Dual Targeting of Epithelial Ovarian Cancer Via Folate Receptor {alpha} and the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-d]pyrimidine Antifolates
Folate uptake in epithelial ovarian cancer (EOC) involves the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), both facilitative transporters and folate receptor (FR) α. Although in primary EOC specimens, FRα is widely expressed and increases with tumor stage, PCFT was expressed independent of tumor stage (by real-time RT-PCR and IHC). EOC cell line models, including cisplatin sensitive (IGROV1 and A2780) and resistant (SKOV3 and TOV112D) cells, expressed a 17-fold range of FRα and similar amounts (within ~2-fold) of PCFT. Novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Hou, Z., Gattoc, L., O'Connor, C., Yang, S., Wallace-Povirk, A., George, C., Orr, S., Polin, L., White, K., Kushner, J., Morris, R. T., Gangjee, A., Matherly, L. H. Tags: Small Molecule Therapeutics Source Type: research
Characterization of a Dual Rac/Cdc42 Inhibitor MBQ-167 in Metastatic Cancer
In conclusion, MBQ-167 is 10x more potent than other currently available Rac/Cdc42 inhibitors and has the potential to be developed as an anticancer drug, as well as a dual inhibitory probe for the study of Rac and Cdc42. Mol Cancer Ther; 16(5); 805–18. ©2017 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Humphries-Bickley, T., Castillo-Pichardo, L., Hernandez-OFarrill, E., Borrero-Garcia, L. D., Forestier-Roman, I., Gerena, Y., Blanco, M., Rivera-Robles, M. J., Rodriguez-Medina, J. R., Cubano, L. A., Vlaar, C. P., Dharmawardhane, S. Tags: Small Molecule Therapeutics Source Type: research
Acquired Resistance to the Hsp90 Inhibitor, Ganetespib, in KRAS-Mutant NSCLC Is Mediated via Reactivation of the ERK-p90RSK-mTOR Signaling Network
Approximately 25% of non–small cell lung cancer (NSCLC) patients have KRAS mutations, and no effective therapeutic strategy exists for these patients. The use of Hsp90 inhibitors in KRAS-mutant NSCLC appeared to be a promising approach, as these inhibitors target many KRAS downstream effectors; however, limited clinical efficacy has been observed due to resistance. Here, we examined the mechanism(s) of acquired resistance to the Hsp90 inhibitor, ganetespib, and identified novel and rationally devised Hsp90 inhibitor combinations, which may prevent and overcome resistance to Hsp90 inhibitors. We derived KRAS-mutant NS...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Chatterjee, S., Huang, E. H.- B., Christie, I., Kurland, B. F., Burns, T. F. Tags: Small Molecule Therapeutics Source Type: research
Nodal Signaling as a Developmental Therapeutics Target in Oncology
The tumor microenvironment is a vital feature of oncogenesis and tumor progression. There are several parallels between cancer cells and early developmental stem cells, including their plasticity and signaling mechanisms. In early fetal development, Nodal is expressed for endodermal and mesodermal differentiation. This expression has been shown reemerge in the setting of epithelial cancers, such as breast and melanoma. High Nodal expression correlates to an aggressive tumor grade in these malignancies. Nodal signal begins with its interaction with its coreceptor, Cripto-1, leading to activation of Smad2/Smad3 and ultimatel...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Kalyan, A., Carneiro, B. A., Chandra, S., Kaplan, J., Chae, Y. K., Matsangou, M., Hendrix, M. J. C., Giles, F. Tags: Reviews Source Type: research
Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment
Hairy and Enhancer-of-split related with YRPW motif (Hey) transcription factors are important regulators of stem cell embryogenesis. Clinical relevance shows that they are also highly expressed in malignant carcinoma. Recent studies have highlighted functions for the Hey factors in tumor metastasis, the maintenance of cancer cell self-renewal, as well as proliferation and the promotion of tumor angiogenesis. Pathways that regulate Hey gene expression, such as Notch and TGFβ signaling, are frequently aberrant in numerous cancers. In addition, Hey factors control downstream targets via recruitment of histone deacetylase...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Liu, Z., Sanders, A. J., Liang, G., Song, E., Jiang, W. G., Gong, C. Tags: Reviews Source Type: research
Highlights of This Issue
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research
Targeted Treatment of Metastatic Breast Cancer by PLK1 siRNA Delivered by an Antioxidant Nanoparticle Platform
Metastatic breast cancer is developed in about 20% to 30% of newly diagnosed patients with early-stage breast cancer despite treatments. Herein, we report a novel nanoparticle platform with intrinsic antimetastatic properties for the targeted delivery of Polo-like kinase 1 siRNA (siPLK1). We first evaluated it in a triple-negative breast cancer (TNBC) model, which shows high metastatic potential. PLK1 was identified as the top therapeutic target for TNBC cells and tumor-initiating cells in a kinome-wide screen. The platform consists of a 50-nm mesoporous silica nanoparticle (MSNP) core coated layer-by-layer with bioreducib...
Source: Molecular Cancer Therapeutics - April 2, 2017 Category: Cancer & Oncology Authors: Morry, J., Ngamcherdtrakul, W., Gu, S., Reda, M., Castro, D. J., Sangvanich, T., Gray, J. W., Yantasee, W. Tags: Models and Technologies Source Type: research
APC Mutations as a Potential Biomarker for Sensitivity to Tankyrase Inhibitors in Colorectal Cancer
In most colorectal cancers, Wnt/β-catenin signaling is activated by loss-of-function mutations in the adenomatous polyposis coli (APC) gene and plays a critical role in tumorigenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize Axins, a negative regulator of β-catenin, and upregulate β-catenin signaling. Tankyrase inhibitors downregulate β-catenin and are expected to be promising therapeutics for colorectal cancer. However, colorectal cancer cells are not always sensitive to tankyrase inhibitors, and predictive biomarkers for the drug sensitivity remain elusive. Here we demonstrate that the short-fo...
Source: Molecular Cancer Therapeutics - April 2, 2017 Category: Cancer & Oncology Authors: Tanaka, N., Mashima, T., Mizutani, A., Sato, A., Aoyama, A., Gong, B., Yoshida, H., Muramatsu, Y., Nakata, K., Matsuura, M., Katayama, R., Nagayama, S., Fujita, N., Sugimoto, Y., Seimiya, H. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
MALAT1 Is Associated with Poor Response to Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients and Promotes Chemoresistance through EZH2
In conclusion, this study illuminates the prognostic role of lncRNA MALAT1 in colorectal cancer patients receiving oxaliplatin-based treatment and further demonstrates how lncRNA MALAT1 confers a chemoresistant function in colorectal cancer. Thus, lncRNA MALAT1 may serve as a promising prognostic and therapeutic target for colorectal cancer patients. Mol Cancer Ther; 16(4); 739–51. ©2017 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - April 2, 2017 Category: Cancer & Oncology Authors: Li, P., Zhang, X., Wang, H., Wang, L., Liu, T., Du, L., Yang, Y., Wang, C. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
In Vitro and In Vivo Synergistic Antitumor Activity of the Combination of BKM120 and Erlotinib in Head and Neck Cancer: Mechanism of Apoptosis and Resistance
This study investigated whether cotargeting of EGFR and PI3K has synergistic antitumor effects and apoptosis induction. We examined growth suppression, apoptosis, and signaling pathway modulation resulting from single and combined targeting of EGFR and PI3K with erlotinib and BKM120, respectively, in a panel of SCCHN cell lines and a xenograft model of SCCHN. In a panel of 12 cell lines, single targeting of EGFR with erlotinib or PI3K with BKM120 suppressed cellular growth without inducing significant apoptosis. Cotargeting of EGFR and PI3K synergistically inhibited SCCHN cell line and xenograft tumor growth, but induced v...
Source: Molecular Cancer Therapeutics - April 2, 2017 Category: Cancer & Oncology Authors: Anisuzzaman, A. S. M., Haque, A., Wang, D., Rahman, M. A., Zhang, C., Chen, Z., Chen, Z. G., Shin, D. M., Amin, A. R. M. R. Tags: Cancer Biology and Signal Transduction Source Type: research
Nuclear Export of Ubiquitinated Proteins Determines the Sensitivity of Colorectal Cancer to Proteasome Inhibitor
Although proteasome inhibitors such as bortezomib had significant therapeutic effects in multiple myeloma and mantel cell lymphoma, they exhibited minimal clinical activity as a monotherapy for solid tumors, including colorectal cancer. We found in this study that proteasome inhibition induced a remarkable nuclear exportation of ubiquitinated proteins. Inhibition of CRM1, the nuclear export carrier protein, hampered protein export and synergistically enhanced the cytotoxic action of bortezomib on colon cancer cells containing wild-type p53, which underwent G2–M cell-cycle block and apoptosis. Further analysis indicat...
Source: Molecular Cancer Therapeutics - April 2, 2017 Category: Cancer & Oncology Authors: Wu, T., Chen, W., Zhong, Y., Hou, X., Fang, S., Liu, C.-Y., Wang, G., Yu, T., Huang, Y.-Y., Ouyang, X., Li, H. Q. X., Cui, L., Yang, Y. Tags: Cancer Biology and Signal Transduction Source Type: research
Insulin-Mediated Signaling Facilitates Resistance to PDGFR Inhibition in Proneural hPDGFB-Driven Gliomas
Despite abundant evidence implicating receptor tyrosine kinases (RTK), including the platelet-derived growth factor receptor (PDGFR), in the pathogenesis of glioblastoma (GBM), the clinical use of RTK inhibitors in this disease has been greatly compromised by the rapid emergence of therapeutic resistance. To study the resistance of proneural gliomas that are driven by a PDGFR-regulated pathway to targeted tyrosine kinase inhibitors, we utilized a mouse model of proneural glioma in which mice develop tumors that become resistant to PDGFR inhibition. We found that tumors resistant to PDGFR inhibition required the expression ...
Source: Molecular Cancer Therapeutics - April 2, 2017 Category: Cancer & Oncology Authors: Almiron Bonnin, D. A., Ran, C., Havrda, M. C., Liu, H., Hitoshi, Y., Zhang, Z., Cheng, C., Ung, M., Israel, M. A. Tags: Cancer Biology and Signal Transduction Source Type: research
Ras-MEK Signaling Mediates a Critical Chk1-Dependent DNA Damage Response in Cancer Cells
Cancer cell line profiling to identify previously unrecognized kinase dependencies revealed a novel nonmutational dependency on the DNA damage response checkpoint kinase Chk1. Although Chk1 is a promising therapeutic target in p53-deficient cancers, we found that Ras–MEK signaling engages Chk1 in a subset of osteosarcoma, ovarian, and breast cancer cells to enable their survival upon DNA damage, irrespective of p53 mutation status. Mechanistically, Ras–MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DN...
Source: Molecular Cancer Therapeutics - April 2, 2017 Category: Cancer & Oncology Authors: Lee, H.-J., Cao, Y., Pham, V., Blackwood, E., Wilson, C., Evangelista, M., Klijn, C., Stokoe, D., Settleman, J. Tags: Cancer Biology and Signal Transduction Source Type: research
Bispecific Antibodies and Antibody-Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs
In this study, we compared the trafficking of HER2, which is the target of the clinically approved ADC ado-trastuzumab emtansine (T-DM1), with that of prolactin receptor (PRLR), another potential target in breast cancer. In contrast to HER2, we found that PRLR is rapidly and constitutively internalized, and traffics efficiently to lysosomes, where it is degraded. The PRLR cytoplasmic domain is necessary to promote rapid internalization and degradation, and when transferred to HER2, enhances HER2 degradation. In accordance with these findings, low levels of cell surface PRLR (~30,000 surface receptors per cell) are sufficie...
Source: Molecular Cancer Therapeutics - April 2, 2017 Category: Cancer & Oncology Authors: Andreev, J., Thambi, N., Perez Bay, A. E., Delfino, F., Martin, J., Kelly, M. P., Kirshner, J. R., Rafique, A., Kunz, A., Nittoli, T., MacDonald, D., Daly, C., Olson, W., Thurston, G. Tags: Large Molecule Therapeutics Source Type: research
Anti-KIT Monoclonal Antibody Treatment Enhances the Antitumor Activity of Immune Checkpoint Inhibitors by Reversing Tumor-Induced Immunosuppression
The receptor tyrosine kinase KIT is an established oncogenic driver of tumor growth in certain tumor types, including gastrointestinal stromal tumors, in which constitutively active mutant forms of KIT represent an actionable target for small-molecule tyrosine kinase inhibitors. There is also considerable potential for KIT to influence tumor growth indirectly based on its expression and function in cell types of the innate immune system, most notably mast cells. We have evaluated syngeneic mouse tumor models for antitumor effects of an inhibitory KIT mAb, dosed either alone or in combination with immune checkpoint inhibito...
Source: Molecular Cancer Therapeutics - April 2, 2017 Category: Cancer & Oncology Authors: Garton, A. J., Seibel, S., Lopresti-Morrow, L., Crew, L., Janson, N., Mandiyan, S., Trombetta, E. S., Pankratz, S., LaVallee, T. M., Gedrich, R. Tags: Large Molecule Therapeutics Source Type: research
