FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors
In this study, we found that colorectal cancer cells containing inactivating mutations of FBW7, a tumor suppressor and E3 ubiquitin ligase, are intrinsically insensitive to Hsp90 inhibitors. The insensitive colorectal cancer cells lack degradation of Mcl-1, a prosurvival Bcl-2 family protein. Hsp90 inhibition promotes GSK3β-dependent phosphorylation of Mcl-1, which subsequently binds to FBW7 and undergoes ubiquitination and proteasomal degradation. Specifically blocking Mcl-1 phosphorylation by genetic knock-in abrogates its degradation and renders in vitro and in vivo resistance to Hsp90 inhibitors, which can be over...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Tong, J., Tan, S., Nikolovska-Coleska, Z., Yu, J., Zou, F., Zhang, L. Tags: Cancer Biology and Signal Transduction Source Type: research
An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer
Chemotherapy remains the mainstay of treatment for advanced breast cancer; however, resistance is an inevitable event for the majority of patients with metastatic disease. Moreover, there is little information available to guide stratification of first-line chemotherapy, crucial given the common development of multidrug resistance. Here, we describe an in vivo screen to interrogate the response to anthracycline-based chemotherapy in a syngeneic metastatic breast cancer model and identify JNK signaling as a key modulator of chemotherapy response. Combining in vitro and in vivo functional analyses, we demonstrate that JNK in...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Ashenden, M., van Weverwijk, A., Murugaesu, N., Fearns, A., Campbell, J., Gao, Q., Iravani, M., Isacke, C. M. Tags: Cancer Biology and Signal Transduction Source Type: research
Wnt/{beta}-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor
Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a KIT or PDGFRA mutation. However, the molecular basis for tumor malignancy is not well defined. Although the Wnt/β-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed β-catenin and contained active, dephosphorylated nuclear β-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4. Accordingly, in human GIST T1 cells, Wnt stimulation in...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Zeng, S., Seifert, A. M., Zhang, J. Q., Cavnar, M. J., Kim, T. S., Balachandran, V. P., Santamaria-Barria, J. A., Cohen, N. A., Beckman, M. J., Medina, B. D., Rossi, F., Crawley, M. H., Loo, J. K., Maltbaek, J. H., Besmer, P., Antonescu, C. R., DeMatteo, Tags: Cancer Biology and Signal Transduction Source Type: research
mTORC1 Inhibition Induces Resistance to Methotrexate and 6-Mercaptopurine in Ph+ and Ph-like B-ALL
Elevated activity of mTOR is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high-risk B-ALL subtypes. Therefore, we tested whether mTOR inhibition can augment the efficacy of current chemotherapy agents in Ph+ and Ph-like B-ALL models. Surprisingly, inhibiting mTOR complex 1 (mTORC1) protected B-ALL cells from killing by methotrexate and 6-me...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Vo, T.-T. T., Lee, J. S., Nguyen, D., Lui, B., Pandori, W., Khaw, A., Mallya, S., Lu, M., Müschen, M., Konopleva, M., Fruman, D. A. Tags: Cancer Biology and Signal Transduction Source Type: research
Inhibition of Aurora A and Aurora B Is Required for the Sensitivity of HPV-Driven Cervical Cancers to Aurora Kinase Inhibitors
The activity and efficacy of Aurora inhibitors have been reported in a wide range of cancer types. The most prominent Aurora inhibitor is alisertib, an investigational Aurora inhibitor that has been the subject of more than 30 clinical trials. Alisertib has inhibitory activity against both Aurora A and B, although it is considered to be primarily an Aurora A inhibitor in vivo. Here, we show that alisertib inhibits both Aurora A and B in vivo in preclinical models of HPV-driven cervical cancer, and that it is the inhibition of Aurora A and B that provides the selectivity and efficacy of this drug in vivo in this disease set...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Martin, D., Fallaha, S., Proctor, M., Stevenson, A., Perrin, L., McMillan, N., Gabrielli, B. Tags: Cancer Biology and Signal Transduction Source Type: research
Herpes Simplex Virus Glycoprotein D Targets a Specific Dendritic Cell Subset and Improves the Performance of Vaccines to Human Papillomavirus-Associated Tumors
Cervical cancer is a major public health problem and one of the leading causes of cancer deaths in women. Virtually all cases of cervical cancer, as well as a growing share of anal and head/neck tumors, are associated with human papillomavirus (HPV) infection. Despite the effectiveness, the available prophylactic vaccines do not benefit women with cervical lesions or cancer. Therefore, the search of new immunotherapeutic approaches to treat HPV-induced tumors is still a priority. The present study characterizes a therapeutic antitumor vaccine based on the genetic fusion of the Herpes simplex virus-1 (HSV-1) glycoprotein D ...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Porchia, B. F. M. M., Moreno, A. C. R., Ramos, R. N., Diniz, M. O., de Andrade, L. H. T. M., Rosa, D. S., Barbuto, J. A. M., Boscardin, S. B., Ferreira, L. C. S. Tags: Large Molecule Therapeutics Source Type: research
A Novel Theranostic Strategy for MMP-14-Expressing Glioblastomas Impacts Survival
Glioblastoma (GBM) has a dismal prognosis. Evidence from preclinical tumor models and human trials indicates the role of GBM-initiating cells (GIC) in GBM drug resistance. Here, we propose a new treatment option with tumor enzyme-activatable, combined therapeutic and diagnostic (theranostic) nanoparticles, which caused specific toxicity against GBM tumor cells and GICs. The theranostic cross-linked iron oxide nanoparticles (CLIO) were conjugated to a highly potent vascular disrupting agent (ICT) and secured with a matrix-metalloproteinase (MMP-14) cleavable peptide. Treatment with CLIO-ICT disrupted tumor vasculature of MM...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Mohanty, S., Chen, Z., Li, K., Morais, G. R., Klockow, J., Yerneni, K., Pisani, L., Chin, F. T., Mitra, S., Cheshier, S., Chang, E., Gambhir, S. S., Rao, J., Loadman, P. M., Falconer, R. A., Daldrup-Link, H. E. Tags: Large Molecule Therapeutics Source Type: research
IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma
Inflammation mediated by activation of JAK/STAT signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL6 receptor (IL6R) as a strategy to inhibit IL6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1Cre (KPC) mice. Plasma from patients with PDAC was assessed for its ability to activate STAT3/SOCS3 in human monocytes using immunofluorescence microscopy and quantitative gene expression assays. KPC m...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Long, K. B., Tooker, G., Tooker, E., Luque, S. L., Lee, J. W., Pan, X., Beatty, G. L. Tags: Large Molecule Therapeutics Source Type: research
Enzymatic Inactivation of Endogenous IgG by IdeS Enhances Therapeutic Antibody Efficacy
Endogenous plasma IgG sets an immunologic threshold that dictates the activity of tumor-directed therapeutic antibodies. Saturation of cellular antibody receptors by endogenous antibody limits antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Here, we show how enzymatic cleavage of IgG using the bacterial enzyme IdeS can be utilized to empty both high and low affinity Fc-receptors and clear the entire endogenous antibody pool. Using in vitro models, tumor animal models as well as ex vivo analysis of sera collected during a previous clinical trial with IdeS, we show ho...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Järnum, S., Runström, A., Bockermann, R., Winstedt, L., Crispin, M., Kjellman, C. Tags: Large Molecule Therapeutics Source Type: research
Inhibition of Megakaryocyte Differentiation by Antibody-Drug Conjugates (ADCs) is Mediated by Macropinocytosis: Implications for ADC-induced Thrombocytopenia
This study aims to elucidate the mechanism of action of ADC-induced thrombocytopenia. ENPP3 expression in platelets and megakaryocytes (MK) was investigated and shown to be negative. The direct effect of AGS-16C3F on platelets was evaluated using platelet rich plasma following the expression of platelet activation markers. Effects of AGS-16C3F, T-DM1, and control ADCs on maturing megakaryocytes were evaluated in an in vitro system in which human hematopoietic stem cells (HSC) were differentiated into MKs. AGS-16C3F, like T-DM1, did not affect platelets directly, but inhibited MK differentiation by the activity of Cys-mcMMA...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Zhao, H., Gulesserian, S., Ganesan, S. K., Ou, J., Morrison, K., Zeng, Z., Robles, V., Snyder, J., Do, L., Avina, H., Karki, S., Stover, D. R., Donate, F. Tags: Large Molecule Therapeutics Source Type: research
A Potential Mechanism for ADC-Induced Neutropenia: Role of Neutrophils in Their Own Demise
Neutropenia is a common adverse event in cancer patients treated with antibody–drug conjugates (ADC) and we aimed to elucidate the potential mechanism of this toxicity. To investigate whether ADCs affect neutrophil production from bone marrow, an in vitro assay was developed in which hematopoietic stem cells (HSC) were differentiated to neutrophils. Several antibodies against targets absent in HSCs and neutrophils were conjugated to MMAE via a cleavable valine-citrulline linker (vcMMAE-ADC) or MMAF via a noncleavable maleimidocaproyl linker (mcMMAF-ADC), and their cytotoxicity was tested in the neutrophil differentia...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Zhao, H., Gulesserian, S., Malinao, M. C., Ganesan, S. K., Song, J., Chang, M. S., Williams, M. M., Zeng, Z., Mattie, M., Mendelsohn, B. A., Stover, D. R., Donate, F. Tags: Large Molecule Therapeutics Source Type: research
Antitumor Synergism and Enhanced Survival with a Tumor Vasculature-Targeted Enzyme Prodrug System, Rapamycin, and Cyclophosphamide
Mutant cystathionine gamma-lyase was targeted to phosphatidylserine exposed on tumor vasculature through fusion with Annexin A1 or Annexin A5. Cystathionine gamma-lyase E58N, R118L, and E338N mutations impart nonnative methionine gamma-lyase activity, resulting in tumor-localized generation of highly toxic methylselenol upon systemic administration of nontoxic selenomethionine. The described therapeutic system circumvents systemic toxicity issues using a novel drug delivery/generation approach and avoids the administration of nonnative proteins and/or DNA required with other enzyme prodrug systems. The enzyme fusion exhibi...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Krais, J. J., Virani, N., McKernan, P. H., Nguyen, Q., Fung, K.-M., Sikavitsas, V. I., Kurkjian, C., Harrison, R. G. Tags: Large Molecule Therapeutics Source Type: research
ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK
Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the MAPK cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell–originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated. In the current study, ADA-07, a novel TOPK inhibitor, was synthesized and charac...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Gao, G., Zhang, T., Wang, Q., Reddy, K., Chen, H., Yao, K., Wang, K., Roh, E., Zykova, T., Ma, W., Ryu, J., Curiel-Lewandrowski, C., Alberts, D., Dickinson, S. E., Bode, A. M., Xing, Y., Dong, Z. Tags: Small Molecule Therapeutics Source Type: research
Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation
Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G2–M checkpoint in the presence of replication stress inflicted by DNA-damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity, and reduced toxicity of chemotherapy. Some recently identified CHK1 inhibitors entered clinical trials in combin...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Samadder, P., Suchankova, T., Hylse, O., Khirsariya, P., Nikulenkov, F., Drapela, S., Strakova, N., Vanhara, P., Vasickova, K., Kolarova, H., Bino, L., Bittova, M., Ovesna, P., Kollar, P., Fedr, R., Esner, M., Jaros, J., Hampl, A., Krejci, L., Paruch, K., Tags: Small Molecule Therapeutics Source Type: research
Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells
Taxane-based therapy provides a survival benefit in patients with metastatic prostate cancer, yet the median survival is less than 20 months in this setting due in part to taxane-associated resistance. Innovative strategies are required to overcome chemoresistance for improved patient survival. Here, NanoOrl, a new experimental nanoparticle formulation of the FDA-approved drug, orlistat, was investigated for its cytotoxicity in taxane-resistant prostate cancer utilizing two established taxane-resistant (TxR) cell lines. Orlistat is a weight loss drug that inhibits gastric lipases, but is also a potent inhibitor of fatty ac...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Souchek, J. J., Davis, A. L., Hill, T. K., Holmes, M. B., Qi, B., Singh, P. K., Kridel, S. J., Mohs, A. M. Tags: Small Molecule Therapeutics Source Type: research
