Digitalis-like Compounds Facilitate Non-Medullary Thyroid Cancer Redifferentiation through Intracellular Ca2+, FOS, and Autophagy-Dependent Pathways
Up to 20%–30% of patients with metastatic non-medullary thyroid cancer have persistent or recurrent disease resulting from tumor dedifferentiation. Tumor redifferentiation to restore sensitivity to radioactive iodide (RAI) therapy is considered a promising strategy to overcome RAI resistance. Autophagy has emerged as an important mechanism in cancer dedifferentiation. Here, we demonstrate the therapeutic potential of autophagy activators for redifferentiation of thyroid cancer cell lines. Five autophagy-activating compounds, all known as digitalis-like compounds, restored hNIS expression and iodide uptake in thyroid ...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Tesselaar, M. H., Crezee, T., Swarts, H. G., Gerrits, D., Boerman, O. C., Koenderink, J. B., Stunnenberg, H. G., Netea, M. G., Smit, J. W. A., Netea-Maier, R. T., Plantinga, T. S. Tags: Cancer Biology and Signal Transduction Source Type: research
Interference with the HSF1/HSP70/BAG3 Pathway Primes Glioma Cells to Matrix Detachment and BH3 Mimetic-Induced Apoptosis
Malignant gliomas exhibit a high intrinsic resistance against stimuli triggering apoptotic cell death. HSF1 acts as transcription factor upstream of HSP70 and the HSP70 co-chaperone BAG3 that is overexpressed in glioblastoma. To specifically target this resistance mechanism, we applied the selective HSF1 inhibitor KRIBB11 and the HSP70/BAG3 interaction inhibitor YM-1 in combination with the pan-Bcl-2 inhibitor AT-101. Here, we demonstrate that lentiviral BAG3 silencing significantly enhances AT-101–induced cell death and reactivates effector caspase-mediated apoptosis in U251 glioma cells with high BAG3 expression, w...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Antonietti, P., Linder, B., Hehlgans, S., Mildenberger, I. C., Burger, M. C., Fulda, S., Steinbach, J. P., Gessler, F., Rödel, F., Mittelbronn, M., Kögel, D. Tags: Cancer Biology and Signal Transduction Source Type: research
MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer
Taxane therapy remains the standard of care for triple-negative breast cancer. However, high frequencies of recurrence and progression in treated patients indicate that metastatic breast cancer cells can acquire resistance to this drug. The actin regulatory protein MENA and particularly its invasive isoform, MENAINV, are established drivers of metastasis. MENAINV expression is significantly correlated with metastasis and poor outcome in human patients with breast cancer. We investigated whether MENA isoforms might play a role in driving resistance to chemotherapeutics. We find that both MENA and MENAINV confer resistance t...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Oudin, M. J., Barbier, L., Schäfer, C., Kosciuk, T., Miller, M. A., Han, S., Jonas, O., Lauffenburger, D. A., Gertler, F. B. Tags: Cancer Biology and Signal Transduction Source Type: research
Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET
Antibody–drug conjugates (ADC) use monoclonal antibodies (mAb) as vehicles to deliver potent cytotoxic drugs selectively to tumor cells expressing the target. Molecular imaging with zirconium-89 (89Zr)-labeled mAbs recapitulates similar targeting biology and might help predict the efficacy of these ADCs. An anti-mesothelin antibody (AMA, MMOT0530A) was used to make comparisons between its efficacy as an ADC and its tumor uptake as measured by 89Zr immunoPET imaging. Mesothelin-targeted tumor growth inhibition by monomethyl auristatin E (MMAE), ADC AMA-MMAE (DMOT4039A), was measured in mice bearing xenografts of ovari...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: van Scheltinga, A. G. T. T., Ogasawara, A., Pacheco, G., Vanderbilt, A. N., Tinianow, J. N., Gupta, N., Li, D., Firestein, R., Marik, J., Scales, S. J., Williams, S.-P. Tags: Large Molecule Therapeutics Source Type: research
Establishment of the In Vivo Efficacy of Pretargeted Radioimmunotherapy Utilizing Inverse Electron Demand Diels-Alder Click Chemistry
This study established that a pretargeted methodology utilizing the IEDDA reaction can rapidly and specifically deliver a radiotherapeutic payload to tumor tissue, thus illustrating its excellent potential for clinical translation. Mol Cancer Ther; 16(1); 124–33. ©2016 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Houghton, J. L., Membreno, R., Abdel-Atti, D., Cunanan, K. M., Carlin, S., Scholz, W. W., Zanzonico, P. B., Lewis, J. S., Zeglis, B. M. Tags: Large Molecule Therapeutics Source Type: research
Optimization of a PEGylated Glucuronide-Monomethylauristatin E Linker for Antibody-Drug Conjugates
The emergence of antibody–drug conjugates (ADC), such as brentuximab vedotin and ado-trastuzumab emtansine, has led to increased efforts to identify new payloads and develop improved drug-linker technologies. Most antibody payloads impart significant hydrophobicity to the ADC, resulting in accelerated plasma clearance and suboptimal in vivo activity, particularly for conjugates with high drug-to-antibody ratios (DAR). We recently reported on the incorporation of a discrete PEG24 polymer as a side chain in a β-glucuronidase-cleavable monomethylauristatin E (MMAE) linker to provide homogeneous DAR 8 conjugates wit...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Burke, P. J., Hamilton, J. Z., Jeffrey, S. C., Hunter, J. H., Doronina, S. O., Okeley, N. M., Miyamoto, J. B., Anderson, M. E., Stone, I. J., Ulrich, M. L., Simmons, J. K., McKinney, E. E., Senter, P. D., Lyon, R. P. Tags: Large Molecule Therapeutics Source Type: research
The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737
This study sought whether AZD8055-induced mTOR inhibition and/or trametinib-induced MEK inhibition could modulate Mcl-1 and its partners to decrease the Mcl-1/BH3-only ratio and thus sensitize various ovarian cancer cell lines to ABT-737. AZD8055 treatment inhibited Mcl-1 and increased Puma expression but did not induce massive apoptosis in combination with ABT-737. In contrast, trametinib, which decreased the Mcl-1/BH3-only protein ratio by upregulating Puma and dephosphorylated active Bim, sensitized IGROV1-R10 and OVCAR3 cells to ABT-737. Adding AZD8055 to trametinib further reduced the Mcl-1/BH3-only protein ratio and ...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Petigny-Lechartier, C., Duboc, C., Jebahi, A., Louis, M.-H., Abeilard, E., Denoyelle, C., Gauduchon, P., Poulain, L., Villedieu, M. Tags: Small Molecule Therapeutics Source Type: research
Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities
Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three pediatric tumor types, we identified Ewing sarcoma–specific interactions of a diverse set of targeted agents including approved ...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Radic-Sarikas, B., Tsafou, K. P., Emdal, K. B., Papamarkou, T., Huber, K. V. M., Mutz, C., Toretsky, J. A., Bennett, K. L., Olsen, J. V., Brunak, S., Kovar, H., Superti-Furga, G. Tags: Small Molecule Therapeutics Source Type: research
Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma
The p21-activated kinase 4 (PAK4) is a key downstream effector of the Rho family GTPases and is found to be overexpressed in pancreatic ductal adenocarcinoma (PDAC) cells but not in normal human pancreatic ductal epithelia (HPDE). Gene copy number amplification studies in PDAC patient cohorts confirmed PAK4 amplification making it an attractive therapeutic target in PDAC. We investigated the antitumor activity of novel PAK4 allosteric modulators (PAM) on a panel of PDAC cell lines and chemotherapy-resistant flow-sorted PDAC cancer stem cells (CSC). The toxicity and efficacy of PAMs were evaluated in multiple subcutaneous m...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Aboukameel, A., Muqbil, I., Senapedis, W., Baloglu, E., Landesman, Y., Shacham, S., Kauffman, M., Philip, P. A., Mohammad, R. M., Azmi, A. S. Tags: Small Molecule Therapeutics Source Type: research
ASP5878, a Novel Inhibitor of FGFR1, 2, 3, and 4, Inhibits the Growth of FGF19-Expressing Hepatocellular Carcinoma
Hepatocellular carcinoma is an aggressive cancer with poor prognosis. Fibroblast growth factor 19, a member of the fibroblast growth factor family, is a ligand for fibroblast growth factor receptor 4. Moreover, it plays a crucial role in the progression of hepatocellular carcinoma. ASP5878 is a novel inhibitor of fibroblast growth factor receptors 1, 2, 3, and 4 that is under development. It inhibits fibroblast growth factor receptor 4 kinase activity with an IC50 of 3.5 nmol/L. ASP5878 potently suppressed the growth of the fibroblast growth factor 19–expressing hepatocellular carcinoma cell lines Hep3B2.1-7, HuH-7, ...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Futami, T., Okada, H., Kihara, R., Kawase, T., Nakayama, A., Suzuki, T., Kameda, M., Shindoh, N., Terasaka, T., Hirano, M., Kuromitsu, S. Tags: Small Molecule Therapeutics Source Type: research
N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation
We report the discovery of a new class of inhibitors for RAS transformation. Compounds in the class represented by endocannabinoid N-arachidonoyl dopamine (NADA) can induce cell oncosis, independent of its ability to engage cannabinoid receptors. Further analyses show that NADA is more active in inhibiting the NRAS transformation and signaling than that of KRAS4B. Mechanistically, NADA blocks the plasma membrane translocation of NRAS, but not that of KRAS4B. In addition, NADA inhibits plasma membrane translocation and neoplastic transformation of oncogenic KRAS4A. Interestingly, NADA also redistributes the cytoplasmic NRAS...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Wu, M., Huang, J., Zhang, J., Benes, C., Jiao, B., Ren, R. Tags: Small Molecule Therapeutics Source Type: research
Identification and Validation of Compounds Selectively Killing Resistant Cancer: Delineating Cell Line-Specific Effects from P-Glycoprotein-Induced Toxicity
In this study, our aim was to catalog various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp)–overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp. In contrast, novel 8-hydroxyquinoline derivatives that we identify in the National Cancer Institute (NCI) drug repository possess a robust Pgp-dependent toxic activity across diverse cell lines. Pgp expression associated with the resistance of the doxorubicin-resistant Br...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Füredi, A., Toth, S., Szebenyi, K., Pape, V. F. S., Türk, D., Kucsma, N., Cervenak, L., Tovari, J., Szakacs, G. Tags: Small Molecule Therapeutics Source Type: research
Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer
Abiraterone suppresses intracrine androgen synthesis via inhibition of CYP17A1. However, clinical evidence suggests that androgen synthesis is not fully inhibited by abiraterone and the sustained androgen production may lead to disease relapse. In the present study, we identified AKR1C3, an important enzyme in the steroidogenesis pathway, as a critical mechanism driving resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. We found that overexpression of AKR1C3 confers resistance to abiraterone while downregulation of AKR1C3 resensitizes resistant cells to abiraterone ...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Liu, C., Armstrong, C. M., Lou, W., Lombard, A., Evans, C. P., Gao, A. C. Tags: Small Molecule Therapeutics Source Type: research
Radiosensitization by the ATR Inhibitor AZD6738 through Generation of Acentric Micronuclei
AZD6738 is an orally active ATR inhibitor (ATRi) currently in phase I clinical trials. We found in vitro growth inhibitory activity of this ATRi in a panel of human cancer cell lines. We demonstrated radiosensitization by AZD6738 to single radiation fractions in multiple cancer cell lines independent of both p53 and BRCA2 status by the clonogenic assay. Radiosensitization by AZD6738 to clinically relevant doses of fractionated radiation was demonstrated in vitro using a 3D tumor spheroid model and, in vivo, AZD6738 radiosensitized by abrogating the radiation-induced G2 cell-cycle checkpoint and inhibiting homologous recomb...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Dillon, M. T., Barker, H. E., Pedersen, M., Hafsi, H., Bhide, S. A., Newbold, K. L., Nutting, C. M., McLaughlin, M., Harrington, K. J. Tags: Small Molecule Therapeutics Source Type: research
TAS-116, a Novel Hsp90 Inhibitor, Selectively Enhances Radiosensitivity of Human Cancer Cells to X-rays and Carbon Ion Radiation
Hsp90 inhibitors have been investigated as cancer therapeutics in monotherapy and to augment radiotherapy; however, serious adverse effects of early-generation Hsp90 inhibitors limited their development. TAS-116 is a novel Hsp90 inhibitor with lower adverse effects than other Hsp90 inhibitors, and here, we investigated the radiosensitizing effects of TAS-116 in low linear energy transfer (LET) X-ray and high LET carbon ion–irradiated human cancer cells and mouse tumor xenografts. TAS-116 decreased cell survival of both X-ray and carbon ion–irradiated human cancer cell lines (HeLa and H1299 cells), and similar t...
Source: Molecular Cancer Therapeutics - January 4, 2017 Category: Cancer & Oncology Authors: Lee, Y., Sunada, S., Hirakawa, H., Fujimori, A., Nickoloff, J. A., Okayasu, R. Tags: Small Molecule Therapeutics Source Type: research
