4,737 results match your criteria Molecular Cancer Therapeutics[Journal]


Neutralization of BCL-2/XL enhances the cytotoxicity of T-DM1 in vivo.

Mol Cancer Ther 2019 Apr 8. Epub 2019 Apr 8.

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

One of the most recent advances in the treatment of HER2+ breast cancer is the development of the antibody-drug conjugate, T-DM1. T-DM1 has proven clinical benefits for patients with advanced and/or metastatic breast cancer who have progressed on prior HER2-targeted therapies. However, T-DM1 resistance ultimately occurs and represents a major obstacle in the effective treatment of this disease. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0743DOI Listing
April 2019
1 Read

Manipulation of cell-type selective antibody internalization by a guide-effector bispecific design.

Mol Cancer Ther 2019 Apr 8. Epub 2019 Apr 8.

Department of Anesthesia, UCSF Helen Diller Family Comprehensive Cancer Center

Cell-type specific intracellular payload delivery is desired for antibody-based targeted therapy development. However, tumor-specific internalizing antigens are rare to find, and even rarer for those that are expressed at uniformly high levels. We constructed a bispecific antibody that is composed of a rapidly internalizing antibody binding to a tumor-associated antigen EphA2 and a non-internalizing antibody binding to a highly expressed tumor-associated antigen ALCAM. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-1313DOI Listing

Establishment and characterization of histologically and molecularly stable soft tissue sarcoma xenograft models for biological studies and preclinical drug testing.

Mol Cancer Ther 2019 Apr 8. Epub 2019 Apr 8.

Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, and Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven.

Soft tissue sarcomas (STS) represent a heterogeneous group of rare, malignant tumors of mesenchymal origin. Reliable in vivo sarcoma research models are scarce. We aimed to establish and characterize histologically and molecularly stable patient-derived xenograft (PDX) models from a broad variety of STS subtypes. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-1045DOI Listing
April 2019
4 Reads

Discovery of a novel EGFR targeting antibody-drug conjugate, SHR-A1307, for the treatment of solid tumors resistant or refractory to anti-EGFR therapies.

Mol Cancer Ther 2019 Apr 8. Epub 2019 Apr 8.

Shanghai Hengrui Medicine Co. Ltd.

While inhibiting EGFR-mediated signaling proved to be effective in treating certain types of cancers, a quickly evolved mechanism that either restores the EGFR signaling or activates an alternative pathway for driving the proliferation and survival of malignant cells limits the efficacy and utility of the approach via suppressing the EGFR functionality. Given the fact that overexpression of EGFR is commonly seen in many cancers, an EGFR-targeting antibody-drug conjugate (ADC) can selectively kill cancer cells independently of blocking EGFR-mediated signaling. Herein, we describe SHR-A1307, a novel anti-EGFR ADC, generated from an anti-EGFR antibody with prolonged half-life, conjugated with a proprietary toxin payload which has increased index of EGFR targeting-dependent vs. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0854DOI Listing
April 2019
5.683 Impact Factor

Inhibition of Ubiquitin-specific protease 14 suppresses cell proliferation and synergizes with chemotherapeutic agents in neuroblastoma.

Mol Cancer Ther 2019 Apr 8. Epub 2019 Apr 8.

Division of Pediatric Surgery, Baylor College of Medicine

Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children, and drug resistance is a major reason for poor outcomes. Elevated proteasome activity plays an important role in NB tumor development and resistance to conventional chemotherapy. Ubiquitin-specific protease 14 (USP14), one of three deubiquitinases associated with the regulatory subunit of the proteasome, is emerging as a potential therapeutic target in multiple tumor types. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0146DOI Listing
April 2019
6 Reads
5.683 Impact Factor

A tumor-peptide based nanoparticle vaccine elicits efficient tumor growth control in anti-tumor immunotherapy.

Mol Cancer Ther 2019 Apr 8. Epub 2019 Apr 8.

Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen

Recognition of immunoactive oligonucleotides by the immune system, such as Toll-like receptor ligand CpG leads to increased antibody and T cell responses. Systemic application often results in unwanted generalized non-antigen specific activation of the immune system. Nanoparticles are ideal carriers for small and large molecules. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0764DOI Listing

Vemurafenib Inhibits Active PTK6 in PTEN-null Prostate Tumor Cells.

Mol Cancer Ther 2019 Mar 29. Epub 2019 Mar 29.

Biochemistry and Molecular Genetics, University of Illinois at Chicago

Protein tyrosine kinase 6 (PTK6, also called BRK) is overexpressed and activated in human prostate cancer. Loss of the tumor suppressor PTEN, a frequent event in prostate cancer, leads to PTK6 activation at the plasma membrane and its oncogenic signaling. The small molecule inhibitor vemurafenib, also known as PLX4032, and its tool analog PLX4720 were designed to inhibit constitutively active BRAF V600E, yet they also have potent effects against PTK6. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0862DOI Listing
March 2019
2 Reads

Targeting the IGF1R/PI3K/AKT Pathway Sensitizes Ewing Sarcoma to BET Bromodomain Inhibitors.

Mol Cancer Ther 2019 Mar 29. Epub 2019 Mar 29.

Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.

Inhibitors of the bromodomain and extra-terminal domain (BET) family proteins modulate EWS-FLI1 activities in Ewing sarcoma. However, the efficacy of BET inhibitors as a monotherapy was moderate and transient in preclinical models. The objective of this study was to identify the mechanisms mediating intrinsic resistance to BET inhibitors and develop more effective combination treatments for Ewing sarcoma. Read More

View Article

Download full-text PDF

Source
http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
Publisher Site
http://dx.doi.org/10.1158/1535-7163.MCT-18-1151DOI Listing
March 2019
2 Reads

GnRH-R targeted lytic peptide sensitizes BRCA wild-type ovarian cancer to PARP inhibition.

Mol Cancer Ther 2019 Mar 29. Epub 2019 Mar 29.

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

EP-100 is a synthetic lytic peptide that specifically targets the gonadotropin-releasing hormone receptor on cancer cells. To extend the utility of EP-100, we aimed to identify effective combination therapies with EP-100 for ovarian cancer and explore potential mechanisms of this combination. A series of in vitro (MTT assay, immunoblot analysis, reverse-phase protein array, comet assay, and immunofluorescence staining) and in vivo experiments were carried out to determine the biological effects of EP-100 alone and in combination with standard-of-care drugs. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0770DOI Listing
March 2019
2 Reads

Prospective Clinical Sequencing of Adult Glioma.

Mol Cancer Ther 2019 Mar 29. Epub 2019 Mar 29.

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Malignant gliomas are a group of intracranial cancers associated with disproportionately high mortality and morbidity. Here, we report ultradeep targeted sequencing of a prospective cohort of 237 tumors from 234 patients consisting of both glioblastoma (GBM) and lower-grade glioma (LGG) using our customized gene panels. We identified 2,485 somatic mutations, including single-nucleotide substitutions and small indels, using a validated in-house protocol. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-1122DOI Listing
March 2019
1 Read

RAC1b overexpression confers resistance to chemotherapy treatment in colorectal cancer.

Mol Cancer Ther 2019 Mar 29. Epub 2019 Mar 29.

Department of Oncology, Georgetown University.

Resistance to chemotherapy represents a major limitation in the treatment of colorectal cancer. Novel strategies to circumvent resistance are critical to prolonging patient survival. Rac1b, a constitutively activated isoform of the small GTPase Rac1, is upregulated with disease progression and promotes cell proliferation and inhibits apoptosis by activation of NFκΒ signaling. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0955DOI Listing

Distribution and Activity of Lenvatinib in Brain Tumor Models of Human Anaplastic Thyroid Cancer Cells in Severe Combined Immune Deficient Mice.

Mol Cancer Ther 2019 Mar 29. Epub 2019 Mar 29.

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

Anaplastic thyroid carcinoma (ATC) is a rare but aggressive undifferentiated tumor that frequently metastasizes to the brain. The multiple kinase inhibitor lenvatinib and sorafenib have been approved to treat unresectable differentiated thyroid cancer, and lenvatinib has been approved in Japan to treat ATC. This study compared the effects of lenvatinib and sorafenib in mouse models of central nervous system metastases of ATC. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0695DOI Listing
March 2019
4 Reads

Next generation sequencing of tissue and circulating tumor DNA: The UC San Diego Moores Center for Personalized Cancer Therapy experience with breast malignancies.

Mol Cancer Ther 2019 Mar 29. Epub 2019 Mar 29.

Center for Personalized Cancer Therapy, Division of Blood and Marrow Transplantation, University of California San Diego Moores Cancer Center.

Clinical-grade next generation sequencing (NGS) of tissue and blood-derived circulating tumor DNA (ctDNA) allows assessment of multiple genomic alterations in patients with cancer. We analyzed ctDNA (54-70 genes) in 62 patients with advanced breast cancer (median = five prior therapies); 38 also had tissue NGS (236-315 genes). Overall, 42 of 62 patients (68%) had detectable (characterized) ctDNA alterations (variants of unknown significance excluded); 37 of 38 (97%), tissue alterations. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-17-1038DOI Listing
March 2019
1 Read

BI1071, a novel Nur77 modulator, induces apoptosis of cancer cells by activating the Nur77-Bcl-2 apoptotic pathway.

Mol Cancer Ther 2019 Mar 29. Epub 2019 Mar 29.

Cancer Center, Sanford-Burnham Medical Research Institute.

Nur77 (also called TR3 or NGFI-B), an orphan member of the nuclear receptor superfamily, induces apoptosis by translocating to mitochondria where it interacts with Bcl-2 to convert Bcl-2 from an anti-apoptotic to a pro-apoptotic molecule. Nur77 posttranslational modification such as phosphorylation has been shown to induce Nur77 translocation from the nucleus to mitochondria. However, small molecules that can bind directly to Nur77 to trigger its mitochondrial localization and Bcl-2 interaction remain to be explored. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0918DOI Listing

Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus-1 with Integrin β1 Blocking Antibody OS2966.

Mol Cancer Ther 2019 Mar 29. Epub 2019 Mar 29.

Neurosurgery, University of Texas Health Science Center at Houston

Integrin β1 receptor, expressed on the surface of tumor cells and macrophages in the tumor microenvironment (TME), has been implicated in both tumor progression as well as resistance to multiple modalities of therapy. OS2966 is the first clinical-ready humanized monoclonal antibody to block integrin β1 and was recently orphan designated by FDA Office of Orphan Products Development (OOPD). Here, we tested therapeutic potential of OS2966-mediated integrin β1 blockade to enhance the efficacy of oncolytic herpes simplex virus-1 (oHSV) through evaluation of virus replication, tumor cell killing efficiency, effect on the antiviral signaling pathway, co-culture assays of oHSV-infected cells with macrophages, and in vivo bioluminescence imaging on mammary fat pad triple negative breast cancer xenograft and subcutaneous and intracranial glioma xenografts. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0953DOI Listing
March 2019
2 Reads

Functional analysis of somatic mutations affecting receptor tyrosine kinase family in metastatic colorectal cancer.

Mol Cancer Ther 2019 Mar 29. Epub 2019 Mar 29.

UMR 8161, Institut de biologie de Lille, French National Centre for Scientific Research

Besides the detection of somatic receptor tyrosine kinases (RTKs) mutations in tumor samples, the current challenge is to interpret their biological relevance in order to give patients effective targeted treatment. By high-throughput sequencing of the 58 RTK exons of healthy tissues, colorectal tumors, and hepatic metastases from 30 patients, 38 different somatic mutations in RTKs were identified. The RTK-kinase-domain mutations present in both tumors and metastases were reconstituted in order to perform an unbiased functional study. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0582DOI Listing

Preclinical investigation of 212Pb-DOTAMTATE for peptide receptor radionuclide therapy in a neuroendocrine tumor model.

Mol Cancer Ther 2019 Mar 29. Epub 2019 Mar 29.

Orano Med LLC.

Somatostatin analogs have been examined as a treatment for somatostatin receptor overexpressing tumors for years; specifically, octreotate (TATE) and octreotide (TOC). Several versions of these analogs coupled to beta or gamma nuclides are currently used as imaging agents, as treatments with peptide receptor radionuclide therapy (PRRT) for patients with neuroendocrine tumors or are being explored in preclinical and clinical settings. Our study describes the use of 212Pb-DOTAMTATE, the octreotate analog, in combination with 212Pb, the parent of an alpha emitter. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-1103DOI Listing

Modelling dose and schedule effects of AZD2811 nanoparticles targeting aurora kinase B for treatment of diffuse large B-cell lymphoma.

Mol Cancer Ther 2019 Mar 14. Epub 2019 Mar 14.

Bioscience, Oncology, IMED Biotech Unit, AstraZeneca (United Kingdom).

Barasertib (AZD1152), a pro-drug of the highly potent and selective Aurora B kinase inhibitor AZD2811, showed promising clinical activity in relapsed/refractory DLBCL patients administered as a 4-day infusion. To improve potential therapeutic benefit of Aurora B kinase inhibition, a nanoparticle formulation of AZD2811 has been developed to address limitations of repeated intravenous infusion. One of the challenges with the use of nanoparticles for chronic treatment of tumors is optimising dose and schedule required to enable repeat administration to sustain tumor growth inhibition. Read More

View Article

Download full-text PDF

Source
http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
Publisher Site
http://dx.doi.org/10.1158/1535-7163.MCT-18-0577DOI Listing
March 2019
15 Reads

TAS-121, a selective mutant EGFR inhibitor, shows activity against tumors expressing various EGFR mutations including T790M and uncommon mutations G719X.

Mol Cancer Ther 2019 Mar 14. Epub 2019 Mar 14.

Discovery and Preclinical Research Division, Taiho pharmaceutical Co.,Ltd

TAS-121 is a novel orally active selective covalent inhibitor of the mutant epidermal growth factor receptor (EGFR). We performed preclinical characterization of TAS-121 and compared its efficacy and selectivity for common EGFR mutations (Ex19del and L858R), first- and second- generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance mutation (T790M), and uncommon mutations (G719X and L861Q) with those of other EGFR-TKIs. We also commenced investigation of the clinical benefits of TAS-121. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0645DOI Listing

Inhibition of the Replication Stress Response Is a Synthetic Vulnerability in SCLC That Acts Synergistically in Combination with Cisplatin.

Mol Cancer Ther 2019 Apr 14;18(4):762-770. Epub 2019 Mar 14.

Oncode Institute, Amsterdam, the Netherlands.

Small cell lung cancer (SCLC) is generally regarded as very difficult to treat, mostly due to the development of metastases early in the disease and a quick relapse with resistant disease. SCLC patients initially show a good response to treatment with the DNA damaging agents cisplatin and etoposide. This is, however, quickly followed by the development of resistant disease, which urges the development of novel therapies for this type of cancer. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451635PMC
April 2019
2 Reads

δ-Catenin Promotes Bevacizumab-Induced Glioma Invasion.

Mol Cancer Ther 2019 Apr 14;18(4):812-822. Epub 2019 Mar 14.

Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

The combination of bevacizumab with temozolomide and radiotherapy was shown to prolong progression-free survival in newly diagnosed patients with glioblastoma, and this emphasizes the potential of bevacizumab as a glioma treatment. However, although bevacizumab effectively inhibits angiogenesis, it has also been reported to induce invasive proliferation. This study examined gene expression in glioma cells to investigate the mechanisms of bevacizumab-induced invasion. Read More

View Article

Download full-text PDF

Source
http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
Publisher Site
http://dx.doi.org/10.1158/1535-7163.MCT-18-0138DOI Listing
April 2019
1 Read

Direct CDKN2 Modulation of CDK4 Alters Target Engagement of CDK4 Inhibitor Drugs.

Mol Cancer Ther 2019 Apr 5;18(4):771-779. Epub 2019 Mar 5.

ActivX Biosciences, La Jolla, California.

The interaction of a drug with its target is critical to achieve drug efficacy. In cases where cellular environment influences target engagement, differences between individuals and cell types present a challenge for prediction of drug efficacy. As such, characterization of environments conducive to achieving the desired pharmacologic outcome is warranted. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0755DOI Listing

Nanobody Targeting of Epidermal Growth Factor Receptor (EGFR) Ectodomain Variants Overcomes Resistance to Therapeutic EGFR Antibodies.

Mol Cancer Ther 2019 Apr 1;18(4):823-833. Epub 2019 Mar 1.

Department of Oncology and Hematology, BMT with section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Epidermal growth factor receptor (EGFR) ectodomain variants mediating primary resistance or secondary treatment failure in cancer patients treated with cetuximab or panitumumab support the need for more resistance-preventive or personalized ways of targeting this essential pathway. Here, we tested the hypothesis that the EGFR nanobody 7D12 fused to an IgG1 Fc portion (7D12-hcAb) would overcome EGFR ectodomain-mediated resistance because it targets a very small binding epitope within domain III of EGFR. Indeed, we found that 7D12-hcAb bound and inhibited all tested cell lines expressing common resistance-mediating EGFR ectodomain variants. Read More

View Article

Download full-text PDF

Source
http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
Publisher Site
http://dx.doi.org/10.1158/1535-7163.MCT-18-0849DOI Listing
April 2019
13 Reads

EPHA2 Is a Predictive Biomarker of Resistance and a Potential Therapeutic Target for Improving Antiepidermal Growth Factor Receptor Therapy in Colorectal Cancer.

Mol Cancer Ther 2019 Apr 1;18(4):845-855. Epub 2019 Mar 1.

Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania L. Vanvitelli, Naples, Italy.

The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as a potential resistance marker to the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer. We studied activation of EPHA2 in a panel of human colorectal cancer cell lines sensitive or resistant to anti-EGFR drugs. Read More

View Article

Download full-text PDF

Source
http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
Publisher Site
http://dx.doi.org/10.1158/1535-7163.MCT-18-0539DOI Listing
April 2019
6 Reads

Inhibition of Copper Transport Induces Apoptosis in Triple Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis.

Mol Cancer Ther 2019 Mar 1. Epub 2019 Mar 1.

Center for Clinical Cancer Genetics, University of Chicago

Treatment of advanced breast cancer remains challenging. Copper and some of the copper-dependent proteins are emerging therapeutic targets as they are essential for cell proliferation and survival, and have been shown to stimulate angiogenesis and metastasis. Here we show that DCAC50, a recently developed small molecule inhibitor of the intracellular copper chaperones, ATOX1 and CCS, reduces cell proliferation and elevates oxidative stress, triggering apoptosis in a panel of triple negative breast cancer cells. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0667DOI Listing

Preclinical development of a WT1 oral cancer vaccine using a bacterial vector to treat castration-resistant prostate cancer.

Mol Cancer Ther 2019 Mar 1. Epub 2019 Mar 1.

Advanced Medical Science, Kobe University Graduate School of Science, Technology and Innovation.

Previously, we constructed a recombinant Bifidobacterium longum displaying a partial mouse Wilms' tumor 1 (WT1) protein (B. longum 420) as an oral cancer vaccine using a bacterial vector and demonstrated that oral administration of B. longum 420 significantly inhibited tumor growth compared with the Db126 WT1 peptide vaccine in the TRAMP-C2, mouse castration-resistant prostate cancer (CRPC) syngeneic tumor model. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-1105DOI Listing

HDAC3 inhibition up-regulates PD-L1 expression in B-cell lymphomas and augments the efficacy of anti-PD-L1 therapy.

Mol Cancer Ther 2019 Mar 1. Epub 2019 Mar 1.

immunology, shanghai institute of immunology

Programmed cell-death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway blockade is a promising therapy for the treatment of advanced cancers including B-cell lymphoma. The clinical response to PD-1/PD-L1 immunotherapy correlates with PD-L1 levels on tumor cells and other cells in the tumor microenvironment. Hence, it is important to understand the molecular mechanisms that regulate PD-L1 expression. Read More

View Article

Download full-text PDF

Source
http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
Publisher Site
http://dx.doi.org/10.1158/1535-7163.MCT-18-1068DOI Listing
March 2019
4 Reads

Reduction of Muscle-Invasive Tumors by Photodynamic Therapy with Tetrahydroporphyrin-Tetratosylat in an Orthotopic Rat Bladder Cancer Model.

Mol Cancer Ther 2019 Apr 1;18(4):743-750. Epub 2019 Mar 1.

Department of Urology, Research Laboratories, University of Leipzig, Leipzig, Germany.

Photodynamic therapy (PDT) is a promising option for minimal-invasive treatment of bladder cancer. Efficacy of PDT in muscle-invasive urothelial cancer is still hampered by low tissue penetration of most photosensitizers due to short excitation wavelength. The novel light reactive agent tetrahydroporphyrin-tetratosylat (THPTS) is excitable at near-infrared (760 nm), allowing tissue penetration of up to 15 mm. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-1194DOI Listing
April 2019
4 Reads

Mouse Strains Influence Clearance and Efficacy of Antibody and Antibody-Drug Conjugate Via Fc-FcγR Interaction.

Mol Cancer Ther 2019 Apr 1;18(4):780-787. Epub 2019 Mar 1.

Research, Seattle Genetics, Inc., Bothell, Washington.

To provide a better understanding of the pharmacokinetics-pharmacodynamics relationships of antibody-based drugs, we analyzed several chimeric and humanized monoclonal antibodies or antibody-drug conjugates (ADC) for PK and efficacy among four strains of mice. Notably, antibodies and ADCs displayed a dose-dependent drug disposition profile in the plasma of NSG mice. The increased clearance rate in NSG mice resulted in the reduction of antitumor activity of ADCs. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0977DOI Listing
April 2019
1 Read

Respiratory Capacity and Reserve Predict Cell Sensitivity to Mitochondria Inhibitors: Mechanism-Based Markers to Identify Metformin-Responsive Cancers.

Mol Cancer Ther 2019 Mar;18(3):693-705

Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.

Metformin has been extensively studied for its impact on cancer cell metabolism and anticancer potential. Despite evidence of significant reduction in cancer occurrence in diabetic patients taking metformin, phase II cancer trials of the agent have been disappointing, quite possibly because of the lack of molecular mechanism-based patient stratification. In an effort to identify cancers that are responsive to metformin, we discovered that mitochondria respiratory capacity and respiratory reserve, which vary widely among cancer cells, correlate strongly to metformin sensitivity in both the and settings. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0766DOI Listing
March 2019
1 Read

What CAR Will Win the CD19 Race?

Mol Cancer Ther 2019 Mar;18(3):498-506

TCR Therapeutics, Cambridge, Massachusetts.

Adoptive transfer of T cells engineered with synthetic receptors is emerging as a new pillar in the treatment of cancer. The adoptive cell therapy furthest along in clinical development is the engineering of T cells to express chimeric antigen receptors (CAR) against the CD19 antigen. Several platforms have shown remarkable activity in patients with relapsed or refractory B-cell malignancies. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-1070DOI Listing
March 2019
5 Reads

A Vision from the New Editor-in-Chief.

Mol Cancer Ther 2019 Mar;18(3):497

National Cancer Institute/National Institutes of Health, Bethesda, Maryland.

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-19-0094DOI Listing
March 2019
2 Reads

CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma.

Mol Cancer Ther 2019 Apr 20;18(4):788-800. Epub 2019 Feb 20.

Cancer Research Unit, VA Medical Center, Kansas City, Missouri.

Pancreatic ductal adenocarcinoma (PDAC) develops extrinsic- and intrinsic-resistant phenotypes to prevent chemotherapies from entering into the cells by promoting desmoplastic reactions (DR) and metabolic malfunctions of the drugs. It is well established that these responses are also associated with pancreatic cancer cells' gemcitabine resistance. However, the mechanism by which these resistant pathways function in the pancreatic cancer cells remains poorly understood. Read More

View Article

Download full-text PDF

Source
http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
Publisher Site
http://dx.doi.org/10.1158/1535-7163.MCT-18-0899DOI Listing
April 2019
8 Reads
5.683 Impact Factor

TAS0728, A Covalent-binding, HER2-selective Kinase Inhibitor Shows Potent Antitumor Activity in Preclinical Models.

Mol Cancer Ther 2019 Apr 20;18(4):733-742. Epub 2019 Feb 20.

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.

Activated HER2 is a promising therapeutic target for various cancers. Although several reports have described HER2 inhibitors in development, no covalent-binding inhibitor selective for HER2 has been reported. Here, we report a novel compound TAS0728 that covalently binds to HER2 at C805 and selectively inhibits its kinase activity. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-1085DOI Listing
April 2019
1 Read

β-Arrestins Regulate Stem Cell-Like Phenotype and Response to Chemotherapy in Bladder Cancer.

Mol Cancer Ther 2019 Apr 20;18(4):801-811. Epub 2019 Feb 20.

Georgia Cancer Center, Augusta University, Augusta, GA.

β-Arrestins are classic attenuators of G-protein-coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. This work shows for the first time that β-arrestins have prognostic significance for predicting metastasis and response to chemotherapy in bladder cancer. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-1167DOI Listing
April 2019
2 Reads

Genipin Enhances the Therapeutic Effects of Oxaliplatin by Upregulating BIM in Colorectal Cancer.

Mol Cancer Ther 2019 Apr 20;18(4):751-761. Epub 2019 Feb 20.

Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea.

Despite an increase in the survival rate of patients with cancer owing to the use of current chemotherapeutic agents, adverse effects of cancer therapies remain a concern. Combination therapies have been developed to increase efficacy, reduce adverse effects, and overcome drug resistance. Genipin is a natural product derived from which has been associated with anti-inflammatory, anti-angiogenic, and anti-proliferative effects; hypertension; and anti-ischemic brain injuries. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0196DOI Listing

Phosphatidylinositol-3-kinase (PI3K)/Akt Signaling is Functionally Essential in Myxoid Liposarcoma.

Mol Cancer Ther 2019 Apr 20;18(4):834-844. Epub 2019 Feb 20.

Gerhard-Domagk-Institute of Pathology, Münster University Hospital, Münster, Germany.

Myxoid liposarcoma (MLS) is an aggressive soft-tissue tumor characterized by a specific reciprocal t(12;16) translocation resulting in expression of the chimeric FUS-DDIT3 fusion protein, an oncogenic transcription factor. Similar to other translocation-associated sarcomas, MLS is characterized by a low frequency of somatic mutations, albeit a subset of MLS has previously been shown to be associated with activating mutations. This study was performed to assess the prevalence of PI3K/Akt signaling alterations in MLS and the potential of PI3K-directed therapeutic concepts. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0763DOI Listing
April 2019
1 Read

Inhibition of Sphingosine Phosphate Receptor 1 Signaling Enhances the Efficacy of VEGF Receptor Inhibition.

Mol Cancer Ther 2019 Apr 20;18(4):856-867. Epub 2019 Feb 20.

Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

Inhibition of VEGFR signaling is an effective treatment for renal cell carcinoma, but resistance continues to be a major problem. Recently, the sphingosine phosphate (S1P) signaling pathway has been implicated in tumor growth, angiogenesis, and resistance to antiangiogenic therapy. S1P is a bioactive lipid that serves an essential role in developmental and pathologic angiogenesis via activation of the S1P receptor 1 (S1P1). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0548DOI Listing
April 2019
2 Reads

A Simple Three-dimensional Hydrogel Platform Enables Cell Culture of Patient and PDX Tumors for Assaying Their Response to Clinically Relevant Therapies.

Mol Cancer Ther 2019 Mar 12;18(3):718-725. Epub 2019 Feb 12.

Department of Neurosurgery, Cedars-Sinai Hospital, Los Angeles, California.

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

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0359DOI Listing
March 2019
1 Read

TGFβ Blockade Enhances Radiotherapy Abscopal Efficacy Effects in Combination with Anti-PD1 and Anti-CD137 Immunostimulatory Monoclonal Antibodies.

Mol Cancer Ther 2019 Mar 25;18(3):621-631. Epub 2019 Jan 25.

Department of Oncology, University of Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.

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 TGFβ expression or activation increases in irradiated tissues, we tested whether TGFβ blockade may further enhance abscopal effects in conjunction with the anti-PD-1 plus anti-CD137 mAb combination. Read More

View Article

Download full-text PDF

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

Combined MEK and BCL-2/X Inhibition Is Effective in High-Grade Serous Ovarian Cancer Patient-Derived Xenograft Models and BIM Levels Are Predictive of Responsiveness.

Mol Cancer Ther 2019 Mar 24;18(3):642-655. Epub 2019 Jan 24.

Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.

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 models. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399746PMC
March 2019
7 Reads
5.683 Impact Factor

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

Mol Cancer Ther 2019 Mar 24;18(3):556-566. Epub 2019 Jan 24.

USA Mitchell Cancer Institute, Mobile, Alabama.

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/), we could find no experimental evidence in the published literature demonstrating the specific engagement of LB-100 with PP2A , in cultured cells, or in animals. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-17-1143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397705PMC
March 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 Mar 24;18(3):531-540. Epub 2019 Jan 24.

Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the 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

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0831DOI Listing
March 2019
6 Reads

Nanoparticle Delivery of miR-708 Mimetic Impairs Breast Cancer Metastasis.

Mol Cancer Ther 2019 Mar 24;18(3):579-591. Epub 2019 Jan 24.

Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, New York.

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-708 cancer cells with tumor-initiating properties, enhanced metastatic potential, and marked sensitivity to miR-708 treatment. Read More

View Article

Download full-text PDF

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

A Kinase Inhibitor with Anti-Pim Kinase Activity is a Potent and Selective Cytotoxic Agent Toward Acute Myeloid Leukemia.

Mol Cancer Ther 2019 Mar 24;18(3):567-578. Epub 2019 Jan 24.

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

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

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-17-1234DOI Listing
March 2019
3 Reads

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

Mol Cancer Ther 2019 Mar 23;18(3):507-516. Epub 2019 Jan 23.

Department of Pediatrics, University of Chicago, Chicago, Illinois.

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. On the basis of these promising preclinical studies, early-phase adult clinical trials testing the MELK inhibitor OTS167 are ongoing. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398941PMC
March 2019
8 Reads

Chemically Modified Antisense Oligonucleotide Against ARL4C Inhibits Primary and Metastatic Liver Tumor Growth.

Mol Cancer Ther 2019 Mar 15;18(3):602-612. Epub 2019 Jan 15.

Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Osaka, Japan.

ADP-ribosylation factor-like 4c (ARL4C) is identified as a small GTP-binding protein, which 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 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 colorectal cancer liver metastases, and that ARL4C expression is associated with poor prognosis for these cancers. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0824DOI Listing
March 2019
3 Reads

The Rolipram-Perillyl Alcohol Conjugate (NEO214) Is A Mediator of Cell Death through the Death Receptor Pathway.

Mol Cancer Ther 2019 Mar 15;18(3):517-530. Epub 2019 Jan 15.

Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California.

Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Treatment with temozolomide, 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

View Article

Download full-text PDF

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