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Molecular Cancer Therapeutics

Chao Jiang, Rui Xu, Xiao-Xing Li, Yu-Feng Zhou, Xiao-Yi Xu, Yang Yang, Hui-Yun Wang, X F Steven Zheng
Hepatocellular carcinoma (HCC) is one of the most common and deadly human cancers. The five-year survival rate is very low. Unfortunately, there are few efficacious therapeutic options. Until recently, Sorafenib has been the only available systemic drug for advanced HCC. However, it has very limited survival benefits and new therapies are urgently needed. In this study, we investigated the anti-HCC activity of carfilzomib, a second-generation, irreversible proteasome inhibitor, as a single agent and in combination with sorafenib...
September 17, 2018: Molecular Cancer Therapeutics
Ping Fan, Balkees Abderrahman, Tina S Chai, Smitha Yerrum, V Craig Jordan
Peroxisome proliferator-activated receptor γ (PPARγ) is an important transcription factor that modulates lipid metabolism and inflammation. However, it remains unclear whether PPARγ is involved in modulation of estrogen (E2)-induced inflammation, thus affecting apoptosis of E2-deprived breast cancer cells, MCF-7:5C and MCF-7:2A. Here, we demonstrated that E2 treatment suppressed the function of PPARγ in both cell lines, although the suppressive effect in MCF-7:2A cells was delayed owing to high PPARγ expression...
September 17, 2018: Molecular Cancer Therapeutics
Fumi Higuchi, Alexandria L Fink, Juri Kiyokawa, Julie J Miller, Mara V A Koerner, Daniel P Cahill, Hiroaki Wakimoto
Mismatch repair (MMR) deficiency through MSH6 inactivation has been identified in up to 30% of recurrent high-grade gliomas, and represents a key molecular mechanism underlying the acquired resistance to the alkylating agent temozolomide (TMZ). To develop a therapeutic strategy that could be effective in these TMZ-refractory gliomas, we first screened 13 DNA damage response modulators for their ability to suppress viability of MSH6-inactivated, TMZ-resistant glioma cells. We identified a PLK1 selective inhibitor, Volasertib, as the most potent in inhibiting proliferation of glioblastoma cells...
September 14, 2018: Molecular Cancer Therapeutics
Fallon K Noto, Valeriya Adjan Steffey, Min Tong, Kameswaran Ravichandran, Wei Zhang, Angela Arey, Christopher B McClain, Eric Ostertag, Sahar Mazhar, Jaya Sangodkar, Analisa Difeo, Jack Crawford, Goutham Narla, Tseten Y Jamling
The rat is the preferred model for toxicology studies, and it offers distinctive advantages over the mouse as a pre-clinical research model including larger sample size collection, lower rates of drug clearance, and relative ease of surgical manipulation. An immunodeficient rat would allow for larger tumor size development, prolonged dosing and drug efficacy studies, and preliminary toxicological testing and PK/PD studies in the same model animal. Here we created an immunodeficient rat with a functional deletion of the Rag2 gene, using genetically modified spermatogonial stem cells (SSCs)...
September 11, 2018: Molecular Cancer Therapeutics
Alexandra Lacey, Erik Hedrick, Yating Cheng, Kumaravel Mohankumar, Melanie Warren, Stephen Safe
Alveolar Rhabdomyosarcoma (ARMS) patients have a poor prognosis and this is primarily due to overexpression of the oncogenic fusion protein PAX3-FOXO1. Results of RNASeq studies show that PAX3-FOXO1 represses expression of interleukin-24 (IL-24) and these two genes are inversely expressed in patient tumors. PAX3-FOXO1 also regulates histone deacetylase 5 (HDAC5) in ARMS cells and results of RNA interference studies confirmed that PAX3-FOXO1-mediated repression of IL-24 is HDAC5-dependent. Knockdown of PAX3-FOXO1 decreases ARMS cell proliferation, survival, and migration and we also observed similar responses in cells after overexpression of IL-24 consistent with results reported for this tumor suppressor-like cytokine in other solid tumors...
September 6, 2018: Molecular Cancer Therapeutics
Satsuki Mochizuki, Masayuki Shimoda, Hitoshi Abe, Yuka Miyamae, Junko Kuramoto, Noriko Aramaki-Hattori, Ken Ishii, Hideki Ueno, Akira Miyakoshi, Kanehisa Kojoh, Yasunori Okada
ADAM28 (a disintegrin and metalloproteinase 28) is overexpressed by carcinoma cells in non-small cell lung carcinomas (NSCLCs) and plays an important role in cancer cell proliferation and metastasis by re-activation of insulin-like growth factor-1 (IGF-1) and escaping from von Willebrand factor (VWF)-induced apoptosis through digestion of IGF-binding protein-3 and VWF, respectively. To aim for new target therapy of NSCLC patients, we developed human neutralizing antibodies 211-12 and 211-14 against ADAM28, which showed IC50 values of 62...
September 6, 2018: Molecular Cancer Therapeutics
Jin H Song, Neha Singh, Libia A Luevano, Sathish K R Padi, Koichi Okumura, Virginie Olive, Stephen M Black, Noel A Warfel, David W Goodrich, Andrew S Kraft
Cancer resistance to PI3K inhibitor therapy can be in part mediated by increases in the PIM1 kinase. However, the exact mechanism by which PIM kinase promotes tumor cell resistance is unknown. Our study unveils the pivotal control of redox signaling by PIM kinases as a driver of this resistance mechanism. PIM1 kinase functions to decrease cellular ROS levels by enhancing NRF2/ARE activity. PIM prevents cell death induced by PI3K-AKT inhibitory drugs through a non-canonical mechanism of NRF2 ubiquitination and degradation and translational control of NRF2 protein levels through modulation of eIF4B and mTORC1 activity...
September 6, 2018: Molecular Cancer Therapeutics
Yong Zhang, Yinhui Dong, Michael W Melkus, Shutao Yin, Su-Ni Tang, Peixin Jiang, Kartick Pramanik, Wei Wu, Sangyub Kim, Min Ye, Hongbo Hu, Junxuan Lu, Cheng Jiang
Bufalin is a major cardiotonic compound in the traditional Chinese medicine Chanshu preparations of toad skin secretions. Cell culture studies have suggested anti-cancer potential involving multiple cellular processes including differentiation, apoptosis, senescence and angiogenesis. In prostate cancer (PCa) cell models, P53-dependent and independent caspase-mediated apoptosis and androgen receptor (AR) antagonism have been described for bufalin at micromolar concentrations. Since a human pharmacokinetic study indicated single nanomolar bufalin was safely achievable in the peripheral circulation, we evaluated its cellular activity within range with the AR-positive and P53-wild type human LNCaP PCa cells in vitro...
August 30, 2018: Molecular Cancer Therapeutics
Niranjan Awasthi, Margaret A Schwarz, Chang-Hua Zhang, Roderich E Schwarz
Gastric adenocarcinoma (GAC) remains the third most common cause of cancer deaths worldwide. Systemic chemotherapy is commonly recommended as a fundamental treatment for metastatic GAC, however, standard treatment has not been established yet. Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated therapeutic benefits of mechanistically diverse antiangiogenic agents in combination with nab-paclitaxel, a next-generation taxane, in preclinical models of GAC. Murine survival studies were performed in peritoneal dissemination models, while tumor growth studies were performed in subcutaneous GAC cell-derived or patient-derived xenografts...
August 30, 2018: Molecular Cancer Therapeutics
Parag P Patwardhan, Elgilda Musi, Gary K Schwartz
Sarcomas are rare cancers that make up about 1% of all cancers in adults; however, they occur more commonly among children and young adolescents. Sarcomas are genetically complex and are often difficult to treat given the lack of clinical efficacy of any of the currently available therapies. Receptor tyrosine kinases (RTKs) such as c-Kit, c-Met, PDGFR, IGF-1R as well as FGFR have all been reported to be involved in driving tumor development and progression in adult and pediatric soft-tissue sarcoma. These driver kinases often act as critical determinants of tumor cell proliferation and targeting these signal transduction pathways remains an attractive therapeutic approach...
August 30, 2018: Molecular Cancer Therapeutics
Christopher M Dower, Neema Bhat, Melat T Gebru, Longgui Chen, Carson A Wills, Barbara A Miller, Hong-Gang Wang
Neuroblastoma is the most common extracranial malignancy in the pediatric population, accounting for over 9% of all cancer-related deaths in children. Autophagy is a cell self-protective mechanism that promotes tumor cell growth and survival, making it an attractive target for treating cancer. However, the role of autophagy in neuroblastoma tumor growth and metastasis is largely undefined. Here we demonstrate that targeted inhibition of an essential autophagy kinase, unc-51 like autophagy kinase 1 (ULK1), with a recently developed small molecular inhibitor of ULK1, SBI-0206965, significantly reduces cell growth and promotes apoptosis in SK-N-AS, SH-SY5Y, and SK-N-DZ neuroblastoma cell lines...
August 30, 2018: Molecular Cancer Therapeutics
Xinyi Tu, Mohamed M Kahila, Qin Zhou, Jia Yu, Krishna R Kalari, Liewei Wang, William S Harmsen, Jian Yuan, Judy C Boughey, Matthew P Goetz, Jann N Sarkaria, Zhenkun Lou, Robert W Mutter
Triple negative breast cancer (TNBC) is characterized by elevated locoregional recurrence risk despite aggressive local therapies. New tumor-specific radiosensitizers are needed. We hypothesized that the ATR inhibitor, VX-970, would preferentially radiosensitize TNBC. Non-cancerous breast epithelial and TNBC cell lines were investigated in clonogenic survival, cell cycle, and DNA damage signaling and repair assays. In addition, patient-derived xenograft (PDX) models generated prospectively as part of a neoadjuvant chemotherapy study from either baseline tumor biopsies or surgical specimens with chemoresistant residual disease were assessed for sensitivity to fractionated radiotherapy, VX-970, or the combination...
August 30, 2018: Molecular Cancer Therapeutics
Marta Peretti, Federica Maddalena Raciti, Valentina Carlini, Ivan Verduci, Sarah Sertic, Sara Barozzi, Massimiliano Garrè, Alessandra Pattarozzi, Antonio Daga, Federica Barbieri, Alex Costa, Tullio Florio, Michele Mazzanti
Glioblastoma (GB) is the most lethal, aggressive and diffuse brain tumor. The main challenge for successful treatment is targeting the cancer stem cell (CSC) sub-population responsible for tumor origin, progression and recurrence. Chloride Intracellular Channel 1 (CLIC1), highly expressed in CSCs, is constitutively present in the plasma membrane where it is associated with chloride ion permeability. In vitro, CLIC1 inhibition leads to a significant arrest of GB CSCs in G1 phase of the cell cycle. Furthermore, CLIC1 knockdown impairs tumor growth in vivo...
August 22, 2018: Molecular Cancer Therapeutics
Marilia Takada, Jeremy M L Hix, Sarah Corner, Peter Z Schall, Matti Kiupel, Vilma Yuzbasiyan-Gurkan
Histiocytic sarcoma in humans is an aggressive orphan disease with a poor prognosis as treatment options are limited. Dogs are the only species that spontaneously develops histiocytic sarcoma with an appreciable frequency, and may have value as a translational model system. In the current study, high throughput drug screening utilizing histiocytic sarcoma cells isolated from canine neoplasms identified these cells as particularly sensitive to a MEK inhibitor, trametinib. One of the canine cell lines carries a mutation in PTPN11 (E76K), and another one in KRAS (Q61H), which are associated with the activation of oncogenic MAPK signaling...
August 22, 2018: Molecular Cancer Therapeutics
Jung-Hyun Cho, Ah-Young Oh, Soyoung Park, So-Mi Kang, Min-Ho Yoon, Tae-Gyun Woo, Shin-Deok Hong, Jihwan Hwang, Nam-Chul Ha, Ho-Young Lee, Bum-Joon Park
Neurofibromatosis type 2 (NF2) syndrome is a very rare human genetic disease and there is no proper treatment for it until now. In our recent study, it has been reported that the loss of NF2 activates MAPK signaling through reduction of RKIP in a mesothelioma model. Here, we show that loss of NF2 induces reduction of the TGF-β receptor 2 (TβR2) expression and an overwhelming expression of TGF-β receptor 1 is activated by physical stimuli such as pressure or heavy materials. Activated TβR1 induces the phosphorylation and degradation of RKIP...
August 22, 2018: Molecular Cancer Therapeutics
Jan-Willem Theunissen, Allen G Cai, Maryam M Bhatti, Anthony B Cooper, Andrew D Avery, Ryan Dorfman, Sebastian Guelman, Zoia Levashova, Thi-Sau Migone
The primary function of Tissue Factor (TF) resides in the vasculature as a cofactor of blood clotting; however, multiple solid tumors aberrantly express this transmembrane receptor on the cell surface. Here, we developed anti-TF antibody-drug conjugates (ADCs) that did not interfere with the coagulation cascade and benchmarked them against previously developed anti-TF ADCs. After screening an affinity-matured antibody panel of diverse paratopes and affinities, we identified one primary paratope family that did not inhibit conversion of Factor X (FX) to activated Factor X (FXa) and did not affect conversion of prothrombin to thrombin...
August 20, 2018: Molecular Cancer Therapeutics
Maria Quanz, Eckhard Bender, Charlotte Kopitz, Sylvia Grünewald, Andreas Schlicker, Wolfgang Schwede, Ashley Eheim, Luisella Toschi, Roland Neuhaus, Carmen Richter, Joern Toedling, Claudia Merz, Ralf Lesche, Atanas Kamburov, Holger Siebeneicher, Marcus Bauser, Andrea Haegebarth
The lactate transporter SLC16A1/MCT1 plays a central role in tumor cell energy homeostasis. In a cell based screen, we identified a novel class of monocarboxylate transporter 1 (MCT1) inhibitors, including BAY-8002, which potently suppress bidirectional lactate transport. We investigated the antiproliferative activity of BAY-8002 in a panel of 246 cancer cell lines and show that hematopoietic tumor cells, in particular diffuse large B-cell lymphoma cell lines, and subsets of solid tumor models are particularly sensitive to MCT1 inhibition...
August 16, 2018: Molecular Cancer Therapeutics
Mohamed Y Elsaid, Ankita Shahi, Albert R Wang, Dana C Baiu, Chunrong Li, Lauryn R Werner, Sorabh Singhal, Lance T Hall, Jamey P Weichert, Eric A Armstrong, Bryan P Bednarz, Paul M Harari, Gopal Iyer, Mario Otto
Anti-tumor alkyl phospholipid analogs comprise a group of structurally related molecules with remarkable tumor selectivity. Some of these compounds have shown radiosensitizing capabilities. CLR127 is a novel, clinical-grade anti-tumor alkyl phospholipid ether analog, a subtype of synthetic alkyl phospholipids broadly targeting cancer cells with limited uptake in normal tissues. The purpose of this study was to investigate the effect of CLR127 to modulate radiation response across several adult and pediatric cancer types in vitro as well as in murine xenograft models of human prostate adenocarcinoma, neuroblastoma, Ewing sarcoma and rhabdomyosarcoma...
August 14, 2018: Molecular Cancer Therapeutics
James T Lynch, Urszula M Polanska, Ursula Hancox, Oona Delpuech, Juliana Maynard, Catherine B Trigwell, Catherine Eberlein, Carol Lenaghan, Radoslaw Polanski, Alvaro Avivar-Valderas, Marie Cumberbatch, Teresa Klinowska, Susan E Critchlow, Francisco Cruzalegui, Simon T Barry
Loss of the tumor suppressor PTEN confers a tumor cell dependency on the PI3Kβ isoform. Achieving maximal inhibition of tumor growth through PI3K pathway inhibition requires sustained inhibition of PI3K signalling, however efficacy is often limited by sub-optimal inhibition or reactivation of the pathway. To select combinations that deliver comprehensive suppression of PI3K signalling in PTEN null tumors, the PI3Kβ inhibitor AZD8186 was combined with inhibitors of kinases implicated in pathway reactivation in an extended cell proliferation assay...
August 10, 2018: Molecular Cancer Therapeutics
Heidi M Namløs, Kjetil Boye, Skyler J Mishkin, Tale Barøy, Susanne Lorenz, Bodil Bjerkehagen, Eva W Stratford, Else Munthe, Brian A Kudlow, Ola Myklebost, Leonardo A Meza-Zepeda
Molecular analysis of circulating tumour DNA (ctDNA) has a large potential for clinical application by capturing tumour-specific aberrations through non-invasive sampling. In gastrointestinal stromal tumour (GIST), analysis of KIT and PDGFRA mutations is important for therapeutic decisions, but the invasiveness of traditional biopsies limits the possibilities for repeated sampling. Using targeted next-generation sequencing, we have analysed circulating cell-free DNA from 50 GIST patients. Tumour-specific mutations were detected in 16 of 44 plasma samples (36%) from treatment-naïve patients and in 3 of 6 (50%) patients treated with tyrosine kinase inhibitors...
August 10, 2018: Molecular Cancer Therapeutics
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