custom-made libraries of inhibitors may reveal novel drugs for treating pancreatic cancer. In this manner, we identified ispinesib as a candidate and attempted...
Screening custom-made libraries of inhibitors may reveal novel drugs for treating pancreatic cancer. In this manner, we identified ispinesib as a candidate and attempted to determine its clinical efficacy and the biological significance of its functional target Eg5 in pancreatic cancer. One hundred compounds in our library were screened for candidate drugs using cell cytotoxicity assays. Ispinesib was found to mediate effective antitumor effects in pancreatic cancer. The clinical significance of the expression of the ispinesib target Eg5 was investigated in 165 pancreatic cancer patients by immunohistochemical staining and in Eg5-positive pancreatic cancer patient-derived xenograft (PDX) mouse models. Patients with Eg5-positive tumors experienced significantly poorer clinical outcomes than those not expressing Eg5 (overall survival; P < .01, recurrence-free survival; P < .01). Ispinesib or Eg5 inhibition with specific siRNA significantly suppressed cell proliferation and induced apoptosis in pancreatic cancer cell lines. Mechanistically, ispinesib acted by inducing incomplete mitosis with nuclear disruption, resulting in multinucleated monoastral spindle cells. In the PDX mouse model, ispinesib dramatically reduced tumor growth relative to vehicle control (652.2 mm vs 18.1 mm in mean tumor volume, P < .01 by ANOVA; 545 mg vs 28 mg in tumor weight, P < .01, by ANOVA). Ispinesib, identified by inhibitor library screening, could be a promising novel therapeutic agent for pancreatic cancer. The expression of its target Eg5 is associated with poorer postoperative prognosis and is important for the clinical efficacy of ispinesib in pancreatic cancer.
Topics: Analysis of Variance; Animals; Antineoplastic Agents; Apoptosis; Benzamides; Cell Line, Tumor; Cell Proliferation; Disease-Free Survival; Drug Discovery; Female; Gene Silencing; Humans; Kinesins; Libraries, Special; Metaphase; Mice; Mice, Nude; Neoplasm Proteins; Pancreatic Neoplasms; Quinazolines; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 34510663
DOI: 10.1111/cas.15134 -
Chemical Science Oct 2019Graphene nanoflakes (GNFs) consist of a graphene sheet approximately 30 nm in diameter with a pristine aromatic system and an edge terminated with carboxylic acid...
Graphene nanoflakes (GNFs) consist of a graphene sheet approximately 30 nm in diameter with a pristine aromatic system and an edge terminated with carboxylic acid groups. Their high water solubility and relative ease of functionalisation using carboxylate chemistry means that GNFs are potential scaffolds for the synthesis of theranostic agents. In this work, GNFs were multi-functionalised with derivatives of (i) a peptide-based Glu-NH-C(O)-NH-Lys ligand that binds prostate-specific membrane antigen (PSMA), (ii) a potent anti-mitotic drug ()-ispinesib, (iii) the chelate desferrioxamine B (DFO), and (iv) an albumin-binding tag reported to extend pharmacokinetic half-life . Subsequent Ga radiochemistry and experiments and were used to evaluate the performance of GNFs in theranostic drug design. Efficient Ga-radiolabelling was achieved and the particle-loading of ()-ispinesib and Glu-NH-C(O)-NH-Lys was confirmed using cellular assays. Using dose-response curves and FACS analysis it was shown that GNFs loaded with ()-ispinesib inhibited the kinesin spindle protein (KSP) and induced G/M-phase cell cycle arrest. Cellular uptake and blocking experiments demonstrated that GNFs functionalised with the Glu-NH-C(O)-NH-Lys ligand showed specificity toward PSMA expressing cells (LNCaP). The distribution profile and excretion rates of Ga-radiolabelled GNFs in athymic nude mice was evaluated using time-activity curves derived from dynamic positron-emission tomography (PET). Image analysis indicated that GNFs have low accumulation and retention in background tissue, with rapid renal clearance. In summary, our study shows that GNFs are suitable candidates for use in theranostic drug design.
PubMed: 32874485
DOI: 10.1039/c9sc03736e -
Cancers Jun 2023Glioblastoma, IDH-wild type (GBM) is the most common and lethal malignant primary brain tumor. Standard of care includes surgery, radiotherapy, and chemotherapy with the...
Glioblastoma, IDH-wild type (GBM) is the most common and lethal malignant primary brain tumor. Standard of care includes surgery, radiotherapy, and chemotherapy with the DNA alkylating agent temozolomide (TMZ). Despite these intensive efforts, current GBM therapy remains mainly palliative with only modest improvement achieved in overall survival. With regards to radiotherapy, GBM is ranked as one of the most radioresistant tumor types. In this study, we wanted to investigate if enriching cells in the most radiosensitive cell cycle phase, mitosis, could improve localized radiotherapy for GBM. To achieve cell cycle arrest in mitosis we used ispinesib, a small molecule inhibitor to the mitotic kinesin, KIF11. Cell culture studies validated that ispinesib radiosensitized patient-derived GBM cells. In vivo, we validated that ispinesib increased the fraction of tumor cells arrested in mitosis as well as increased apoptosis. Critical for the translation of this approach, we validated that combination therapy with ispinesib and irradiation led to the greatest increase in survival over either monotherapy alone. Our data highlight KIF11 inhibition in combination with radiotherapy as a new combinatorial approach that reduces the overall radioresistance of GBM and which can readily be moved into clinical trials.
PubMed: 37370783
DOI: 10.3390/cancers15123173 -
BMC Bioinformatics May 2023This study aimed to observe the potential impact of known cuproptosis-related genes (CRGs) on triple negative breast cancer (TNBC) development, as well as their...
BACKGROUND
This study aimed to observe the potential impact of known cuproptosis-related genes (CRGs) on triple negative breast cancer (TNBC) development, as well as their associated molecular mechanisms, immune infiltration mechanisms and potential therapeutic agents.
RESULTS
Based on the Cox Proportional Hazard Model, 11 CRGs may be especially important in TNBC development and progression (considered as the Key-TNBC-CRGs). The expression of several Key-TNBC-CRGs (e.g., ATP7A, PIK3CA, LIAS, and LIPT) are associated with common mutations. The SCNA variation of 11 Key-TNBC-CRGs are related to differences immune infiltration profiles. In particular, depletion of ATP7A, ATP7B, CLS, LIAS, and SCL31A1 and while high amplification of NLRP3 and LIPT2 are correlated with decreased immune infiltration. In our Cox proportional hazards regression model, there is a significant difference in the overall survival between high-risk and low-risk groups. The HR in the high-risk group is 3.891 versus the low-risk group. And this model has a satisfactory performance in Prediction of 5-15-year survival, in particular in the 10-year survival (AUC = 0.836). Finally, we discovered some potential drugs for TNBC treatment based on the strategy of targeting 11 Key-TNBC-CRGs, such as Dasatinib combined with ABT-737, Erastin or Methotrexate, and Docetaxel/Ispinesib combination.
CONCLUSION
In conclusion, CRGs may play important roles in TNBC development, and they can impact tumor immune microenvironment and patient survival. The Key-TNBC-CRGs interact mutually and can be influenced by common BC-related mutations. Additionally, we established a 11-gene risk model with a robust performance in prediction of 5-15-year survival. As well, some new drugs are proposed potentially effective in TNBC based on the CRG strategy.
Topics: Humans; Dasatinib; Docetaxel; Mutation; Prognosis; Triple Negative Breast Neoplasms; Tumor Microenvironment; Copper; Apoptosis
PubMed: 37259036
DOI: 10.1186/s12859-023-05348-3 -
BioRxiv : the Preprint Server For... Sep 2023Glioblastoma (GBM) is a deadly brain tumor, and the kinesin motor KIF11 is an attractive therapeutic target because of its dual roles in proliferation and invasion. The...
Glioblastoma (GBM) is a deadly brain tumor, and the kinesin motor KIF11 is an attractive therapeutic target because of its dual roles in proliferation and invasion. The clinical utility of KIF11 inhibitors has been limited by drug resistance, which has mainly been studied in animal models. We used multiplexed lineage tracing barcodes and scRNA-seq to analyze drug resistance time courses for patient-derived GBM neurospheres treated with ispinesib, a potent KIF11 inhibitor. Similar to GBM progression in patients, untreated cells lost their neural lineage identity and transitioned to a mesenchymal phenotype, which is associated with poor prognosis. In contrast, cells subjected to long-term ispinesib treatment exhibited a proneural phenotype. We generated patient-derived xenografts to show that ispinesib-resistant cells form less aggressive tumors , even in the absence of drug. Finally, we used lineage barcodes to nominate drug combination targets by retrospective analysis of ispinesib-resistant clones in the drug-naïve setting and identified drugs that are synergistic with ispinesib.
PubMed: 37745469
DOI: 10.1101/2023.09.09.557001