Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma
We examined the combination of the FDA-approved drug ingenol-3-angelate (PEP005) with epigenetic drugs as a rational therapeutic approach for KSHV-mediated malignancies. JQ1, a bromodomain and extra terminal (BET) protein inhibitor, in combination with PEP005, not only robustly induced KSHV lytic replication, but also inhibited IL6 production from PEL cells. Using the dosages of these agents that were found to be effective in reactivating HIV (as a means to clear latent virus with highly active antiretroviral therapy), we were able to inhibit PEL growth in vitro and delay tumor growth in a PEL xenograft tumor model. KSHV r...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Zhou, F., Shimoda, M., Olney, L., Lyu, Y., Tran, K., Jiang, G., Nakano, K., Davis, R. R., Tepper, C. G., Maverakis, E., Campbell, M., Li, Y., Dandekar, S., Izumiya, Y. Tags: Models and Technologies Source Type: research

Estrogen Receptor {beta} Is a Novel Target in Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a devastating disease characterized by poor patient outcome and suboptimal chemotherapeutics. Here, a high-throughput screen identified diosmetin, a citrus flavonoid, with anti-AML activity. Diosmetin imparted selective toxicity against leukemia and leukemia stem cells in vitro and in vivo with no effect on normal hematopoietic stem cells. Mechanistically, we demonstrated that diosmetin targets estrogen receptor (ER) β. ERβ expression conferred cell sensitivity, as patient-derived AML cells with high levels of ERβ were sensitive, whereas cells with low ERβ were insensitiv...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Rota, S.-G., Roma, A., Dude, I., Ma, C., Stevens, R., MacEachern, J., Graczyk, J., Espiritu, S. M. G., Rao, P. N., Minden, M. D., Kreinin, E., Hess, D. A., Doxey, A. C., Spagnuolo, P. A. Tags: Companion Diagnostic, Pharmacogenomic, and Cancer Biomarkers Source Type: research

TTK Inhibitors as a Targeted Therapy for CTNNB1 ({beta}-catenin) Mutant Cancers
The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small-molecule inhibitors. Although the first TTK inhibitors have entered phase I dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy is still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, we profiled a set of preclinical and clinical TTK inhibitors from different chemical series on a panel of 66 genetically characterized cell lines derived from differen...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Zaman, G. J. R., de Roos, J. A. D. M., Libouban, M. A. A., Prinsen, M. B. W., de Man, J., Buijsman, R. C., Uitdehaag, J. C. M. Tags: Companion Diagnostic, Pharmacogenomic, and Cancer Biomarkers Source Type: research

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers
Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non–small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independe...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Goodman, A. M., Kato, S., Bazhenova, L., Patel, S. P., Frampton, G. M., Miller, V., Stephens, P. J., Daniels, G. A., Kurzrock, R. Tags: Companion Diagnostic, Pharmacogenomic, and Cancer Biomarkers Source Type: research

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL
The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2. Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regressi...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Brach, D., Johnston-Blackwell, D., Drew, A., Lingaraj, T., Motwani, V., Warholic, N. M., Feldman, I., Plescia, C., Smith, J. J., Copeland, R. A., Keilhack, H., Chan-Penebre, E., Knutson, S. K., Ribich, S. A., Raimondi, A., Thomenius, M. J. Tags: Cancer Biology and Translational Studies Source Type: research

Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance
Approximately 10% of non–small cell lung cancer (NSCLC) patients in the United States and 40% of NSCLC patients in Asia have activating epidermal growth factor receptor (EGFR) mutations and are eligible to receive targeted anti-EGFR therapy. Despite an extension of life expectancy associated with this treatment, resistance to EGFR tyrosine kinase inhibitors and anti-EGFR antibodies is almost inevitable. To identify additional signaling routes that can be cotargeted to overcome resistance, we quantified tumor-specific molecular changes that govern resistant cancer cell growth and survival. Mass spectrometry–base...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Emdal, K. B., Dittmann, A., Reddy, R. J., Lescarbeau, R. S., Moores, S. L., Laquerre, S., White, F. M. Tags: Cancer Biology and Translational Studies Source Type: research

T790M-Selective EGFR-TKI Combined with Dasatinib as an Optimal Strategy for Overcoming EGFR-TKI Resistance in T790M-Positive Non-Small Cell Lung Cancer
T790M mutation–selective EGFR tyrosine kinase inhibitors (EGFR-TKI) have demonstrated clinical benefits in non–small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as cooncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced antitumor activity in T790M-positive cells. In the current study, ...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Watanabe, S., Yoshida, T., Kawakami, H., Takegawa, N., Tanizaki, J., Hayashi, H., Takeda, M., Yonesaka, K., Tsurutani, J., Nakagawa, K. Tags: Cancer Biology and Translational Studies Source Type: research

Synthetic Lethality Interaction Between Aurora Kinases and CHEK1 Inhibitors in Ovarian Cancer
Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair genes, so they rely on DNA-damage checkpoint proteins, like the checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 and mitotic aurora kinase A (AURKA) inhibitors. Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1, and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA inhibitor and LY2603618 as...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Alcaraz-Sanabria, A., Nieto-Jimenez, C., Corrales-Sanchez, V., Serrano-Oviedo, L., Andres-Pretel, F., Montero, J. C., Burgos, M., Llopis, J., Galan-Moya, E. M., Pandiella, A., Ocana, A. Tags: Cancer Biology and Translational Studies Source Type: research

TDP1 is Critical for the Repair of DNA Breaks Induced by Sapacitabine, a Nucleoside also Targeting ATM- and BRCA-Deficient Tumors
2'-C-cyano-2'-deoxy-1-β-d-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes β-elimination that generates single-strand breaks with abnormal 3'-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes nonphosphorylated 3'-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1–/– DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC. We also ...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Abo, M. A., Sasanuma, H., Liu, X., Rajapakse, V. N., Huang, S.-y., Kiselev, E., Takeda, S., Plunkett, W., Pommier, Y. Tags: Cancer Biology and Translational Studies Source Type: research

PPAR{gamma} Ligand-induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers
In this study, our clinical data have established that basal and claudin-low subtypes of breast cancer (TNBC types) express significantly higher levels of Annexin A1 (ANXA1) with poor survival outcomes. Using human cancer cell lines that model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and PPAR. A similar correlation between these two markers was also established in our clinical breast cancer patients' specimens. To establish a link between these two markers in TNBC, we show de novo expression of ANXA1 is induced by activation of PPAR both in vitro and in vivo and it has a predi...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Chen, L., Yuan, Y., Kar, S., Kanchi, M. M., Arora, S., Kim, J. E., Koh, P. F., Yousef, E., Samy, R. P., Shanmugam, M. K., Tan, T. Z., Shin, S. W., Arfuso, F., Shen, H. M., Yang, H., Goh, B. C., Park, J. I., Gaboury, L., Lobie, P. E., Sethi, G., Lim, L. H. Tags: Cancer Biology and Translational Studies Source Type: research

Sphingosine-1-Phosphate Receptor-1 Promotes Environment-Mediated and Acquired Chemoresistance
Drug resistance is a major barrier for the development of effective and durable cancer therapies. Overcoming this challenge requires further defining the cellular and molecular mechanisms underlying drug resistance, both acquired and environment-mediated drug resistance (EMDR). Here, using neuroblastoma (NB), a childhood cancer with high incidence of recurrence due to resistance to chemotherapy, as a model we show that human bone marrow–mesenchymal stromal cells induce tumor expression of sphingosine-1-phosphate receptor-1 (S1PR1), leading to their resistance to chemotherapy. Targeting S1PR1 by shRNA markedly enhance...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Lifshitz, V., Priceman, S. J., Li, W., Cherryholmes, G., Lee, H., Makovski-Silverstein, A., Borriello, L., DeClerck, Y. A., Yu, H. Tags: Cancer Biology and Translational Studies Source Type: research

Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism
Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in prima...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Wiedmer, T., Blank, A., Pantasis, S., Normand, L., Bill, R., Krebs, P., Tschan, M. P., Marinoni, I., Perren, A. Tags: Cancer Biology and Translational Studies Source Type: research

The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors
Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockad...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Harney, A. S., Karagiannis, G. S., Pignatelli, J., Smith, B. D., Kadioglu, E., Wise, S. C., Hood, M. M., Kaufman, M. D., Leary, C. B., Lu, W.-P., Al-Ani, G., Chen, X., Entenberg, D., Oktay, M. H., Wang, Y., Chun, L., Palma, M. D., Jones, J. G., Flynn, D. Tags: Cancer Biology and Translational Studies Source Type: research

Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma
The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated protumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells. Pha...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Aguilera, K. Y., Huang, H., Du, W., Hagopian, M. M., Wang, Z., Hinz, S., Hwang, T. H., Wang, H., Fleming, J. B., Castrillon, D. H., Ren, X., Ding, K., Brekken, R. A. Tags: Cancer Biology and Translational Studies Source Type: research

Wilms Tumor NCAM-Expressing Cancer Stem Cells as Potential Therapeutic Target for Polymeric Nanomedicine
Cancer stem cells (CSC) form a specific population within the tumor that has been shown to have self-renewal and differentiation properties, increased ability to migrate and form metastases, and increased resistance to chemotherapy. Consequently, even a small number of cells remaining after therapy can repopulate the tumor and cause recurrence of the disease. CSCs in Wilms tumor, a pediatric renal cancer, were previously shown to be characterized by neural cell adhesion molecule (NCAM) expression. Therefore, NCAM provides a specific biomarker through which the CSC population in this tumor can be targeted. We have recently ...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Markovsky, E., Vax, E., Ben-Shushan, D., Eldar-Boock, A., Shukrun, R., Yeini, E., Barshack, I., Caspi, R., Harari-Steinberg, O., Pode-Shakked, N., Dekel, B., Satchi-Fainaro, R. Tags: Large Molecule Therapeutics Source Type: research

Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes
Cationic liposomes have been used for targeted drug delivery to tumor blood vessels, via mechanisms that are not fully elucidated. Doxorubicin (Dox)-loaded liposomes were prepared that incorporate a cationic lipid; 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), along with a small amount of porphyrin-phospholipid (PoP). Near-infrared (NIR) light caused release of entrapped Dox via PoP-mediated DOTAP photo-oxidation. The formulation was optimized to enable extremely rapid NIR light-triggered Dox release (i.e., in 15 seconds), while retaining reasonable serum stability. In vitro, cationic PoP liposomes readily bound to bot...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Luo, D., Geng, J., Li, N., Carter, K. A., Shao, S., Atilla-Gokcumen, G. E., Lovell, J. F. Tags: Large Molecule Therapeutics Source Type: research

Potency-matched Dual Cytokine-Antibody Fusion Proteins for Cancer Therapy
A novel biopharmaceutical, consisting of the F8 mAb (specific to a splice isoform of fibronectin) simultaneously fused to both TNF and IL2, was found to react with the majority of solid tumors and hematologic malignancies in mouse and man, but not with healthy adult tissues. The product selectively localized to neoplastic lesions in vivo, as evidenced by quantitative biodistribution studies using radioiodinated protein preparations. When the potency of the cytokine payloads was matched by a single-point mutation, the resulting fusion protein (IL2-F8-TNFmut) eradicated soft-tissue sarcomas in immunocompetent mice, which did...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Luca, R. D., Soltermann, A., Pretto, F., Pemberton-Ross, C., Pellegrini, G., Wulhfard, S., Neri, D. Tags: Large Molecule Therapeutics Source Type: research

mTOR Kinase Inhibition Effectively Decreases Progression of a Subset of Neuroendocrine Tumors that Progress on Rapalog Therapy and Delays Cardiac Impairment
In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared with placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long-term cardioprotective benefit in those NET patients prone to carcinoid syndrome. Mol Cancer Ther; 16(11); 2432–41. ©2017 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Orr-Asman, M. A., Chu, Z., Jiang, M., Worley, M., LaSance, K., Koch, S. E., Carreira, V. S., Dahche, H. M., Plas, D. R., Komurov, K., Qi, X., Mercer, C. A., Anthony, L. B., Rubinstein, J., Thomas, H. E. Tags: Small Molecule Therapeutics Source Type: research

Targeting Phosphatidylinositol 3-Kinase Signaling Pathway for Therapeutic Enhancement of Vascular-Targeted Photodynamic Therapy
Vascular-targeted photodynamic therapy (PDT) selectively disrupts vascular function by inducing oxidative damages to the vasculature, particularly endothelial cells. Although effective tumor eradication and excellent safety profile are well demonstrated in both preclinical and clinical studies, incomplete vascular shutdown and angiogenesis are known to cause tumor recurrence after vascular-targeted PDT. We have explored therapeutic enhancement of vascular-targeted PDT with PI3K signaling pathway inhibitors because the activation of PI3K pathway was involved in promoting endothelial cell survival and proliferation after PDT...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Kraus, D., Palasuberniam, P., Chen, B. Tags: Small Molecule Therapeutics Source Type: research

Targeting TAO Kinases Using a New Inhibitor Compound Delays Mitosis and Induces Mitotic Cell Death in Centrosome Amplified Breast Cancer Cells
Thousand-and-one amino acid kinases (TAOK) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and TAOK2 activity with IC50 values of 11 to 15 nmol/L, is ATP-competitive, and targets these kinases selectively. TAOK inhibition or depletion in centrosome-amplified SKBR3 or BT549 breast cancer cell models increases the mitotic population, the percentages of mitotic cells displaying amplified centrosomes and multipolar spindles, induces cell death, and inhibits cell growth. In contrast, nontumorigenic and di...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Koo, C.-Y., Giacomini, C., Reyes-Corral, M., Olmos, Y., Tavares, I. A., Marson, C. M., Linardopoulos, S., Tutt, A. N., Morris, J. D. H. Tags: Small Molecule Therapeutics Source Type: research

Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment
In this study, utilizing mouse models of PDAC, we showed that inhibition of either HGF/c-Met or Hh pathways sensitize the PDAC tumors to gemcitabine, resulting in decreased primary tumor volume as well as significant reduction of metastatic tumor burden. However, prolonged treatment of single HGF/c-Met or Hh inhibitor leads to resistance to these single inhibitors, likely because the single c-Met treatment leads to enhanced expression of Shh, and vice versa. Targeting both the HGF/c-Met and Hh pathways simultaneously overcame the resistance to the single-inhibitor treatment and led to a more potent antitumor effect in comb...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Rucki, A. A., Xiao, Q., Muth, S., Chen, J., Che, X., Kleponis, J., Sharma, R., Anders, R. A., Jaffee, E. M., Zheng, L. Tags: Small Molecule Therapeutics Source Type: research

Combination Therapy with c-Met and Src Inhibitors Induces Caspase-Dependent Apoptosis of Merlin-Deficient Schwann Cells and Suppresses Growth of Schwannoma Cells
This study demonstrates that simultaneous inhibition of c-Met and Src signaling in MD-MSCs triggers apoptosis and reveals vulnerable pathways that could be exploited to develop NF2 therapies. Mol Cancer Ther; 16(11); 2387–98. ©2017 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Fuse, M. A., Plati, S. K., Burns, S. S., Dinh, C. T., Bracho, O., Yan, D., Mittal, R., Shen, R., Soulakova, J. N., Copik, A. J., Liu, X. Z., Telischi, F. F., Chang, L.-S., Franco, M. C., Fernandez-Valle, C. Tags: Small Molecule Therapeutics Source Type: research

The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma
Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple my...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Moigne, R. L., Aftab, B. T., Djakovic, S., Dhimolea, E., Valle, E., Murnane, M., King, E. M., Soriano, F., Menon, M.-K., Wu, Z. Y., Wong, S. T., Lee, G. J., Yao, B., Wiita, A. P., Lam, C., Rice, J., Wang, J., Chesi, M., Bergsagel, P. L., Kraus, M., Driess Tags: Small Molecule Therapeutics Source Type: research

Animacroxam, a Novel Dual-Mode Compound Targeting Histone Deacetylases and Cytoskeletal Integrity of Testicular Germ Cell Cancer Cells
Novel approaches for the medical treatment of advanced solid tumors, including testicular germ cell tumors (TGCT), are desperately needed. Especially, TGCT patients not responding to cisplatin-based therapy need therapeutic alternatives, as there is no effective medical treatment available for this particular subgroup. Here, we studied the suitability of the novel dual-mode compound animacroxam for TGCT treatment. Animacroxam consists of an HDAC-inhibitory hydroxamate moiety coupled to a 4,5-diarylimidazole with inherent cytoskeleton disrupting potency. Animacroxam revealed pronounced antiproliferative, cell-cycle arrestin...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Steinemann, G., Dittmer, A., Kuzyniak, W., Hoffmann, B., Schrader, M., Schobert, R., Biersack, B., Nitzsche, B., Höpfner, M. Tags: Small Molecule Therapeutics Source Type: research

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)
Aberrant activation of signaling through the RAS–RAF–MEK–ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro B...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Germann, U. A., Furey, B. F., Markland, W., Hoover, R. R., Aronov, A. M., Roix, J. J., Hale, M., Boucher, D. M., Sorrell, D. A., Martinez-Botella, G., Fitzgibbon, M., Shapiro, P., Wick, M. J., Samadani, R., Meshaw, K., Groover, A., DeCrescenzo, G., Namchu Tags: Small Molecule Therapeutics Source Type: research

A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis
Responses to targeted therapies frequently are brief, with patients relapsing with drug-resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways. Treatment with ST-162 produced regression of mutant KRAS- or BRAF-addicted xenograft models of colorectal cancer and melanoma and stasis of BRAF/PTEN–mutant melanomas. Co...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Galban, S., Apfelbaum, A. A., Espinoza, C., Heist, K., Haley, H., Bedi, K., Ljungman, M., Galban, C. J., Luker, G. D., Dort, M. V., Ross, B. D. Tags: Small Molecule Therapeutics Source Type: research

Inhibition of the V-ATPase by Archazolid A: A New Strategy to Inhibit EMT
Epithelial–mesenchymal transition (EMT) induces tumor-initiating cells (TIC), which account for tumor recurrence, metastasis, and therapeutic resistance. Strategies to interfere with EMT are rare but urgently needed to improve cancer therapy. By using the myxobacterial natural compound Archazolid A as a tool, we elucidate the V-ATPase, a multimeric proton pump that regulates lysosomal acidification, as a crucial player in EMT and identify the inhibition of V-ATPase by Archazolid A as a promising strategy to block EMT. Genetic knockdown and pharmacologic inhibition of the V-ATPase by Archazolid A interfere with the EM...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Merk, H., Messer, P., Ardelt, M. A., Lamb, D. C., Zahler, S., Müller, R., Vollmar, A. M., Pachmayr, J. Tags: Small Molecule Therapeutics Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research

Retraction: EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E-Mutant NSCLC Cell Lines
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Tags: Retraction Source Type: research

Wnt Signaling Inhibition Promotes Apoptosis in Sarcomas--Response
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Martinez-Font, E., Vögler, O., Alemany, R., Obrador-Hevia, A. Tags: Letter to the Editor Source Type: research

Wnt Signaling Inhibition Promotes Apoptosis in Sarcomas--Letter
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Bertucci, F., Finetti, P., Birnbaum, D. Tags: Letter to the Editor Source Type: research

Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma
This study provides evidence of a translational exo-metabolomic plasma readout predictive of clinical efficacy together with pharmacodynamic utility following treatment with a signal transduction inhibitor. Mol Cancer Ther; 16(10); 2315–23. ©2017 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Ang, J. E., Pal, A., Asad, Y. J., Henley, A. T., Valenti, M., Box, G., de haven Brandon, A., Revell, V. L., Skene, D. J., Venturi, M., Rueger, R., Meresse, V., Eccles, S. A., de Bono, J. S., Kaye, S. B., Workman, P., Banerji, U., Raynaud, F. I. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research

Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the Mucin 1 C-terminal subunit (MUC1-C) plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals. Cell lines, primary samples, and xenograft models of CTCL were us...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Jain, S., Washington, A., Leaf, R. K., Bhargava, P., Clark, R. A., Kupper, T. S., Stroopinsky, D., Pyzer, A., Cole, L., Nahas, M., Apel, A., Rosenblatt, J., Arnason, J., Kufe, D., Avigan, D. Tags: Cancer Biology and Signal Transduction Source Type: research

Inactivation of the Kinase Domain of CDK10 Prevents Tumor Growth in a Preclinical Model of Colorectal Cancer, and Is Accompanied by Downregulation of Bcl-2
This study examines the function of CDK10 in colorectal cancer, and demonstrates its role in suppressing apoptosis and in promoting tumor growth in vitro and in vivo. Modulation of CDK10 expression in colorectal cancer cell lines demonstrates that CDK10 promotes cell growth, reduces chemosensitivity and inhibits apoptosis by upregulating the expression of Bcl-2. This effect appears to depend on its kinase activity, as kinase-defective mutant colorectal cancer cell lines have an exaggerated apoptotic response and reduced proliferative capacity. In vivo, inhibiting CDK10 in colorectal cancer following intratumoral injections...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Weiswald, L.-B., Hasan, M. R., Wong, J. C. T., Pasiliao, C. C., Rahman, M., Ren, J., Yin, Y., Gusscott, S., Vacher, S., Weng, A. P., Kennecke, H. F., Bieche, I., Schaeffer, D. F., Yapp, D. T., Tai, I. T. Tags: Cancer Biology and Signal Transduction Source Type: research

Bypassing Drug Resistance Mechanisms of Prostate Cancer with Small Molecules that Target Androgen Receptor-Chromatin Interactions
Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug target in the treatment of prostate cancer. Current small-molecule AR antagonists, such as enzalutamide, compete with androgens that bind to the steroid-binding pocket of the AR ligand–binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug resistance can manifest through AR-LBD mutations that convert AR antagonists into agonists, or by expression of AR variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR. Previously, we reported the developm...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Dalal, K., Che, M., Que, N. S., Sharma, A., Yang, R., Lallous, N., Borgmann, H., Ozistanbullu, D., Tse, R., Ban, F., Li, H., Tam, K. J., Roshan-Moniri, M., LeBlanc, E., Gleave, M. E., Gewirth, D. T., Dehm, S. M., Cherkasov, A., Rennie, P. S. Tags: Cancer Biology and Signal Transduction Source Type: research

Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic {beta}-catenin Signaling and EMT Progression
Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β. In molecular docking analysis, ormeloxifene show...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Hafeez, B. B., Ganju, A., Sikander, M., Kashyap, V. K., Hafeez, Z. B., Chauhan, N., Malik, S., Massey, A. E., Tripathi, M. K., Halaweish, F. T., Zafar, N., Singh, M. M., Yallapu, M. M., Chauhan, S. C., Jaggi, M. Tags: Cancer Biology and Signal Transduction Source Type: research

ABCB1 Mediates Cabazitaxel-Docetaxel Cross-Resistance in Advanced Prostate Cancer
In this study, we use C4-2B and DU145 derived docetaxel-resistant cell lines to test response to cabazitaxel. Our results demonstrate that docetaxel resistance confers cross-resistance to cabazitaxel. We show that increased ABCB1 expression is responsible for cross-resistance to cabazitaxel and that inhibition of ABCB1 function through the small-molecule inhibitor elacridar resensitizes taxane-resistant cells to treatment. In addition, the antiandrogens bicalutamide and enzalutamide, previously demonstrated to be able to resensitize taxane-resistant cells to docetaxel through inhibition of ABCB1 ATPase activity, are also a...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Lombard, A. P., Liu, C., Armstrong, C. M., Cucchiara, V., Gu, X., Lou, W., Evans, C. P., Gao, A. C. Tags: Cancer Biology and Signal Transduction Source Type: research

The Tumor-Suppressor Protein OPCML Potentiates Anti-EGFR- and Anti-HER2-Targeted Therapy in HER2-Positive Ovarian and Breast Cancer
Opioid-binding protein/cell adhesion molecule-like (OPCML) is a tumor-suppressor gene that is frequently inactivated in ovarian cancer and many other cancers by somatic methylation. We have previously shown that OPCML exerts its suppressor function by negatively regulating a spectrum of receptor tyrosine kinases (RTK), such as ErbB2/HER2, FGFR1, and EphA2, thus attenuating their related downstream signaling. The physical interaction of OPCML with this defined group of RTKs is a prerequisite for their downregulation. Overexpression/gene amplification of EGFR and HER2 is a frequent event in multiple cancers, including ovaria...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Zanini, E., Louis, L. S., Antony, J., Karali, E., Okon, I. S., McKie, A. B., Vaughan, S., El-Bahrawy, M., Stebbing, J., Recchi, C., Gabra, H. Tags: Cancer Biology and Signal Transduction Source Type: research

JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer
Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non–small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine IL6 and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAF). We also analyzed the prognostic s...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Shien, K., Papadimitrakopoulou, V. A., Ruder, D., Behrens, C., Shen, L., Kalhor, N., Song, J., Lee, J. J., Wang, J., Tang, X., Herbst, R. S., Toyooka, S., Girard, L., Minna, J. D., Kurie, J. M., Wistuba, I. I., Izzo, J. G. Tags: Cancer Biology and Signal Transduction Source Type: research

The IGF1R/INSR Inhibitor BI 885578 Selectively Inhibits Growth of IGF2-Overexpressing Colorectal Cancer Tumors and Potentiates the Efficacy of Anti-VEGF Therapy
Clinical studies of pharmacologic agents targeting the insulin-like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, the identification of selection biomarkers for enrichment of potential responders represents a high priority for future trials of these agents. Several reports have described high IGF2 expression in a subset of colorectal cancers, with focal IGF2 amplification being responsible for some of these cases. We defined a novel cut-off value for IGF2 overexpression based on differential expression between color...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Sanderson, M. P., Hofmann, M. H., Garin-Chesa, P., Schweifer, N., Wernitznig, A., Fischer, S., Jeschko, A., Meyer, R., Moll, J., Pecina, T., Arnhof, H., Weyer-Czernilofsky, U., Zahn, S. K., Adolf, G. R., Kraut, N. Tags: Cancer Biology and Signal Transduction Source Type: research

Exposure-Response Analyses of Ramucirumab from Two Randomized, Phase III Trials of Second-line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer
Ramucirumab is an IgG1 monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure–efficacy and exposure–safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials. Sparse pharmacokinetic samples were collected, and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum tr...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Tabernero, J., Ohtsu, A., Muro, K., Van Cutsem, E., Oh, S. C., Bodoky, G., Shimada, Y., Hironaka, S., Ajani, J. A., Tomasek, J., Safran, H., Chandrawansa, K., Hsu, Y., Heathman, M., Khan, A., Ni, L., Melemed, A. S., Gao, L., Ferry, D., Fuchs, C. S. Tags: Large Molecule Therapeutics Source Type: research

Epidermal Growth Factor Receptor (EGFR)-targeted Photoimmunotherapy (PIT) for the Treatment of EGFR-expressing Bladder Cancer
The use of light as a means of therapy for bladder cancer has a long history but has been hampered by a lack of tumor specificity and therefore, damage to the normal bladder mucosa. Here, we describe a targeted form of phototherapy called photoimmunotherapy (PIT), which targets EGFR-expressing bladder cancer. Anti-EGFR antibody panitumumab was labeled with the photoabsorber (PA), IRDye 700Dx (IR700), to create a panitumumab-IR700 antibody–PA conjugate that is activated by near-infrared radiation (NIR). Bladder cancer tissue microarray (TMA) and bladder cancer cell lines were analyzed for expression of EGFR. Mechanism...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Railkar, R., Krane, L. S., Li, Q. Q., Sanford, T., Siddiqui, M. R., Haines, D., Vourganti, S., Brancato, S. J., Choyke, P. L., Kobayashi, H., Agarwal, P. K. Tags: Large Molecule Therapeutics Source Type: research

Alpha Particle Enhanced Blood Brain/Tumor Barrier Permeabilization in Glioblastomas Using Integrin Alpha-v Beta-3-Targeted Liposomes
Glioblastoma (GBM) is the most common primary malignant astrocytoma characterized by extensive invasion, angiogenesis, hypoxia, and micrometastasis. Despite the relatively leaky nature of GBM blood vessels, effective delivery of antitumor therapeutics has been a major challenge due to the complications caused by the blood–brain barrier (BBB) and the highly torturous nature of newly formed tumor vasculature (blood tumor barrier-BTB). External beam radiotherapy was previously shown to be an effective means of permeabilizing central nervous system (CNS) barriers. By using targeted short-ranged radionuclides, we show for...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Sattiraju, A., Xiong, X., Pandya, D. N., Wadas, T. J., Xuan, A., Sun, Y., Jung, Y., Sai, K. K. S., Dorsey, J. F., Li, K. C., Mintz, A. Tags: Large Molecule Therapeutics Source Type: research

A Novel Combination Treatment Targeting BCL-XL and MCL1 for KRAS/BRAF-mutated and BCL2L1-amplified Colorectal Cancers
In this study, we have found that a subgroup of colorectal cancers, defined by having either KRAS or BRAF (KRAS/BRAF) mutations and BCL2L1 (encoding BCL-XL) amplification, can be effectively targeted by simultaneous inhibition of BCL-XL (with ABT-263) and MCL1 (with YM-155). This combination treatment of ABT-263 and YM-155 was shown to have a synergistic effect in vitro as well as in in vivo patient-derived xenograft models. Our data suggest that combined inhibition of BCL-XL and MCL1 provides a promising treatment strategy for this genomically defined colorectal cancer subgroup. Mol Cancer Ther; 16(10); 2178–90. &co...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Cho, S.-Y., Han, J. Y., Na, D., Kang, W., Lee, A., Kim, J., Lee, J., Min, S., Kang, J., Chae, J., Kim, J.-I., Park, H., Lee, W.-S., Lee, C. Tags: Small Molecule Therapeutics Source Type: research

The DNA-Binding Polyamine Moiety in the Vectorized DNA Topoisomerase II Inhibitor F14512 Alters Reparability of the Consequent Enzyme-Linked DNA Double-Strand Breaks
We report that targeting of TOP2α and not TOP2β impacts cell killing by F14512, contrary to etoposide that kills cells through targeting both isoforms. Then, we show that despite being more cytotoxic, F14512 is less efficient than etoposide at producing TOP2α cleavage-complex (TOP2αcc) in cells. Finally, we report that compared with TOP2αcc mediated by etoposide, those generated by F14512 persist longer in the genome, are not dependent on TDP2 for cleaning break ends from TOP2α, are channeled to a larger extent to resection-based repair processes relying on CtIP and BRCA1 and promote RAD5...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Bombarde, O., Larminat, F., Gomez, D., Frit, P., Racca, C., Gomes, B., Guilbaud, N., Calsou, P. Tags: Small Molecule Therapeutics Source Type: research

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