Maltotriose Conjugation to a Chlorin Derivative Enhances the Antitumor Effects of Photodynamic Therapy in Peritoneal Dissemination of Pancreatic Cancer
Peritoneal dissemination is a major clinical issue associated with dismal prognosis and poor quality of life for patients with pancreatic cancer; however, no effective treatment strategies have been established. Herein, we evaluated the effects of photodynamic therapy (PDT) with maltotriose-conjugated chlorin (Mal3-chlorin) in culture and in a peritoneal disseminated mice model of pancreatic cancer. The Mal3-chlorin was prepared as a water-soluble chlorin derivative conjugated with four Mal3 molecules to improve cancer selectivity. In vitro, Mal3-chlorin showed superior uptake into pancreatic cancer cells compared with tal...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Kato, A., Kataoka, H., Yano, S., Hayashi, K., Hayashi, N., Tanaka, M., Naitoh, I., Ban, T., Miyabe, K., Kondo, H., Yoshida, M., Fujita, Y., Hori, Y., Natsume, M., Murakami, T., Narumi, A., Nomoto, A., Naiki-Ito, A., Takahashi, S., Joh, T. Tags: Large Molecule Therapeutics Source Type: research
Preclinical Mammalian Safety Studies of EPHARNA (DOPC Nanoliposomal EphA2-Targeted siRNA)
To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we developed 1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-targeted therapeutic (EPHARNA). Here, we performed safety studies of EPHARNA in murine and primate models. Single dosing of EPHARNA was tested at 5 concentrations in mice (N = 15 per group) and groups were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice and Rhesus macaques twice weekly at two dose levels in each model. Possible effects on hematologic param...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Wagner, M. J., Mitra, R., McArthur, M. J., Baze, W., Barnhart, K., Wu, S. Y., Rodriguez-Aguayo, C., Zhang, X., Coleman, R. L., Lopez-Berestein, G., Sood, A. K. Tags: Large Molecule Therapeutics Source Type: research
A Fas Ligand (FasL)-Fused Humanized Antibody Against Tumor-Associated Glycoprotein 72 Selectively Exhibits the Cytotoxic Effect Against Oral Cancer Cells with a Low FasL/Fas Ratio
In this study, we evaluated whether a fusion protein (hcc49scFv-FasL) comprising of the cytotoxicity domain of the FasL fused to a humanized antibody (CC49) against tumor-associated glycoprotein 72, which is expressed on oral squamous cell carcinoma (OSCC), can selectively kill OSCC cells with different FasL/Fas ratios. In clinical samples, the significantly low FasL and high Fas transcripts were observed in tumors compared with normal tissues. A lower FasL/Fas ratio was correlated with a worse prognosis of OSCC patients and higher proliferative and invasive abilities of OSCC cells. The hcc49scFv-FasL showed a selective cy...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Chien, M.-H., Chang, W.-M., Lee, W.-J., Chang, Y.-C., Lai, T.-C., Chan, D. V., Sharma, R., Lin, Y.-F., Hsiao, M. Tags: Large Molecule Therapeutics Source Type: research
Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death
Photodynamic therapy (PDT), using 5-aminolevulinic acid (ALA) to drive synthesis of protoporphryin IX (PpIX) is a promising, scar-free alternative to surgery for skin cancers, including squamous cell carcinoma (SCC) and SCC precursors called actinic keratoses. In the United States, PDT is only FDA approved for treatment of actinic keratoses; this narrow range of indications could be broadened if PDT efficacy were improved. Toward that goal, we developed a mechanism-based combination approach using 5-fluorouracil (5-FU) as a neoadjuvant for ALA-based PDT. In mouse models of SCC (orthotopic UV-induced lesions, and subcutaneo...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Anand, S., Rollakanti, K. R., Brankov, N., Brash, D. E., Hasan, T., Maytin, E. V. Tags: Small Molecule Therapeutics Source Type: research
G-1 Inhibits Breast Cancer Cell Growth via Targeting Colchicine-Binding Site of Tubulin to Interfere with Microtubule Assembly
G-protein–coupled estrogen receptor 1 (GPER1) has been reported to play a significant role in mediating the rapid estrogen actions in a wide range of normal and cancer cells. G-1 was initially developed as a selective agonist for GPER. However, the molecular mechanisms underlying the actions of G-1 are unknown, and recent studies report inconsistent effects of G-1 on the growth of breast cancer cells. By employing high-resolution laser scanning confocal microscopy and time-lapse imaging technology, as well as biochemical analyses, in the current study, we provide convincing in vitro and in vivo evidence that G-1 is a...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Lv, X., He, C., Huang, C., Hua, G., Wang, Z., Remmenga, S. W., Rodabough, K. J., Karpf, A. R., Dong, J., Davis, J. S., Wang, C. Tags: Small Molecule Therapeutics Source Type: research
The TLR3 Agonist Inhibit Drug Efflux and Sequentially Consolidates Low-Dose Cisplatin-Based Chemoimmunotherapy while Reducing Side Effects
The traditional maximum dose density chemotherapy renders the tumor patients not only the tumor remission but the chemotherapy resistance and more adverse side effects. According to the widely positive expression of Toll-like receptor (TLR)-3 in oral squamous cell carcinoma (OSCC) patients (n = 166), we here provided an alternative strategy involved the orderly treatment of TLR3 agonist polyinosine–polycytidylic acid (PIC) and low-dose cisplatin. The optimal dose of cisplatin, the novel role of PIC and the side effects of the combined chemotherapy were determined in vitro and in distinct human tumor models in vivo. T...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Ding, L., Ren, J., Zhang, D., Li, Y., Huang, X., Ji, J., Hu, Q., Wang, H., Ni, Y., Hou, Y. Tags: Small Molecule Therapeutics Source Type: research
Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics
Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348, we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from patients with myeloproliferative neoplasm. Screening across 931 cancer cell lines revealed differentia...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Ember, S. W., Lambert, Q. T., Berndt, N., Gunawan, S., Ayaz, M., Tauro, M., Zhu, J.-Y., Cranfill, P. J., Greninger, P., Lynch, C. C., Benes, C. H., Lawrence, H. R., Reuther, G. W., Lawrence, N. J., Schönbrunn, E. Tags: Small Molecule Therapeutics Source Type: research
Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor
Pancreatic adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death in the United States. PDAC is difficult to manage effectively, with a five-year survival rate of only 5%. PDAC is largely driven by activating KRAS mutations, and as such, cannot be directly targeted with therapeutic agents that affect the activated protein. Instead, inhibition of downstream signaling and other targets will be necessary to effectively manage PDAC. Here, we describe a tiered single-agent and combination compound screen to identify targeted agents that impair growth of a panel of PDAC cell lines. Several of the combinati...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Langdon, C. G., Platt, J. T., Means, R. E., Iyidogan, P., Mamillapalli, R., Klein, M., Held, M. A., Lee, J. W., Koo, J. S., Hatzis, C., Hochster, H. S., Stern, D. F. Tags: Small Molecule Therapeutics Source Type: research
Optimizing Therapeutic Effect of Aurora B Inhibition in Acute Myeloid Leukemia with AZD2811 Nanoparticles
Barasertib (AZD1152), a highly potent and selective aurora kinase B inhibitor, gave promising clinical activity in elderly acute myeloid leukemia (AML) patients. However, clinical utility was limited by the requirement for a 7-day infusion. Here we assessed the potential of a nanoparticle formulation of the selective Aurora kinase B inhibitor AZD2811 (formerly known as AZD1152-hQPA) in preclinical models of AML. When administered to HL-60 tumor xenografts at a single dose between 25 and 98.7 mg/kg, AZD2811 nanoparticle treatment delivered profound inhibition of tumor growth, exceeding the activity of AZD1152. The improved ...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Floc'h, N., Ashton, S., Taylor, P., Trueman, D., Harris, E., Odedra, R., Maratea, K., Derbyshire, N., Caddy, J., Jacobs, V. N., Hattersley, M., Wen, S., Curtis, N. J., Pilling, J. E., Pease, E. J., Barry, S. T. Tags: Small Molecule Therapeutics Source Type: research
The BTK Inhibitor Ibrutinib (PCI-32765) Overcomes Paclitaxel Resistance in ABCB1- and ABCC10-Overexpressing Cells and Tumors
Paclitaxel is one of the most widely used antineoplastic drugs in the clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP-binding cassette subfamily B member 1 (ABCB1/P-glycoprotein) and subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance. Here, we demonstrated that the Bruton tyrosine kinase inhibitor, ibrutinib, significantly enhanced the antitumor activity of paclitaxel by antagonizing the efflux function of ABCB1 and A...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Zhang, H., Patel, A., Wang, Y.-J., Zhang, Y.-K., Kathawala, R. J., Qiu, L.-H., Patel, B. A., Huang, L.-H., Shukla, S., Yang, D.-H., Ambudkar, S. V., Fu, L.-W., Chen, Z.-S. Tags: Small Molecule Therapeutics Source Type: research
Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor
Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which i...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Perera, T. P. S., Jovcheva, E., Mevellec, L., Vialard, J., De Lange, D., Verhulst, T., Paulussen, C., Van De Ven, K., King, P., Freyne, E., Rees, D. C., Squires, M., Saxty, G., Page, M., Murray, C. W., Gilissen, R., Ward, G., Thompson, N. T., Newell, D. R Tags: Small Molecule Therapeutics Source Type: research
The Slow Cycling Phenotype: A Growing Problem for Treatment Resistance in Melanoma
Treatment resistance in metastatic melanoma is a longstanding issue. Current targeted therapy regimes in melanoma largely target the proliferating cancer population, leaving slow-cycling cancer cells undamaged. Consequently, slow-cycling cells are enriched upon drug therapy and can remain in the body for years until acquiring proliferative potential that triggers cancer relapse. Here we overview the molecular mechanisms of slow-cycling cells that underlie treatment resistance in melanoma. Three main areas of molecular reprogramming are discussed that mediate slow cycling and treatment resistance. First, a low microphthalmi...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Ahn, A., Chatterjee, A., Eccles, M. R. Tags: Reviews Source Type: research
FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions
The receptor tyrosine kinase fms-like tyrosine kinase 3 (FLT3), involved in regulating survival, proliferation, and differentiation of hematopoietic stem/progenitor cells, is expressed on acute myeloid leukemia (AML) cells in most patients. Mutations of FLT3 resulting in constitutive signaling are common in AML, including internal tandem duplication (ITD) in the juxtamembrane domain in 25% of patients and point mutations in the tyrosine kinase domain in 5%. Patients with AML with FLT3-ITD have a high relapse rate and short relapse-free and overall survival after chemotherapy and after transplant. A number of inhibitors of ...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Larrosa-Garcia, M., Baer, M. R. Tags: Reviews Source Type: research
The Role of CtBP1 in Oncogenic Processes and Its Potential as a Therapeutic Target
Transcriptional corepressor proteins have emerged as an important facet of cancer etiology. These corepressor proteins are often altered by loss- or gain-of-function mutations, leading to transcriptional imbalance. Thus, research directed at expanding our current understanding of transcriptional corepressors could impact the future development of new cancer diagnostics, prognostics, and therapies. In this review, our current understanding of the CtBP corepressors, and their role in both development and disease, is discussed in detail. Importantly, the role of CtBP1 overexpression in adult tissues in promoting the progressi...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Blevins, M. A., Huang, M., Zhao, R. Tags: Reviews Source Type: research
Highlights of This Issue
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research
