Efficacy of AKT Inhibitor ARQ 092 Compared with Sorafenib in a Cirrhotic Rat Model with Hepatocellular Carcinoma
In conclusion, we demonstrated that ARQ 092 blocks AKT phosphorylation in vitro and in vivo. In the HCC-rat model, ARQ 092 was well tolerated, showed antifibrotic effect, and had stronger antitumor effect than sorafenib. Our results confirm the importance of targeting AKT in HCC. Mol Cancer Ther; 16(10); 2157–65. ©2017 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Roth, G. S., Macek Jilkova, Z., Zeybek Kuyucu, A., Kurma, K., Ahmad Pour, S. T., Abbadessa, G., Yu, Y., Busser, B., Marche, P. N., Leroy, V., Decaens, T. Tags: Small Molecule Therapeutics Source Type: research
Dual Inhibition of NOX2 and Receptor Tyrosine Kinase by BJ-1301 Enhances Anticancer Therapy Efficacy via Suppression of Autocrine-Stimulatory Factors in Lung Cancer
In this study, we report that BJ-1301, a hybrid of pyridinol and alpha-tocopherol, exerts anticancer effects by dual inhibition of NADPH oxidase and RTK activities in endothelial and lung cancer cells. BJ-1301 suppresses ROS production by blocking translocation of NADPH oxidase cytosolic subunits to the cell membrane, thereby inhibiting activation. The potency of RTK inhibition by BJ-1301 was lower than that of sunitinib (a multi-RTK inhibitor), but the inhibition of downstream signaling pathways (e.g., ROS generation) and subsequent biological changes (e.g., NOX2 induction) by BJ-1301 was superior. Consistently, BJ-1301 i...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Gautam, J., Ku, J.-M., Regmi, S. C., Jeong, H., Wang, Y., Banskota, S., Park, M.-H., Nam, T.-g., Jeong, B.-S., Kim, J.-A. Tags: Small Molecule Therapeutics Source Type: research
Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged Cancers
We examined the sensitivity of TPM3-NTRK1-transformed Ba/F3 cells and TPM3-NTRK1-harboring KM12 cells to multiple NTRK inhibitors. Acquired NTRK inhibitor-resistant mutations were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3-TPM3-NTRK1 cells or by the establishment of NTRK-TKI-resistant cells from KM12 cells continuously treated with NTRK-TKIs. We identified multiple novel NTRK-TKI resistance mutations in the NTRK1 kinase domain, including G595R, and insulin growth factor receptor type 1 (IGF1R) bypass pathway-mediated resistance. After identifying the resistance mechanisms, we performed drug screening with sma...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Fuse, M. J., Okada, K., Oh-hara, T., Ogura, H., Fujita, N., Katayama, R. Tags: Small Molecule Therapeutics Source Type: research
Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules
The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. A key step in androgen action, which is amplified in castration-resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high-throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells. We show that these two small molecules, 3-(4-ethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (EPPI) and ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Masoodi, K. Z., Xu, Y., Dar, J. A., Eisermann, K., Pascal, L. E., Parrinello, E., Ai, J., Johnston, P. A., Nelson, J. B., Wipf, P., Wang, Z. Tags: Small Molecule Therapeutics Source Type: research
The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy
In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107–19. ©2017 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Clemenson, C., Chargari, C., Liu, W., Mondini, M., Ferte, C., Burbridge, M. F., Cattan, V., Jacquet-Bescond, A., Deutsch, E. Tags: Small Molecule Therapeutics Source Type: research
MiR-125b Increases Nasopharyngeal Carcinoma Radioresistance by Targeting A20/NF-{kappa}B Signaling Pathway
In this study, we investigated the function and mechanism of miR-125b in NPC radioresistance, one of upregulated miRNAs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-125b was frequently upregulated in the radioresistant NPCs, and its increment was significantly correlated with NPC radioresistance, and was an independent predictor for poor patient survival. In vitro radioresponse assays showed that miR-125b inhibitor decreased, whereas miR-125b mimic increased NPC cell radioresistance. In a mouse model, therapeutic administration of miR-125b antagomir dramatically sensi...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Li, L.-N., Xiao, T., Yi, H.-M., Zheng, Z., Qu, J.-Q., Huang, W., Ye, X., Yi, H., Lu, S.-S., Li, X.-H., Xiao, Z.-Q. Tags: Small Molecule Therapeutics Source Type: research
Disruption of Aneuploidy and Senescence Induced by Aurora Inhibition Promotes Intrinsic Apoptosis in Double Hit or Double Expressor Diffuse Large B-cell Lymphomas
Double hit (DH) or double expressor (DE) diffuse large B-cell lymphomas (DLBCL) are aggressive non-Hodgkin's lymphomas (NHL) with translocations and/or overexpressions of MYC and BCL-2, which are difficult to treat. Aurora kinase (AK) inhibition with alisertib in DH/DE-DLBCL induces cell death in ~30%, while ~70% are aneuploid and senescent cells (AASC), a mitotic escape mechanism contributing to drug resistance. These AASCs elaborated a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway. Combinations of alisertib + ibrutinib or alisert...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Islam, S., Qi, W., Morales, C., Cooke, L., Spier, C., Weterings, E., Mahadevan, D. Tags: Small Molecule Therapeutics Source Type: research
PI3K{gamma}/{delta} and NOTCH1 Cross-Regulate Pathways That Define the T-cell Acute Lymphoblastic Leukemia Disease Signature
PI3K/AKT and NOTCH1 signaling pathways are frequently dysregulated in T-cell acute lymphoblastic leukemias (T-ALL). Although we have shown that the combined activities of the class I PI3K isoforms p110 and p110 play a major role in the development and progression of PTEN-null T-ALL, it has yet to be determined whether their contribution to leukemogenic programing is unique from that associated with NOTCH1 activation. Using an Lmo2-driven mouse model of T-ALL in which both the PI3K/AKT and NOTCH1 pathways are aberrantly upregulated, we now demonstrate that the combined activities of PI3K/ have both overlapping and distinct ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Efimenko, E., Dave, U. P., Lebedeva, I. V., Shen, Y., Sanchez-Quintero, M. J., Diolaiti, D., Kung, A., Lannutti, B. J., Chen, J., Realubit, R., Niatsetskaya, Z., Ten, V., Karan, C., Chen, X., Califano, A., Diacovo, T. G. Tags: Small Molecule Therapeutics Source Type: research
A Small-Molecule Inhibitor of WEE1, AZD1775, Synergizes with Olaparib by Impairing Homologous Recombination and Enhancing DNA Damage and Apoptosis in Acute Leukemia
Although some patients with acute leukemia have good prognoses, the prognosis of adult and pediatric patients who relapse or cannot tolerate standard chemotherapy is poor. Inhibition of WEE1 with AZD1775 has been shown to sensitize cancer cells to genotoxic chemotherapies, including cytarabine in acute myeloid leukemia (AML) and T-ALL. Inhibition of WEE1 impairs homologous recombination by indirectly inhibiting BRCA2. Thus, we sought to determine whether AZD1775 could sensitize cells to the PARP1/2 inhibitor olaparib. We found that combined treatment with AZD1775 and olaparib was synergistic in AML and ALL cells, and this ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Garcia, T. B., Snedeker, J. C., Baturin, D., Gardner, L., Fosmire, S. P., Zhou, C., Jordan, C. T., Venkataraman, S., Vibhakar, R., Porter, C. C. Tags: Small Molecule Therapeutics Source Type: research
Antitumor Effect of the Atypical Retinoid ST1926 in Acute Myeloid Leukemia and Nanoparticle Formulation Prolongs Lifespan and Reduces Tumor Burden of Xenograft Mice
Acute myeloid leukemia (AML) is one of the most frequent types of blood malignancies. It is a complex disorder of undifferentiated hematopoietic progenitor cells. The majority of patients generally respond to intensive therapy. Nevertheless, relapse is the major cause of death in AML, warranting the need for novel treatment strategies. Retinoids have demonstrated potent differentiation and growth regulatory effects in normal, transformed, and hematopoietic progenitor cells. All-trans retinoic acid (ATRA) is the paradigm of treatment in acute promyelocytic leukemia, an AML subtype. The majority of AML subtypes are, however,...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: El-Houjeiri, L., Saad, W., Hayar, B., Aouad, P., Tawil, N., Abdel-Samad, R., Hleihel, R., Hamie, M., Mancinelli, A., Pisano, C., El Hajj, H., Darwiche, N. Tags: Small Molecule Therapeutics Source Type: research
Highlights of This Issue
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research
Abstract B39: Small Molecule Disruption of RAD52 Rings as a Mechanism for Precision Medicine in BRCA Deficient Cancers
Suppression of RAD52 causes synthetic lethality in BRCA deficient cells. Yet pharmacological inhibition of RAD52, which binds single-strand DNA (ssDNA) and lacks enzymatic activity, has not been demonstrated. Here, we identify the small molecule 6-hydroxy-dopa (6-OH-dopa) as a major allosteric inhibitor of the RAD52 ssDNA binding domain. For example, we find that multiple small molecules bind to and completely transform RAD52 undecamer rings into dimers, which abolishes the ssDNA binding channel observed in crystal structures. 6-OH-dopa also disrupts RAD52 heptamer and undecamer ring superstructures, and suppresses RAD52 r...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Pomerantz, R. T. Tags: Chemical Biology: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A39: Pomhex, a cell-permeable high potency enolase inhibitor with utility for collateral lethality treatment of cancer
Glycolysis inhibition is an active area of investigation for the treatment of cancer. However, few compounds have progressed beyond the cell culture stage. We have recently demonstrated that genomic passenger deletion of the glycolytic enzyme Enolase 1 (ENO1) leaves gliomas harboring such deletions solely reliant on ENO2, rendering them exquisitely sensitive to enolase inhibitors Collateral Lethality. However, the tool compound that we employed for these in vitro studies, Phosphonoacetohydroxamate (PhAH), has very poor pharmacological properties and was ineffective in vivo. We recently reported that a structural analogue o...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Lin, Y.-H., Satani, N., Hammoudi, N., Pisaneschi, F., Leonard, P., Maxwell, D., Peng, Z., Link, T., Gilbert, L. I. R., Bosajou, A., Sun, D., Marszalek, J., Sun, Y., McMurray, J. S., Mandal, P. K., Francesco, M. E. D., Czako, B., Wang, A., Bornmann, W., De Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B38: Exploring targeting potassium channels in cancer: A novel strategy for therapeutic intervention
We present data showing for the first time that pharmacologic stimulation of specific K+ channels with small molecules strongly reduced tumor growth and metastatic spread in different animal model of cancer biology including Drosophila and mice without discernible side effects.For example, use of two chemically distinct Kv11.1 potassium channel activators showed growth arrest in an in vivo Drosophila tumor model and strongly inhibited tumor growth in SCID mice bearing the aggressive TNBC cell line MDA-MB-231.In addition, the metastatic spread of this cancer cell line in NOD-scid-IL2Rnull was significantly reduced in terms ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Breuer, E.-K., Osipo, C., Zartman, J., Wells, C., Nishimura, M., Jones, W., Gentile, S. Tags: Chemical Biology: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A38: Genome-wide CRISPR-Cas9 screens reveal modulators of temozolomide sensitivity in glioblastoma
In conclusion, our results have identified a core set of genes that can be targeted to increase sensitivity to the chemotherapeutic agent TMZ responsive GBMs and elucidated opportunities for restoring TMZ sensitivity in resistant GBMs. These genes, many of which are targetable enzymes represent promising therapeutic targets for increasing efficacy of chemotherapy and decreasing lethality in GBM.Citation Format: Graham MacLeod, Nishani Rajakulendran, Traver Hart, Helen Yu, Peter B. Dirks, Stephane Angers. Genome-wide CRISPR-Cas9 screens reveal modulators of temozolomide sensitivity in glioblastoma [abstract]. In: Proceeding...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: MacLeod, G., Rajakulendran, N., Hart, T., Yu, H., Dirks, P. B., Angers, S. Tags: New Technology and Bioinformatics: Poster Presentations - Proffered Abstracts Source Type: research
