Retraction: Proteasome Inhibition Blocks NF-{kappa}B and ERK1/2 Pathways, Restores Antigen Expression, and Sensitizes Resistant Human Melanoma to TCR-Engineered CTLs
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Tags: Retraction Source Type: research
HSP70 Inhibition Synergistically Enhances the Effects of Magnetic Fluid Hyperthermia in Ovarian Cancer
Hyperthermia has been investigated as a potential treatment for cancer. However, specificity in hyperthermia application remains a significant challenge. Magnetic fluid hyperthermia (MFH) may be an alternative to surpass such a challenge, but implications of MFH at the cellular level are not well understood. Therefore, the present work focused on the examination of gene expression after MFH treatment and using such information to identify target genes that when inhibited could produce an enhanced therapeutic outcome after MFH. Genomic analyzes were performed using ovarian cancer cells exposed to MFH for 30 minutes at 43&de...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Court, K. A., Hatakeyama, H., Wu, S. Y., Lingegowda, M. S., Rodriguez-Aguayo, C., Lopez-Berestein, G., Ju-Seog, L., Rinaldi, C., Juan, E. J., Sood, A. K., Torres-Lugo, M. Tags: Models and Technologies Source Type: research
Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR
Sarcomas differ from carcinomas in their mesenchymal origin. Therapeutic advancements have come slowly, so alternative drugs and models are urgently needed. These studies report a new drug for sarcomas that simultaneously targets both tumor and tumor neovasculature. eBAT is a bispecific angiotoxin consisting of truncated, deimmunized Pseudomonas exotoxin fused to EGF and the amino terminal fragment of urokinase. Here, we study the drug in an in vivo "ontarget" companion dog trial as eBAT effectively kills canine hemangiosarcoma and human sarcoma cells in vitro. We reasoned the model has value due to the common occurrence o...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Borgatti, A., Koopmeiners, J. S., Sarver, A. L., Winter, A. L., Stuebner, K., Todhunter, D., Rizzardi, A. E., Henriksen, J. C., Schmechel, S., Forster, C. L., Kim, J.-H., Froelich, J., Walz, J., Henson, M. S., Breen, M., Lindblad-Toh, K., Oh, F., Pilbeam, Tags: Models and Technologies Source Type: research
Cell-Free DNA from Ascites and Pleural Effusions: Molecular Insights into Genomic Aberrations and Disease Biology
Collection of cell-free DNA (cfDNA) from the blood of individuals with cancer has permitted noninvasive tumor genome analysis. Detection and characterization of cfDNA in ascites and pleural effusions have not yet been reported. Herein, we analyzed cfDNA in the ascites and pleural effusions from six individuals with metastatic cancer. In all cases, cfDNA copy number variations (CNV) were discovered within the effusate. One individual had a relevant alteration with a high copy amplification in EGFR in a never smoker with lung cancer, who showed only MDM2 and CDK4 amplification in a prior tissue biopsy. Another subject with m...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Husain, H., Nykin, D., Bui, N., Quan, D., Gomez, G., Woodward, B., Venkatapathy, S., Duttagupta, R., Fung, E., Lippman, S. M., Kurzrock, R. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
Calcium-Dependent Enhancement by Extracellular Acidity of the Cytotoxicity of Mitochondrial Inhibitors against Melanoma
We report here that drugs which abrogate mitochondrial respiration show enhanced cytotoxicity against melanoma cells in a normoxic but acidic extracellular pH, independent from P53 mutations, BRAF (V600E) mutations, and/or resistance against BRAF inhibitors. Conversely, the cytotoxicity against melanoma cells of mitochondrial inhibitors is impaired by a neutral or alkaline extracellular pH, and in vivo systemic alkalinization with NaHCO3 enhanced subcutaneous tumor growth and lung metastasis of B16F10 cells in mice treated with the mitochondrial inhibitor phenformin. Intracellular calcium (Ca2+) was significantly increased...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Noguchi, F., Inui, S., Fedele, C., Shackleton, M., Itami, S. Tags: Cancer Biology and Signal Transduction Source Type: research
Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145
Although miR-145 is the most frequently downregulated miRNA in bladder cancer, its exact stage association and downstream effector have not been defined. Here, we found that miR-145 was upregulated in human patients with bladder cancer with lymph node metastasis and in metastatic T24T cell line. Forced expression of miR-145 promoted anchorage-independent growth of T24T cells accompanied by the downregulation of forkhead box class O1 (FOXO1). In contrast, in non-metastatic T24 cells, miR-145 overexpression inhibited cell growth with upregulation of FOXO1, and the knockdown of FOXO1 abolished the miR-145–mediated inhib...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Jiang, G., Huang, C., Li, J., Huang, H., Jin, H., Zhu, J., Wu, X.-R., Huang, C. Tags: Cancer Biology and Signal Transduction Source Type: research
Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Cell-Cycle Arrest and Apoptosis through p21 and p21-Regulated BNIP3 Induction in Pancreatic Cancer
In this study, we have evaluated a panel of human pancreatic cancer cell lines and identified those that are sensitive to ICMT inhibition. In these cells, ICMT suppression inhibited proliferation and induced apoptosis. This responsiveness to ICMT inhibition was confirmed in in vivo xenograft tumor mouse models using both a small-molecule inhibitor and shRNA-targeting ICMT. Mechanistically, we found that, in sensitive pancreatic cancer cells, ICMT inhibition induced mitochondrial respiratory deficiency and cellular energy depletion, leading to significant upregulation of p21. Furthermore, we characterized the role of p21 as...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Manu, K. A., Chai, T. F., Teh, J. T., Zhu, W. L., Casey, P. J., Wang, M. Tags: Cancer Biology and Signal Transduction Source Type: research
Lipid Nanoparticle-Mediated Delivery of Anti-miR-17 Family Oligonucleotide Suppresses Hepatocellular Carcinoma Growth
In this study, we validated that the miR-17 family was upregulated in a subset of HCC tumors and cell lines and its inhibition by a tough decoy inhibitor suppressed the growth of Hep3B and HepG2 cells, which overexpress the miR-17 family. Furthermore, inhibition of the miR-17 family led to a global derepression of direct targets of the family in all three HCC cell lines tested. Pathway analysis of the deregulated genes indicated that the genes associated with TGFβ signaling pathway were highly enriched in Hep3B and HepG2 cells. A miR-17 family target gene signature was established and used to identify RL01-17(5), a li...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Huang, X., Magnus, J., Kaimal, V., Karmali, P., Li, J., Walls, M., Prudente, R., Sung, E., Sorourian, M., Lee, R., Davis, S., Yang, X., Estrella, H., Lee, E. C., Chau, B. N., Pavlicek, A., Zabludoff, S. Tags: Large Molecule Therapeutics Source Type: research
Preclinical Antitumor Efficacy of BAY 1129980--a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody-Drug Conjugate for the Treatment of Non-Small Cell Lung Cancer
C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non–small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.4A expression is scarce in normal tissues, presenting an opportunity to selectively treat cancers with a C4.4A-directed antibody–drug conjugate (ADC). We have generated BAY 1129980 (C4.4A-ADC), an ADC consisting of a fully human C4.4A-targeting mAb conjugated to a novel, highly potent derivativ...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Willuda, J., Linden, L., Lerchen, H.-G., Kopitz, C., Stelte-Ludwig, B., Pena, C., Lange, C., Golfier, S., Kneip, C., Carrigan, P. E., Mclean, K., Schuhmacher, J., von Ahsen, O., Müller, J., Dittmer, F., Beier, R., El Sheikh, S., Tebbe, J., Leder, Tags: Large Molecule Therapeutics Source Type: research
Highly Potent, Anthracycline-based Antibody-Drug Conjugates Generated by Enzymatic, Site-specific Conjugation
Antibody–drug conjugates (ADC) are highly potent and specific antitumor drugs, combining the specific targeting of mAbs with the potency of small-molecule toxic payloads. ADCs generated by conventional chemical conjugation yield heterogeneous mixtures with variable pharmacokinetics, stability, safety, and efficacy profiles. To address these issues, numerous site-specific conjugation technologies are currently being developed allowing the manufacturing of homogeneous ADCs with predetermined drug-to-antibody ratios. Here, we used sortase-mediated antibody conjugation (SMAC) technology to generate homogeneous ADCs based...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Stefan, N., Gebleux, R., Waldmeier, L., Hell, T., Escher, M., Wolter, F. I., Grawunder, U., Beerli, R. R. Tags: Large Molecule Therapeutics Source Type: research
Modulating Therapeutic Activity and Toxicity of Pyrrolobenzodiazepine Antibody-Drug Conjugates with Self-Immolative Disulfide Linkers
A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody–drug conjugates (ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC. This novel disulfide ADC was compared with a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker. Both ADCs had similar ef...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Pillow, T. H., Schutten, M., Yu, S.-F., Ohri, R., Sadowsky, J., Poon, K. A., Solis, W., Zhong, F., Del Rosario, G., Go, M. A. T., Lau, J., Yee, S., He, J., Liu, L., Ng, C., Xu, K., Leipold, D. D., Kamath, A. V., Zhang, D., Masterson, L., Gregson, S. J., H Tags: Large Molecule Therapeutics Source Type: research
Characterization of the Anti-PD-1 Antibody REGN2810 and Its Antitumor Activity in Human PD-1 Knock-In Mice
This report describes the preclinical characterization of REGN2810, a fully human hinge-stabilized IgG4(S228P) high-affinity anti–PD-1 antibody that potently blocks PD-1 interactions with PD-L1 and PD-L2. REGN2810 was characterized in a series of binding, blocking, and functional cell-based assays, and preclinical in vivo studies in mice and monkeys. In cell-based assays, REGN2810 reverses PD-1–dependent attenuation of T-cell receptor signaling in engineered T cells and enhances responses of human primary T cells. To test the in vivo activity of REGN2810, which does not cross-react with murine PD-1, knock-in mi...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Burova, E., Hermann, A., Waite, J., Potocky, T., Lai, V., Hong, S., Liu, M., Allbritton, O., Woodruff, A., Wu, Q., DOrvilliers, A., Garnova, E., Rafique, A., Poueymirou, W., Martin, J., Huang, T., Skokos, D., Kantrowitz, J., Popke, J., Mohrs, M., MacDonal Tags: Large Molecule Therapeutics Source Type: research
Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models
The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sens...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Chan-Penebre, E., Armstrong, K., Drew, A., Grassian, A. R., Feldman, I., Knutson, S. K., Kuplast-Barr, K., Roche, M., Campbell, J., Ho, P., Copeland, R. A., Chesworth, R., Smith, J. J., Keilhack, H., Ribich, S. A. Tags: Small Molecule Therapeutics Source Type: research
Synthesis and Evaluation of the Novel Prostamide, 15-Deoxy, {Delta}12,14-Prostamide J2, as a Selective Antitumor Therapeutic
15-deoxy, 12,14-prostaglandin J2-ethanolamide, also known as 15-deoxy, 12,14-prostamide J2 (15d-PMJ2) is a novel product of the metabolism of arachidonoyl ethanolamide (AEA) by COX-2. 15d-PMJ2 preferentially induced cell death and apoptosis in tumorigenic A431 keratinocytes and B16F10 melanoma cells compared with nontumorigenic HaCaT keratinocytes and Melan-A melanocytes. Activation of the ER stress execution proteins, PERK and CHOP10, was evaluated to determine whether this process was involved in 15d-PMJ2 cell death. 15d-PMJ2 increased the phosphorylation of PERK and expression of CHOP10 in tumorigenic but not nontumorig...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Ladin, D. A., Soliman, E., Escobedo, R., Fitzgerald, T. L., Yang, L. V., Burns, C., Van Dross, R. Tags: Small Molecule Therapeutics Source Type: research
Fluorinated N,N'-Diarylureas As Novel Therapeutic Agents Against Cancer Stem Cells
In this study, we examined the effects of novel AMP-activated protein kinase (AMPK) activating compounds on colorectal cancer metastatic and stem cell lines as potential candidates for chemotherapy. We found that activation of AMPK by all fluorinated N,N-diarylureas (FND) compounds at micromolar levels significantly inhibited the cell-cycle progression and subsequent cellular proliferation. In addition, we demonstrated that select FNDs significantly increased apoptosis in colorectal cancer metastatic and cancer stem cells. Therefore, FNDs hold considerable promise in the treatment of metastatic colorectal cancer, through e...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Kenlan, D. E., Rychahou, P., Sviripa, V. M., Weiss, H. L., Liu, C., Watt, D. S., Evers, B. M. Tags: Small Molecule Therapeutics Source Type: research
