Wnt Signaling Inhibition Promotes Apoptosis in Sarcomas--Letter
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Bertucci, F., Finetti, P., Birnbaum, D. Tags: Letter to the Editor Source Type: research
Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma
This study provides evidence of a translational exo-metabolomic plasma readout predictive of clinical efficacy together with pharmacodynamic utility following treatment with a signal transduction inhibitor. Mol Cancer Ther; 16(10); 2315–23. ©2017 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Ang, J. E., Pal, A., Asad, Y. J., Henley, A. T., Valenti, M., Box, G., de haven Brandon, A., Revell, V. L., Skene, D. J., Venturi, M., Rueger, R., Meresse, V., Eccles, S. A., de Bono, J. S., Kaye, S. B., Workman, P., Banerji, U., Raynaud, F. I. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the Mucin 1 C-terminal subunit (MUC1-C) plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals. Cell lines, primary samples, and xenograft models of CTCL were us...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Jain, S., Washington, A., Leaf, R. K., Bhargava, P., Clark, R. A., Kupper, T. S., Stroopinsky, D., Pyzer, A., Cole, L., Nahas, M., Apel, A., Rosenblatt, J., Arnason, J., Kufe, D., Avigan, D. Tags: Cancer Biology and Signal Transduction Source Type: research
Inactivation of the Kinase Domain of CDK10 Prevents Tumor Growth in a Preclinical Model of Colorectal Cancer, and Is Accompanied by Downregulation of Bcl-2
This study examines the function of CDK10 in colorectal cancer, and demonstrates its role in suppressing apoptosis and in promoting tumor growth in vitro and in vivo. Modulation of CDK10 expression in colorectal cancer cell lines demonstrates that CDK10 promotes cell growth, reduces chemosensitivity and inhibits apoptosis by upregulating the expression of Bcl-2. This effect appears to depend on its kinase activity, as kinase-defective mutant colorectal cancer cell lines have an exaggerated apoptotic response and reduced proliferative capacity. In vivo, inhibiting CDK10 in colorectal cancer following intratumoral injections...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Weiswald, L.-B., Hasan, M. R., Wong, J. C. T., Pasiliao, C. C., Rahman, M., Ren, J., Yin, Y., Gusscott, S., Vacher, S., Weng, A. P., Kennecke, H. F., Bieche, I., Schaeffer, D. F., Yapp, D. T., Tai, I. T. Tags: Cancer Biology and Signal Transduction Source Type: research
Bypassing Drug Resistance Mechanisms of Prostate Cancer with Small Molecules that Target Androgen Receptor-Chromatin Interactions
Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug target in the treatment of prostate cancer. Current small-molecule AR antagonists, such as enzalutamide, compete with androgens that bind to the steroid-binding pocket of the AR ligand–binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug resistance can manifest through AR-LBD mutations that convert AR antagonists into agonists, or by expression of AR variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR. Previously, we reported the developm...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Dalal, K., Che, M., Que, N. S., Sharma, A., Yang, R., Lallous, N., Borgmann, H., Ozistanbullu, D., Tse, R., Ban, F., Li, H., Tam, K. J., Roshan-Moniri, M., LeBlanc, E., Gleave, M. E., Gewirth, D. T., Dehm, S. M., Cherkasov, A., Rennie, P. S. Tags: Cancer Biology and Signal Transduction Source Type: research
Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic {beta}-catenin Signaling and EMT Progression
Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β. In molecular docking analysis, ormeloxifene show...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Hafeez, B. B., Ganju, A., Sikander, M., Kashyap, V. K., Hafeez, Z. B., Chauhan, N., Malik, S., Massey, A. E., Tripathi, M. K., Halaweish, F. T., Zafar, N., Singh, M. M., Yallapu, M. M., Chauhan, S. C., Jaggi, M. Tags: Cancer Biology and Signal Transduction Source Type: research
ABCB1 Mediates Cabazitaxel-Docetaxel Cross-Resistance in Advanced Prostate Cancer
In this study, we use C4-2B and DU145 derived docetaxel-resistant cell lines to test response to cabazitaxel. Our results demonstrate that docetaxel resistance confers cross-resistance to cabazitaxel. We show that increased ABCB1 expression is responsible for cross-resistance to cabazitaxel and that inhibition of ABCB1 function through the small-molecule inhibitor elacridar resensitizes taxane-resistant cells to treatment. In addition, the antiandrogens bicalutamide and enzalutamide, previously demonstrated to be able to resensitize taxane-resistant cells to docetaxel through inhibition of ABCB1 ATPase activity, are also a...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Lombard, A. P., Liu, C., Armstrong, C. M., Cucchiara, V., Gu, X., Lou, W., Evans, C. P., Gao, A. C. Tags: Cancer Biology and Signal Transduction Source Type: research
The Tumor-Suppressor Protein OPCML Potentiates Anti-EGFR- and Anti-HER2-Targeted Therapy in HER2-Positive Ovarian and Breast Cancer
Opioid-binding protein/cell adhesion molecule-like (OPCML) is a tumor-suppressor gene that is frequently inactivated in ovarian cancer and many other cancers by somatic methylation. We have previously shown that OPCML exerts its suppressor function by negatively regulating a spectrum of receptor tyrosine kinases (RTK), such as ErbB2/HER2, FGFR1, and EphA2, thus attenuating their related downstream signaling. The physical interaction of OPCML with this defined group of RTKs is a prerequisite for their downregulation. Overexpression/gene amplification of EGFR and HER2 is a frequent event in multiple cancers, including ovaria...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Zanini, E., Louis, L. S., Antony, J., Karali, E., Okon, I. S., McKie, A. B., Vaughan, S., El-Bahrawy, M., Stebbing, J., Recchi, C., Gabra, H. Tags: Cancer Biology and Signal Transduction Source Type: research
JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer
Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non–small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine IL6 and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAF). We also analyzed the prognostic s...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Shien, K., Papadimitrakopoulou, V. A., Ruder, D., Behrens, C., Shen, L., Kalhor, N., Song, J., Lee, J. J., Wang, J., Tang, X., Herbst, R. S., Toyooka, S., Girard, L., Minna, J. D., Kurie, J. M., Wistuba, I. I., Izzo, J. G. Tags: Cancer Biology and Signal Transduction Source Type: research
The IGF1R/INSR Inhibitor BI 885578 Selectively Inhibits Growth of IGF2-Overexpressing Colorectal Cancer Tumors and Potentiates the Efficacy of Anti-VEGF Therapy
Clinical studies of pharmacologic agents targeting the insulin-like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, the identification of selection biomarkers for enrichment of potential responders represents a high priority for future trials of these agents. Several reports have described high IGF2 expression in a subset of colorectal cancers, with focal IGF2 amplification being responsible for some of these cases. We defined a novel cut-off value for IGF2 overexpression based on differential expression between color...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Sanderson, M. P., Hofmann, M. H., Garin-Chesa, P., Schweifer, N., Wernitznig, A., Fischer, S., Jeschko, A., Meyer, R., Moll, J., Pecina, T., Arnhof, H., Weyer-Czernilofsky, U., Zahn, S. K., Adolf, G. R., Kraut, N. Tags: Cancer Biology and Signal Transduction Source Type: research
Exposure-Response Analyses of Ramucirumab from Two Randomized, Phase III Trials of Second-line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer
Ramucirumab is an IgG1 monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure–efficacy and exposure–safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials. Sparse pharmacokinetic samples were collected, and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum tr...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Tabernero, J., Ohtsu, A., Muro, K., Van Cutsem, E., Oh, S. C., Bodoky, G., Shimada, Y., Hironaka, S., Ajani, J. A., Tomasek, J., Safran, H., Chandrawansa, K., Hsu, Y., Heathman, M., Khan, A., Ni, L., Melemed, A. S., Gao, L., Ferry, D., Fuchs, C. S. Tags: Large Molecule Therapeutics Source Type: research
Epidermal Growth Factor Receptor (EGFR)-targeted Photoimmunotherapy (PIT) for the Treatment of EGFR-expressing Bladder Cancer
The use of light as a means of therapy for bladder cancer has a long history but has been hampered by a lack of tumor specificity and therefore, damage to the normal bladder mucosa. Here, we describe a targeted form of phototherapy called photoimmunotherapy (PIT), which targets EGFR-expressing bladder cancer. Anti-EGFR antibody panitumumab was labeled with the photoabsorber (PA), IRDye 700Dx (IR700), to create a panitumumab-IR700 antibody–PA conjugate that is activated by near-infrared radiation (NIR). Bladder cancer tissue microarray (TMA) and bladder cancer cell lines were analyzed for expression of EGFR. Mechanism...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Railkar, R., Krane, L. S., Li, Q. Q., Sanford, T., Siddiqui, M. R., Haines, D., Vourganti, S., Brancato, S. J., Choyke, P. L., Kobayashi, H., Agarwal, P. K. Tags: Large Molecule Therapeutics Source Type: research
Alpha Particle Enhanced Blood Brain/Tumor Barrier Permeabilization in Glioblastomas Using Integrin Alpha-v Beta-3-Targeted Liposomes
Glioblastoma (GBM) is the most common primary malignant astrocytoma characterized by extensive invasion, angiogenesis, hypoxia, and micrometastasis. Despite the relatively leaky nature of GBM blood vessels, effective delivery of antitumor therapeutics has been a major challenge due to the complications caused by the blood–brain barrier (BBB) and the highly torturous nature of newly formed tumor vasculature (blood tumor barrier-BTB). External beam radiotherapy was previously shown to be an effective means of permeabilizing central nervous system (CNS) barriers. By using targeted short-ranged radionuclides, we show for...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Sattiraju, A., Xiong, X., Pandya, D. N., Wadas, T. J., Xuan, A., Sun, Y., Jung, Y., Sai, K. K. S., Dorsey, J. F., Li, K. C., Mintz, A. Tags: Large Molecule Therapeutics Source Type: research
A Novel Combination Treatment Targeting BCL-XL and MCL1 for KRAS/BRAF-mutated and BCL2L1-amplified Colorectal Cancers
In this study, we have found that a subgroup of colorectal cancers, defined by having either KRAS or BRAF (KRAS/BRAF) mutations and BCL2L1 (encoding BCL-XL) amplification, can be effectively targeted by simultaneous inhibition of BCL-XL (with ABT-263) and MCL1 (with YM-155). This combination treatment of ABT-263 and YM-155 was shown to have a synergistic effect in vitro as well as in in vivo patient-derived xenograft models. Our data suggest that combined inhibition of BCL-XL and MCL1 provides a promising treatment strategy for this genomically defined colorectal cancer subgroup. Mol Cancer Ther; 16(10); 2178–90. &co...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Cho, S.-Y., Han, J. Y., Na, D., Kang, W., Lee, A., Kim, J., Lee, J., Min, S., Kang, J., Chae, J., Kim, J.-I., Park, H., Lee, W.-S., Lee, C. Tags: Small Molecule Therapeutics Source Type: research
The DNA-Binding Polyamine Moiety in the Vectorized DNA Topoisomerase II Inhibitor F14512 Alters Reparability of the Consequent Enzyme-Linked DNA Double-Strand Breaks
We report that targeting of TOP2α and not TOP2β impacts cell killing by F14512, contrary to etoposide that kills cells through targeting both isoforms. Then, we show that despite being more cytotoxic, F14512 is less efficient than etoposide at producing TOP2α cleavage-complex (TOP2αcc) in cells. Finally, we report that compared with TOP2αcc mediated by etoposide, those generated by F14512 persist longer in the genome, are not dependent on TDP2 for cleaning break ends from TOP2α, are channeled to a larger extent to resection-based repair processes relying on CtIP and BRCA1 and promote RAD5...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Bombarde, O., Larminat, F., Gomez, D., Frit, P., Racca, C., Gomes, B., Guilbaud, N., Calsou, P. Tags: Small Molecule Therapeutics Source Type: research
