4,697 results match your criteria Molecular Cancer Therapeutics[Journal]


A simple three-dimensional hydrogel platform enables ex vivo cell culture of patient and PDX tumors for assaying their response to clinically relevant therapies.

Mol Cancer Ther 2019 Feb 12. Epub 2019 Feb 12.

Department of Neurosurgery, Cedars-Sinai Medical Center

A cell culture platform that enables ex vivo tissue growth from patients or patient-derived xenograft (PDX) models and assesses sensitivity to approved therapies (e.g. Temozolomide, TMZ) in a clinically relevant timeframe would be very useful in translational research and personalized medicine. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0359DOI Listing
February 2019

TGFβ blockade enhances radiotherapy abscopal efficacy effects in combination with anti-PD1 and anti-CD137 immunostimulatory monoclonal antibodies.

Mol Cancer Ther 2019 Jan 25. Epub 2019 Jan 25.

Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA)

Radiotherapy can be synergistically combined with immunotherapy in mouse models, extending its efficacious effects outside of the irradiated field (abscopal effects). We previously reported that a regimen encompassing local radiotherapy in combination with anti-CD137 plus anti-PD-1 mAbs achieves potent abscopal effects against syngeneic transplanted murine tumors up to a certain tumor size. Knowing that TGF-beta expression or activation increases in irradiated tissues, we tested whether TGF-beta blockade may further enhance abscopal effects in conjunction with the anti-PD-1 plus anti-CD137 mAb combination. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0558DOI Listing
January 2019
1 Read

Combined MEK and BCL-2/XL inhibition is effective in high-grade serous ovarian cancer patient-derived xenograft models and BIM levels are predictive of responsiveness.

Mol Cancer Ther 2019 Jan 24. Epub 2019 Jan 24.

Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School

Most patients with late stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient-derived xenograft (PDX) models. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0413DOI Listing
January 2019
5.683 Impact Factor

The Antitumor Drug LB-100 is a Catalytic Inhibitor of Protein Phosphatase 2A (PPP2CA) and 5 (PPP5C) Coordinating with the Catalytic Metals in the Active Site of PP5C.

Mol Cancer Ther 2019 Jan 24. Epub 2019 Jan 24.

Biochemistry and Molecular Biology, University of South Alabama College of Medicine

LB-100 is an experimental cancer-therapeutic with cytotoxic activity against cancer cells in culture and antitumor activity in animals. The first Phase I trial (NCT01837667) evaluating LB-100 recently concluded that safety and efficacy parameters are favorable for further clinical testing. Although LB-100 is widely reported as a specific inhibitor of serine/threonine phosphatase 2A (PP2AC/PPP2CA:PPP2CB), we could find no experimental evidence in the published literature demonstrating the specific engagement of LB-100 with PP2A in vitro, in cultured cells, or in animals. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-17-1143DOI Listing
January 2019
1 Read

First-in-human phase I study of an oral HSP90 inhibitor, TAS-116, in patients with advanced solid tumors.

Mol Cancer Ther 2019 Jan 24. Epub 2019 Jan 24.

Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation For Cancer Research.

HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of TAS-116, a novel class, orally available, highly selective inhibitor of HSP90. Patients with advanced solid tumors received TAS-116 orally once daily (QD, step 1), or every other day (QOD, step 2) in 21-day cycles. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0831DOI Listing
January 2019

Nanoparticle delivery of miR-708 mimetic impairs breast cancer metastasis.

Mol Cancer Ther 2019 Jan 24. Epub 2019 Jan 24.

Cardiothoracic Surgery, Weill Cornell Medicine

Triple-negative breast cancer (TNBC) patients exhibit the worst clinical outcome due to its aggressive clinical course, higher rate of recurrence, and a conspicuous lack of FDA approved targeted therapies. Here, we show that multilayered nanoparticles (NPs) carrying the metastasis suppressor microRNA miR-708 (miR708-NP) localize to orthotopic primary TNBC, and efficiently deliver the miR-708 cargo to reduce lung metastasis. Using a SOX2/OCT4 promoter reporter, we identified a population of miR-708low cancer cells with tumor-initiating properties, enhanced metastatic potential and marked sensitivity to miR-708 treatment. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0702DOI Listing
January 2019

A kinase inhibitor with anti-Pim kinase activity is a potent and selective cytotoxic agent towards acute myeloid leukemia.

Mol Cancer Ther 2019 Jan 24. Epub 2019 Jan 24.

Centre for Pharmacy, Department of Clinical Science, University of Bergen

More than 40 years ago, the present standard induction therapy for acute myeloid leukemia (AML) was developed. This consists of the metabolic inhibitor cytarabine (AraC) and the cytostatic topoisomerase 2 inhibitor daunorubucin (DNR). In light of the high chance for relapse, as well as the large heterogeneity, novel therapies are needed to improve patient outcome. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-17-1234DOI Listing
January 2019
1 Read

Maternal Embryonic Leucine Zipper Kinase (MELK), a Potential Therapeutic Target for Neuroblastoma.

Mol Cancer Ther 2019 Jan 23. Epub 2019 Jan 23.

Pediatrics, University of Chicago

Maternal Embryonic Leucine Zipper Kinase (MELK) activates pathways that mediate aggressive tumor growth and therapy resistance in many types of adult cancers. Pharmacologic and genomic inhibition of MELK impairs tumor growth and increases sensitivity to radiation and chemotherapy. Based on these promising preclinical studies, early phase adult clinical trials testing the MELK inhibitor OTS167 are ongoing. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0819DOI Listing
January 2019
5 Reads

Chemically modified antisense oligonucleotide against ARL4C inhibits primary and metastatic liver tumor growth.

Mol Cancer Ther 2019 Jan 15. Epub 2019 Jan 15.

Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University

ADP-ribosylation factor-like 4c (ARL4C) is identified as a small GTP-binding protein that is expressed by Wnt and EGF signaling and plays an important role in tubulogenesis of cultured cells and the ureters. ARL4C is little expressed in adult tissues, but it is highly expressed in lung cancer and colorectal cancer (CRC) and shown to represent a molecular target for cancer therapy based on siRNA experiments. This study revealed that ARL4C is highly expressed in primary hepatocellular carcinoma (HCC) tumors and CRC liver metastases and that ARL4C expression is associated with poor prognosis for these cancers. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0824DOI Listing
January 2019
2 Reads

The Rolipram-Perillyl Alcohol Conjugate (NEO214) Is A Mediator Of Cell Death Through The Death Receptor Pathway.

Mol Cancer Ther 2019 Jan 15. Epub 2019 Jan 15.

Neurosurgery, University of Southern California

Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Treatment with temozolomide (TMZ), standard of care for gliomas, usually results in drug resistance and tumor recurrence. Therefore, there is a great need for drugs that target GBM. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0465DOI Listing
January 2019
2 Reads

Antimalarial drug pyrimethamine plays a dual role in anti-tumor proliferation and metastasis through targeting DHFR and TP.

Mol Cancer Ther 2019 Jan 14. Epub 2019 Jan 14.

State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University.

Pyrimethamine (Pyr), an antimalarial drug that targeting plasmodium dihydrofolate reductase (pDHFR), has been proved to have antitumor activity. However, its direct target on cancer cells remains unclear. Methotrexate (MTX) is a widely used anticancer drug that blocks human dihydrofolate reductase (hDHFR). Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0936DOI Listing
January 2019
8 Reads

Blood Interactions, Pharmacokinetics and Depth-Dependent Ablation of Rat Mammary Tumors with Photoactivatable, Liposomal Doxorubicin.

Mol Cancer Ther 2018 Dec 26. Epub 2018 Dec 26.

Biomedical Engineering, University at Buffalo, State University of New York

Photosensitizers can be integrated with drug delivery vehicles to develop chemophototherapy agents with anti-tumor synergy between chemo- and photo- components. Long-circulating doxorubicin (Dox) in porphyrin-phospholipid (PoP) liposomes (LC-Dox-PoP) incorporates a phospholipid-like photosensitizer (2 mole %) in the bilayer of Dox-loaded stealth liposomes. Hematological effects of endotoxin-minimized LC-Dox-PoP were characterized via standardized assays. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0549DOI Listing
December 2018
2 Reads

TSR-033, a novel therapeutic antibody targeting LAG-3 enhances T cell function and the activity of PD-1 blockade in vitro and in vivo.

Mol Cancer Ther 2018 Dec 26. Epub 2018 Dec 26.

External Innovation, Ipsen.

Progressive upregulation of checkpoints on tumor infiltrating lymphocytes promotes an immunosuppressive tumor microenvironment, severely compromising tumor immunity. Lymphocyte activation gene-3 (LAG-3) is a co-inhibitory receptor associated with impaired T cell function and is frequently co-expressed with programmed cell death protein-1 (PD-1) in the context of human cancers. Targeting LAG-3 in conjunction with PD-1 thus represents a strategy to amplify and broaden the therapeutic impact of PD-1 blockade alone. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0836DOI Listing
December 2018
15 Reads

TGFβ Blockade Augments PD-1 Inhibition to Promote T-Cell Mediated Regression of Pancreatic Cancer.

Mol Cancer Ther 2018 Dec 26. Epub 2018 Dec 26.

Department of Surgery, University of Illinois at Chicago.

Pancreatic ductal adenocarcinoma (PDAC) remains remarkably lethal with a 5-year survival rate of 8%. This is mainly attributed to the late stage of presentation, as well as widespread resistance to conventional therapy. Additionally, PDAC tumors are largely non-immunogenic, and most patients have displayed incomplete responses to cancer immunotherapies. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0850DOI Listing
December 2018
4 Reads
5.683 Impact Factor

Enhancing chemosensitivity of breast cancer stem cells by down regulating SOX2 and ABCG2 using Wedelolactone-encapsulated nanoparticles.

Mol Cancer Ther 2018 Dec 26. Epub 2018 Dec 26.

ZOOLOGY, University of Calcutta

A major caveat in the treatment of breast cancer is disease recurrence after therapeutic regime at both local and distal sites. Tumor relapse is attributed to the persistence of chemoresistant cancer stem cells (CSCs), which need to be obliterated along with conventional chemotherapy. Wedelolactone (Wdl), a naturally occurring coumestan, demonstrates anticancer effects in different cancer cells, though with several limitations, and is mostly ineffective against CSCs. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0409DOI Listing
December 2018
1 Read

Germline variant in SLCO2B1 and response to abiraterone acetate plus prednisone (AA) in new onset metastatic castration-resistant prostate cancer (mCRPC).

Mol Cancer Ther 2018 Dec 26. Epub 2018 Dec 26.

Medicine, University of Utah/Huntsman Cancer Institute

There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently available. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate (AA) for men with advanced prostate cancer. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0739DOI Listing
December 2018
3 Reads

The secretome engages STAT3 to favor a cytokine-rich microenvironment in mediating acquired resistance to FGFR inhibitors.

Mol Cancer Ther 2018 Dec 6. Epub 2018 Dec 6.

Anti-tumor Pharmacology, Shanghai Institute of Materia Medica.

Acquired resistance severely hinders the application of small molecule inhibitors. Our understanding of acquired resistance related to fibroblast growth factor receptors (FGFRs) is limited. Here, to explore the underlying mechanism of acquired resistance in FGFR-aberrant cancer cells, we generated cells resistant to multiple FGFR inhibitors and investigated the potential mechanisms underlying acquired resistance. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0179DOI Listing
December 2018
3 Reads

Genome-Wide Sequencing of Cell-Free DNA Identifies Copy-Number Alterations That Can Be Used for Monitoring Response to Immunotherapy in Cancer Patients.

Mol Cancer Ther 2019 Feb 6;18(2):448-458. Epub 2018 Dec 6.

Division of Hematology/Oncology, Department of Medicine, Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, San Diego, California.

Inhibitors of the PD-1/PD-L1/CTLA-4 immune checkpoint pathway have revolutionized cancer treatment. Indeed, some patients with advanced, refractory malignancies achieve durable responses; however, only a subset of patients benefit, necessitating new biomarkers to predict outcome. Interrogating cell-free DNA (cfDNA) isolated from plasma (liquid biopsy) provides a promising method for monitoring response. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0535DOI Listing
February 2019
2 Reads

KDM5B Promotes Drug Resistance by Regulating Melanoma Propagating Cell Subpopulations.

Mol Cancer Ther 2018 Dec 6. Epub 2018 Dec 6.

Department of Pathology, Yale School of Medicine

Tumor heterogeneity is a major challenge for cancer treatment, especially due to the presence of various subpopulations with stem cell or progenitor cell properties. In mouse melanomas, both CD34+p75- (CD34+) and CD34-p75- (CD34-) tumor subpopulations were characterized as melanoma-propagating cells (MPCs) that exhibit some of those key features. However, these two subpopulations differ from each other in tumorigenic potential, ability to recapitulate heterogeneity, and chemo-resistance. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0395DOI Listing
December 2018
1 Read

Combined PPARγ Activation and XIAP Inhibition as a Potential Therapeutic Strategy for Ovarian Granulosa Cell Tumors.

Mol Cancer Ther 2019 Feb 7;18(2):364-375. Epub 2018 Dec 7.

Hudson Institute of Medical Research and the Monash University Department of Molecular and Translational Science, Clayton, Victoria, Australia.

Ovarian granulosa cell tumors (GCT) are characterized by indolent growth and late relapse. No therapeutic modalities aside from surgery have proven effective. We previously reported overexpression of the nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPARγ), and constitutive activity of the NFκB and AP1 signaling pathways in GCT. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0078DOI Listing
February 2019
7 Reads

Cooperative Effect of Oncogenic and in an HGF-Dominant Environment in Breast Cancer.

Mol Cancer Ther 2019 Feb 5;18(2):399-412. Epub 2018 Dec 5.

Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

There is compelling evidence that oncogenic and signaling pathways contribute to breast cancer. However, the activity of pharmacologic targeting of either pathway is modest. Mechanisms of resistance to these monotherapies have not been clarified. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0710DOI Listing
February 2019
11 Reads

XPO1 Inhibitor Selinexor Overcomes Intrinsic Ibrutinib Resistance in Mantle Cell Lymphoma via Nuclear Retention of IκB.

Mol Cancer Ther 2018 Dec;17(12):2564-2574

Department of Pathology, University of Chicago, Chicago, Illinois.

Inhibition of B-cell receptor (BCR) signaling through the BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one third of patients do not respond well to the drug, and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-17-0789-ATRDOI Listing
December 2018
1 Read
5.683 Impact Factor

Targeting the Sphingosine 1-Phosphate Axis Exerts Potent Antitumor Activity in BRAFi-Resistant Melanomas.

Mol Cancer Ther 2019 Feb 27;18(2):289-300. Epub 2018 Nov 27.

Université Fédérale de Toulouse Midi-Pyrénées, Université Toulouse III Paul-Sabatier, Inserm, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France.

BRAF inhibitors (BRAFi) are used to treat patients with melanoma harboring the V600E mutation. However, resistance to BRAFi is inevitable. Here, we identified sphingosine 1-phosphate (S1P) receptors as regulators of BRAF-mutant melanoma cell-autonomous resistance to BRAFi. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-17-1141DOI Listing
February 2019
3 Reads

Inhibition of MERTK Promotes Suppression of Tumor Growth in BRAF Mutant and BRAF Wild-Type Melanoma.

Mol Cancer Ther 2019 Feb 27;18(2):278-288. Epub 2018 Nov 27.

Aflac Cancer Center of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia.

Molecularly-targeted agents have improved outcomes for a subset of patients with -mutated melanoma, but treatment of resistant and wild-type tumors remains a challenge. The MERTK receptor tyrosine kinase is aberrantly expressed in melanoma and can contribute to oncogenic phenotypes. Here we report the effect of treatment with a MERTK-selective small molecule inhibitor, UNC2025, in preclinical models of melanoma. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0456DOI Listing
February 2019
2 Reads

Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer.

Mol Cancer Ther 2019 Feb 26;18(2):389-398. Epub 2018 Nov 26.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri.

Ovarian cancer, one of the deadliest malignancies in female cancer patients, is characterized by recurrence and poor response to cytotoxic chemotherapies. Fewer than 30% of patients with resistant disease will respond to additional chemotherapy treatments. This study aims to determine whether and how inhibition of the receptor tyrosine kinase AXL can restore sensitivity to first-line platinum and taxane therapy in ovarian cancer. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363844PMC
February 2019
9 Reads

Targeting of BRM sensitizes BRG1 mutant lung cancer cell lines to radiotherapy.

Mol Cancer Ther 2018 Nov 26. Epub 2018 Nov 26.

Radiotherapy, University Hospital in Essen.

Targeting of epigenetic regulators as the chromatin remodeler SWI/SNF is proving to be a promising therapeutic strategy for individualized treatment of cancer patients. Here we tested whether targeting one of the two mutually exclusive subdomains of the SWI/SNF complex BRM/SMARCA2 can sensitize specifically NSCLC cells with mutations in the other subunit BRG1/SMARCA4 towards ionizing radiation (IR). Knock-down of BRM with siRNA or shRNA and its consequences for radiation sensitivity as measured by clonogenic survival and plaque-monolayer control was studied in different NSCLC lines with or without BRG1 mutations and in primary fibroblasts. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0067DOI Listing
November 2018
1 Read

3D Growth of Cancer Cells Elicits Sensitivity to Kinase Inhibitors but Not Lipid Metabolism Modifiers.

Mol Cancer Ther 2019 Feb 26;18(2):376-388. Epub 2018 Nov 26.

Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

Tumor cells exhibit altered lipid metabolism compared with normal cells. Cell signaling kinases are important for regulating lipid synthesis and energy storage. How upstream kinases regulate lipid content, versus direct targeting of lipid-metabolizing enzymes, is currently unexplored. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0857DOI Listing
February 2019
9 Reads

Induction of MNK Kinase-dependent eIF4E Phosphorylation by Inhibitors Targeting BET Proteins Limits Efficacy of BET Inhibitors.

Mol Cancer Ther 2019 Feb 16;18(2):235-244. Epub 2018 Nov 16.

Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

BET inhibitors (BETi), which target transcription of key oncogenic genes, are currently being evaluated in early-phase clinical trials. However, because BETis show limited single-agent activity, there is increasing interest in identifying signaling pathways to enhance the efficacy of BETis. Here, we demonstrate increased MNK kinase-dependent eIF4E phosphorylation following treatment with BETis, indicating activation of a prosurvival feedback mechanism in response to BETis. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363873PMC
February 2019
1 Read

AKT Inhibition Modulates H3K4 Demethylase Levels in PTEN-Null Prostate Cancer.

Mol Cancer Ther 2019 Feb 16;18(2):356-363. Epub 2018 Nov 16.

Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.

Hyperactivated AKT kinase due to loss of its negative regulator PTEN influences many aspects of cancer biology, including chromatin. AKT primarily regulates acetyl-CoA production and phosphorylates many histone-modulating enzymes, resulting in their activation or inhibition. Therefore, understanding the therapeutic impact of AKT inhibition on chromatin-related events is essential. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0141DOI Listing
February 2019
9 Reads
5.683 Impact Factor

The T197A Knock-in Model of Gene to Study the Effects of p27 Restoration .

Mol Cancer Ther 2019 Feb 13;18(2):482-493. Epub 2018 Nov 13.

Department of Experimental and Clinical Medicine, University "Magna Graecia," Catanzaro, Italy.

The CDK inhibitor, p27, encoded by the gene can negatively modulate cell proliferation. The control of p27 activity during the cell cycle is regulated at multiple levels, including transcription, translation, and protein stability. The last residue of p27 (threonine 198 in human, threonine 197 in mouse) is involved in the control of protein stability. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0134DOI Listing
February 2019
15 Reads

MTORC1/2 Inhibition as a Therapeutic Strategy for Mutant Cancers.

Mol Cancer Ther 2019 Feb 13;18(2):346-355. Epub 2018 Nov 13.

Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.

mutations are common in clinical molecular profiling, yet an effective means to target these cancers has yet to be developed. MTORC1 inhibitors are often used off-label for patients with mutant cancers with only limited data to support this approach. Here we describe a cohort of patients treated with cancers possessing mutations activating the PI3K signaling cascade with minimal benefit to treatment with the MTORC1 inhibitor everolimus. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363831PMC
February 2019
11 Reads

Predicting Novel Therapies and Targets: Regulation of Notch3 by the Bromodomain Protein BRD4.

Mol Cancer Ther 2019 Feb 12;18(2):421-436. Epub 2018 Nov 12.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Systematic approaches for accurate repurposing of targeted therapies are needed. We developed and aimed to biologically validate our therapy predicting tool (TPT) for the repurposing of targeted therapies for specific tumor types by testing the role of Bromodomain and Extra-Terminal motif inhibitors (BETi) in inhibiting BRD4 function and downregulating Notch3 signaling in ovarian cancer.Utilizing established ovarian cancer preclinical models, we carried out and studies with clinically relevant BETis to determine their therapeutic effect and impact on Notch3 signaling. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363833PMC
February 2019
12 Reads

miR-454-3p Is an Exosomal Biomarker and Functions as a Tumor Suppressor in Glioma.

Mol Cancer Ther 2019 Feb 9;18(2):459-469. Epub 2018 Nov 9.

Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.

Glioma is the most common type of primary malignant brain tumor in adults. Our previous work discovered that plasma miR-454-3p may have some advantages in glioma prognosis, but the clinical significance and the regulatory mechanism of miR-454-3p in glioma have not been systematically investigated, especially regarding the relationship between circulating and tissue miR-454-3p. The expression level of miR-454-3p in glioma serum and tissues was analyzed through quantitative real-time PCR (qRT-PCR). Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0725DOI Listing
February 2019
29 Reads

Pleiotropic Action of Novel Bruton's Tyrosine Kinase Inhibitor BGB-3111 in Mantle Cell Lymphoma.

Mol Cancer Ther 2019 Feb 9;18(2):267-277. Epub 2018 Nov 9.

Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas.

Bruton's tyrosine kinase (BTK) is a key mediator of BCR-dependent cell growth signaling and a clinically effective therapeutic target in mantle cell lymphoma (MCL). The molecular impact of BTK inhibition remains unclear particularly in hematopoietic malignancies. We analyzed the molecular mechanisms of BTK inhibition with the novel inhibitor BGB-3111 (zanubrutinib) in MCL models. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363842PMC
February 2019
18 Reads

APOMAB Antibody-Drug Conjugates Targeting Dead Tumor Cells are Effective .

Mol Cancer Ther 2019 Feb 9;18(2):335-345. Epub 2018 Nov 9.

Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.

Antibody-drug conjugates (ADC) have revolutionized the field of cancer therapy. ADCs combine the high specificity of tumor-targeting monoclonal antibodies with potent cytotoxic drugs, which cannot be used alone because of their high toxicity. Till date, all ADCs have either targeted cell membrane proteins on tumors or the tumor vasculature and microenvironment. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0842DOI Listing
February 2019
7 Reads

Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer.

Mol Cancer Ther 2019 Feb 7;18(2):301-311. Epub 2018 Nov 7.

Department of Surgery, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against , a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363854PMC
February 2019
17 Reads
5.683 Impact Factor

Circulating Tumor Cells with Stemness and Epithelial-to-Mesenchymal Transition Features Are Chemoresistant and Predictive of Poor Outcome in Metastatic Breast Cancer.

Mol Cancer Ther 2019 Feb 6;18(2):437-447. Epub 2018 Nov 6.

Laboratory of Translational Oncology, School of Medicine, University of Crete, Crete, Greece.

Circulating tumor cells (CTCs) bearing phenotypes related to cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) have been identified in breast cancer; however, their clinical significance is not clear. In the current study, we investigated the prognostic relevance of single CSC/partial-EMT CTCs in patients with metastatic breast cancer and the effect of first-line chemotherapy on their incidence. For this purpose, triple immunofluorescence against cytokeratin, ALDH1, and TWIST1 was performed in peripheral blood mononuclear cell (PBMC) cytospins from 130 patients before and after first-line chemotherapy. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0584DOI Listing
February 2019
9 Reads

Combining DNA Vaccine and AIM2 in H1 Nanoparticles Exert Anti-Renal Carcinoma Effects via Enhancing Tumor-Specific Multi-functional CD8 T-cell Responses.

Mol Cancer Ther 2019 Feb 6;18(2):323-334. Epub 2018 Nov 6.

Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.

Renal carcinoma presents a rapid progression in patients with high metastasis with no effective therapeutic strategy. In this study, we designed a folate-grafted PEI600-CyD (H1) nanoparticle-mediated DNA vaccine containing an adjuvant of absent in melanoma 2 (AIM2) and a tumor-specific antigen of carbonic anhydrase IX (CAIX) for renal carcinoma therapy. Mice bearing subcutaneous human CAIX (hCAIX)-Renca tumor were intramuscularly immunized with H1-pAIM2/pCAIX, H1-pCAIX, H1-pAIM2, or Mock vaccine, respectively. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0832DOI Listing
February 2019
7 Reads

Intestinal Toxicity in Rats Following Administration of CDK4/6 Inhibitors Is Independent of Primary Pharmacology.

Mol Cancer Ther 2019 Feb 6;18(2):257-266. Epub 2018 Nov 6.

Pfizer Inc., Drug Safety Research and Development, San Diego, California.

Recently three different cyclin-dependent kinase 4 and 6 (CDK4/6) dual inhibitors were approved for the treatment of breast cancer (palbociclib, ribociclib, and abemaciclib), all of which offer comparable therapeutic benefits. Their safety profiles, however, are different. For example, neutropenia is observed at varying incidences in patients treated with these drugs; however, it is the most common adverse event for palbociclib and ribociclib, whereas diarrhea is the most common adverse event observed in patients treated with abemaciclib. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0734DOI Listing
February 2019
15 Reads

Necuparanib, A Multitargeting Heparan Sulfate Mimetic, Targets Tumor and Stromal Compartments in Pancreatic Cancer.

Mol Cancer Ther 2019 Feb 6;18(2):245-256. Epub 2018 Nov 6.

Momenta Pharmaceuticals, Inc. Cambridge, Massachusetts.

Pancreatic cancer has an abysmal 5-year survival rate of 8%, making it a deadly disease with a need for novel therapies. Here we describe a multitargeting heparin-based mimetic, necuparanib, and its antitumor activity in both and models of pancreatic cancer. Necuparanib reduced tumor cell proliferation and invasion in a three-dimensional (3D) culture model; , it extended survival and reduced metastasis. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0417DOI Listing
February 2019
12 Reads

CD3-Bispecific Antibody Therapy Turns Solid Tumors into Inflammatory Sites but Does Not Install Protective Memory.

Mol Cancer Ther 2019 Feb 31;18(2):312-322. Epub 2018 Oct 31.

Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands.

Immunotherapy of cancer with CD3-targeting bispecific antibodies (CD3 bsAb) is a fast developing field, and multiple tumor-associated antigens (TAA) are evaluated for hematologic and solid malignancies. The efficacy of these CD3 bsAb is usually examined in xenograft mouse tumor models with human T cells or in genetically engineered mouse models, where human TAA are introduced. These models often fail to fully recapitulate the natural tumor environment, especially for solid cancers, because of interspecies differences. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0679DOI Listing
February 2019
11 Reads

Combined Cellular and Biochemical Profiling to Identify Predictive Drug Response Biomarkers for Kinase Inhibitors Approved for Clinical Use between 2013 and 2017.

Mol Cancer Ther 2019 Feb 31;18(2):470-481. Epub 2018 Oct 31.

Netherlands Translational Research Center B.V., Oss, the Netherlands.

Kinase inhibitors form the largest class of precision medicine. From 2013 to 2017, 17 have been approved, with 8 different mechanisms. We present a comprehensive profiling study of all 17 inhibitors on a biochemical assay panel of 280 kinases and proliferation assays of 108 cancer cell lines. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0877DOI Listing
February 2019
2 Reads

Identification of the Novel Role of CD24 as an Oncogenesis Regulator and Therapeutic Target for Triple-Negative Breast Cancer.

Mol Cancer Ther 2019 Jan 31;18(1):147-161. Epub 2018 Oct 31.

Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with unfavorable prognosis and 5-year survival. The purpose of this study was to investigate the underlying mechanisms involved in TNBC progression. We determined that CD24 expression was elevated in highly lung and lymph node metastatic TNBC cells. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0292DOI Listing
January 2019
1 Read
5.683 Impact Factor

Glycoprotein-130 Expression Is Associated with Aggressive Bladder Cancer and Is a Potential Therapeutic Target.

Mol Cancer Ther 2019 Feb 31;18(2):413-420. Epub 2018 Oct 31.

Department of Urology, Yale University, New Haven, Connecticut.

Predicting bladder cancer progression is important in selecting the optimal treatment for bladder cancer. Because current diagnostic factors regarding progression are lacking, new factors are needed to further stratify the curative potential of bladder cancer. Glycoprotein-130 (GP130), a transmembrane protein, is central to a number of signal transduction pathways involved in tumor aggressiveness, making it an attractive target. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-17-1079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363894PMC
February 2019
1 Read

TRAF2 Cooperates with Focal Adhesion Signaling to Regulate Cancer Cell Susceptibility to Anoikis.

Mol Cancer Ther 2019 Jan 29;18(1):139-146. Epub 2018 Oct 29.

Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Departments of Medicine, Oncology, and Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.

TRAF2, a RING finger adaptor protein, plays an important function in tumor necrosis factor (TNF)- and TNF-like weak inducer of apoptosis (TWEAK)-dependent signaling, in particular during inflammatory and immune responses. We identified a functional interaction of TRAF2 with focal adhesion (FA) signaling involving the focal adhesion kinase (FAK) in the regulation of cell susceptibility to anoikis. Comparison of TRAF2-proficient (TRAF2) versus TRAF2-deficient (TRAF2), and FAK-proficient (FAK) versus FAK-deficient (FAK) mouse embryonic fibroblasts and their matched reconstituted cells demonstrated that TRAF2 interacts physically with the N-terminal portion of FAK and colocalizes to cell membrane protrusions. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-17-1261DOI Listing
January 2019
16 Reads
5.683 Impact Factor

Anti-MET VHH Pool Overcomes MET-Targeted Cancer Therapeutic Resistance.

Mol Cancer Ther 2019 Jan 25;18(1):100-111. Epub 2018 Oct 25.

The Therapeutic Antibody Research Center of SEU-Alphamab, Institute of Life Sciences, Southeast University, Nanjing, China.

Receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) play crucial roles in many human malignancies. Numerous drugs have been developed against kinase center of MET or HGF-mediated activation; however, the outcomes in patients are not so promising. Increasing evidence show that MET has kinase-independent effects on tumorigenesis and dissemination, which explains the low efficacy in kinase inhibition-based strategy. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0351DOI Listing
January 2019
9 Reads

Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties.

Mol Cancer Ther 2019 Jan 23;18(1):3-16. Epub 2018 Oct 23.

PTC Therapeutics, Inc., South Plainfield, New Jersey.

PTC299 was identified as an inhibitor of VEGFA mRNA translation in a phenotypic screen and evaluated in the clinic for treatment of solid tumors. To guide precision cancer treatment, we performed extensive biological characterization of the activity of PTC299 and demonstrated that inhibition of VEGF production and cell proliferation by PTC299 is linked to a decrease in uridine nucleotides by targeting dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for pyrimidine nucleotide synthesis. Unlike previously reported DHODH inhibitors that were identified using enzyme assays, PTC299 is a more potent inhibitor of DHODH in isolated mitochondria suggesting that mitochondrial membrane lipid engagement in the DHODH conformation is required for its optimal activity. Read More

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http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318026PMC
January 2019
22 Reads

Improved Therapeutic Window in -mutant Tumors with Antibody-linked Pyrrolobenzodiazepine Dimers with and without PARP Inhibition.

Mol Cancer Ther 2019 Jan 23;18(1):89-99. Epub 2018 Oct 23.

Oncology Research, MedImmune, Gaithersburg, Maryland.

Pyrrolobenzodiazepine dimers (PBD) form cross-links within the minor groove of DNA causing double-strand breaks (DSB). DNA repair genes such as and play important roles in homologous recombination repair of DSB. We hypothesized that PBD-based antibody-drug conjugates (ADC) will have enhanced killing of cells in which homologous recombination processes are defective by inactivation of or genes. Read More

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http://dx.doi.org/10.1158/1535-7163.MCT-18-0314DOI Listing
January 2019
2 Reads
5.683 Impact Factor