Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma
We examined the combination of the FDA-approved drug ingenol-3-angelate (PEP005) with epigenetic drugs as a rational therapeutic approach for KSHV-mediated malignancies. JQ1, a bromodomain and extra terminal (BET) protein inhibitor, in combination with PEP005, not only robustly induced KSHV lytic replication, but also inhibited IL6 production from PEL cells. Using the dosages of these agents that were found to be effective in reactivating HIV (as a means to clear latent virus with highly active antiretroviral therapy), we were able to inhibit PEL growth in vitro and delay tumor growth in a PEL xenograft tumor model. KSHV r...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Zhou, F., Shimoda, M., Olney, L., Lyu, Y., Tran, K., Jiang, G., Nakano, K., Davis, R. R., Tepper, C. G., Maverakis, E., Campbell, M., Li, Y., Dandekar, S., Izumiya, Y. Tags: Models and Technologies Source Type: research
Estrogen Receptor {beta} Is a Novel Target in Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a devastating disease characterized by poor patient outcome and suboptimal chemotherapeutics. Here, a high-throughput screen identified diosmetin, a citrus flavonoid, with anti-AML activity. Diosmetin imparted selective toxicity against leukemia and leukemia stem cells in vitro and in vivo with no effect on normal hematopoietic stem cells. Mechanistically, we demonstrated that diosmetin targets estrogen receptor (ER) β. ERβ expression conferred cell sensitivity, as patient-derived AML cells with high levels of ERβ were sensitive, whereas cells with low ERβ were insensitiv...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Rota, S.-G., Roma, A., Dude, I., Ma, C., Stevens, R., MacEachern, J., Graczyk, J., Espiritu, S. M. G., Rao, P. N., Minden, M. D., Kreinin, E., Hess, D. A., Doxey, A. C., Spagnuolo, P. A. Tags: Companion Diagnostic, Pharmacogenomic, and Cancer Biomarkers Source Type: research
TTK Inhibitors as a Targeted Therapy for CTNNB1 ({beta}-catenin) Mutant Cancers
The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small-molecule inhibitors. Although the first TTK inhibitors have entered phase I dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy is still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, we profiled a set of preclinical and clinical TTK inhibitors from different chemical series on a panel of 66 genetically characterized cell lines derived from differen...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Zaman, G. J. R., de Roos, J. A. D. M., Libouban, M. A. A., Prinsen, M. B. W., de Man, J., Buijsman, R. C., Uitdehaag, J. C. M. Tags: Companion Diagnostic, Pharmacogenomic, and Cancer Biomarkers Source Type: research
Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers
Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non–small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independe...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Goodman, A. M., Kato, S., Bazhenova, L., Patel, S. P., Frampton, G. M., Miller, V., Stephens, P. J., Daniels, G. A., Kurzrock, R. Tags: Companion Diagnostic, Pharmacogenomic, and Cancer Biomarkers Source Type: research
EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL
The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2. Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regressi...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Brach, D., Johnston-Blackwell, D., Drew, A., Lingaraj, T., Motwani, V., Warholic, N. M., Feldman, I., Plescia, C., Smith, J. J., Copeland, R. A., Keilhack, H., Chan-Penebre, E., Knutson, S. K., Ribich, S. A., Raimondi, A., Thomenius, M. J. Tags: Cancer Biology and Translational Studies Source Type: research
Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance
Approximately 10% of non–small cell lung cancer (NSCLC) patients in the United States and 40% of NSCLC patients in Asia have activating epidermal growth factor receptor (EGFR) mutations and are eligible to receive targeted anti-EGFR therapy. Despite an extension of life expectancy associated with this treatment, resistance to EGFR tyrosine kinase inhibitors and anti-EGFR antibodies is almost inevitable. To identify additional signaling routes that can be cotargeted to overcome resistance, we quantified tumor-specific molecular changes that govern resistant cancer cell growth and survival. Mass spectrometry–base...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Emdal, K. B., Dittmann, A., Reddy, R. J., Lescarbeau, R. S., Moores, S. L., Laquerre, S., White, F. M. Tags: Cancer Biology and Translational Studies Source Type: research
T790M-Selective EGFR-TKI Combined with Dasatinib as an Optimal Strategy for Overcoming EGFR-TKI Resistance in T790M-Positive Non-Small Cell Lung Cancer
T790M mutation–selective EGFR tyrosine kinase inhibitors (EGFR-TKI) have demonstrated clinical benefits in non–small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as cooncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced antitumor activity in T790M-positive cells. In the current study, ...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Watanabe, S., Yoshida, T., Kawakami, H., Takegawa, N., Tanizaki, J., Hayashi, H., Takeda, M., Yonesaka, K., Tsurutani, J., Nakagawa, K. Tags: Cancer Biology and Translational Studies Source Type: research
Synthetic Lethality Interaction Between Aurora Kinases and CHEK1 Inhibitors in Ovarian Cancer
Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair genes, so they rely on DNA-damage checkpoint proteins, like the checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 and mitotic aurora kinase A (AURKA) inhibitors. Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1, and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA inhibitor and LY2603618 as...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Alcaraz-Sanabria, A., Nieto-Jimenez, C., Corrales-Sanchez, V., Serrano-Oviedo, L., Andres-Pretel, F., Montero, J. C., Burgos, M., Llopis, J., Galan-Moya, E. M., Pandiella, A., Ocana, A. Tags: Cancer Biology and Translational Studies Source Type: research
TDP1 is Critical for the Repair of DNA Breaks Induced by Sapacitabine, a Nucleoside also Targeting ATM- and BRCA-Deficient Tumors
2'-C-cyano-2'-deoxy-1-β-d-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes β-elimination that generates single-strand breaks with abnormal 3'-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes nonphosphorylated 3'-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1–/– DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC. We also ...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Abo, M. A., Sasanuma, H., Liu, X., Rajapakse, V. N., Huang, S.-y., Kiselev, E., Takeda, S., Plunkett, W., Pommier, Y. Tags: Cancer Biology and Translational Studies Source Type: research
PPAR{gamma} Ligand-induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers
In this study, our clinical data have established that basal and claudin-low subtypes of breast cancer (TNBC types) express significantly higher levels of Annexin A1 (ANXA1) with poor survival outcomes. Using human cancer cell lines that model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and PPAR. A similar correlation between these two markers was also established in our clinical breast cancer patients' specimens. To establish a link between these two markers in TNBC, we show de novo expression of ANXA1 is induced by activation of PPAR both in vitro and in vivo and it has a predi...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Chen, L., Yuan, Y., Kar, S., Kanchi, M. M., Arora, S., Kim, J. E., Koh, P. F., Yousef, E., Samy, R. P., Shanmugam, M. K., Tan, T. Z., Shin, S. W., Arfuso, F., Shen, H. M., Yang, H., Goh, B. C., Park, J. I., Gaboury, L., Lobie, P. E., Sethi, G., Lim, L. H. Tags: Cancer Biology and Translational Studies Source Type: research
Sphingosine-1-Phosphate Receptor-1 Promotes Environment-Mediated and Acquired Chemoresistance
Drug resistance is a major barrier for the development of effective and durable cancer therapies. Overcoming this challenge requires further defining the cellular and molecular mechanisms underlying drug resistance, both acquired and environment-mediated drug resistance (EMDR). Here, using neuroblastoma (NB), a childhood cancer with high incidence of recurrence due to resistance to chemotherapy, as a model we show that human bone marrow–mesenchymal stromal cells induce tumor expression of sphingosine-1-phosphate receptor-1 (S1PR1), leading to their resistance to chemotherapy. Targeting S1PR1 by shRNA markedly enhance...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Lifshitz, V., Priceman, S. J., Li, W., Cherryholmes, G., Lee, H., Makovski-Silverstein, A., Borriello, L., DeClerck, Y. A., Yu, H. Tags: Cancer Biology and Translational Studies Source Type: research
Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism
Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in prima...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Wiedmer, T., Blank, A., Pantasis, S., Normand, L., Bill, R., Krebs, P., Tschan, M. P., Marinoni, I., Perren, A. Tags: Cancer Biology and Translational Studies Source Type: research
The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors
Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockad...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Harney, A. S., Karagiannis, G. S., Pignatelli, J., Smith, B. D., Kadioglu, E., Wise, S. C., Hood, M. M., Kaufman, M. D., Leary, C. B., Lu, W.-P., Al-Ani, G., Chen, X., Entenberg, D., Oktay, M. H., Wang, Y., Chun, L., Palma, M. D., Jones, J. G., Flynn, D. Tags: Cancer Biology and Translational Studies Source Type: research
Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma
The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated protumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells. Pha...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Aguilera, K. Y., Huang, H., Du, W., Hagopian, M. M., Wang, Z., Hinz, S., Hwang, T. H., Wang, H., Fleming, J. B., Castrillon, D. H., Ren, X., Ding, K., Brekken, R. A. Tags: Cancer Biology and Translational Studies Source Type: research
Wilms Tumor NCAM-Expressing Cancer Stem Cells as Potential Therapeutic Target for Polymeric Nanomedicine
Cancer stem cells (CSC) form a specific population within the tumor that has been shown to have self-renewal and differentiation properties, increased ability to migrate and form metastases, and increased resistance to chemotherapy. Consequently, even a small number of cells remaining after therapy can repopulate the tumor and cause recurrence of the disease. CSCs in Wilms tumor, a pediatric renal cancer, were previously shown to be characterized by neural cell adhesion molecule (NCAM) expression. Therefore, NCAM provides a specific biomarker through which the CSC population in this tumor can be targeted. We have recently ...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Markovsky, E., Vax, E., Ben-Shushan, D., Eldar-Boock, A., Shukrun, R., Yeini, E., Barshack, I., Caspi, R., Harari-Steinberg, O., Pode-Shakked, N., Dekel, B., Satchi-Fainaro, R. Tags: Large Molecule Therapeutics Source Type: research
