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Molecular Cancer Therapeutics

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https://www.readbyqxmd.com/read/28223427/calcium-dependent-enhancement-by-extracellular-acidity-of-the-cytotoxicity-of-mitochondrial-inhibitors-against-melanoma
#1
Fumihito Noguchi, Shigeki Inui, Clare Fedele, Mark Shackleton, Satoshi Itami
Extracellular acidity is a hallmark of cancers and is independent of hypoxia. Since acidity potentiates malignant phenotypes, therapeutic strategies that enhance the targeting of oncogenic mechanisms in an acidic microenvironment should be effective. We report here that drugs which abrogate mitochondrial respiration show enhanced cytotoxicity against melanoma cells in a normoxic but acidic extracellular pH, independent from P53 mutations, BRAF (V600E) mutations and/or resistance against BRAF inhibitors. Conversely, the cytotoxicity against melanoma cells of mitochondrial inhibitors is impaired by a neutral or alkaline extracellular pH and in vivo systemic alkalinization with NaHCO3 enhanced subcutaneous tumor growth and lung metastasis of B16F10 cells in mice treated with the mitochondrial inhibitor phenformin...
February 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28223426/resistance-mechanism-against-trastuzumab-in-her2-positive-cancer-cells-and-its-negation-by-src-inhibition
#2
Mei Hua Jin, Ah-Rong Nam, Ji Eun Park, Ju-Hee Bang, Yung-Jue Bang, Do-Youn Oh
Trastuzumab in combination with chemotherapy is the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancers. Several resistance mechanisms against anti-HER2 therapy have been proposed. Src activation has been suggested to be responsible for the resistance of HER2-positive breast cancer. In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from HER2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773)...
February 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28223425/role-of-stat3-and-foxo1-in-the-divergent-therapeutic-responses-of-non-metastatic-and-metastatic-bladder-cancer-cells-to-mir-145
#3
Guosong Jiang, Chao Huang, Jingxia Li, Haishan Huang, Honglei Jin, Junlan Zhu, Xue-Ru Wu, Chuanshu Huang
Although miR-145 is the most frequently down-regulated miRNA in bladder cancer (BC), its exact stage-association and downstream effector have not been defined. Here, we found that miR-145 was upregulated in human BC patients with lymph node metastasis and in metastatic T24T cell line. Forced expression of miR-145 promoted anchorage-independent growth of T24T cells accompanied by the down-regulation of forkhead box class O1 (FOXO1). In contrast, in non-metastatic T24 cells, miR-145 overexpression inhibited cell growth with upregulation of FOXO1 and the knockdown of FOXO1 abolished the miR-145-mediated inhibition of cell growth...
February 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28223424/hsp70-inhibition-synergistically-enhances-the-effects-of-magnetic-fluid-hyperthermia-in-ovarian-cancer
#4
Karem A Court, Hiroto Hatakeyama, Sherry Y Wu, Mangala S Lingegowda, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Lee Ju-Seog, Carlos Rinaldi, Eduardo J Juan, Anil K Sood, Madeline Torres-Lugo
Hyperthermia has been investigated as a potential treatment for cancer. However, specificity in hyperthermia application remains a significant challenge. Magnetic fluid hyperthermia (MFH) may be an alternative to surpass such a challenge, but implications of MFH at the cellular level are not well understood. Therefore, the present work focused on the examination of gene expression after MFH treatment and using such information to identify target genes that when inhibited could produce an enhanced therapeutic outcome after MFH...
February 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28223423/modulating-therapeutic-activity-and-toxicity-of-pyrrolobenzodiazepine-antibody-drug-conjugates-with-self-immolative-disulfide-linkers
#5
Thomas H Pillow, Melissa Schutten, Shang-Fan Yu, Rachana Ohri, Jack Sadowsky, Kirsten Achilles Poon, Willy Solis, Fiona Zhong, Geoffrey Del Rosario, Mary Ann T Go, Jeffery Lau, Sharon Yee, Jintang He, Luna Liu, Carl Ng, Keyang Xu, Douglas D Leipold, Amrita V Kamath, Donglu Zhang, Luke Masterson, Stephen J Gregson, Philip W Howard, Fan Fang, Jinhua Chen, Janet Gunzner-Toste, Katherine K Kozak, Susan Spencer, Paul Polakis, Andrew G Polson, John A Flygare, Jagath R Junutula
A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody-drug conjugates (ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC. This novel disulfide ADC was compared to a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker...
February 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28193671/safe-and-effective-sarcoma-therapy-through-bispecific-targeting-of-egfr-and-upar
#6
Antonella Borgatti, Joseph S Koopmeiners, Aaron L Sarver, Amber L Winter, Kathleen Stuebner, Deborah Todhunter, Anthony E Rizzardi, Jonathan C Henricksen, Stephen Schmechel, Colleen L Forster, Jong-Hyuk Kim, Jerry Froelich, Jillian Walz, Michael S Henson, Matthew Breen, Kerstin Lindblad-Toh, Felix Oh, Kristy Pilbeam, Jaime F Modiano, Daniel A Vallera
Sarcomas differ from carcinomas in their mesenchymal origin. Therapeutic advancements have come slowly so alternative drugs and models are urgently needed. These studies report a new drug for sarcomas that simultaneously targets both tumor and tumor neovasculature. eBAT is a bispecific angiotoxin consisting of truncated, deimmunized Pseudomonas exotoxin fused to epidermal growth factor (EGF) and the amino terminal fragment (ATF) of urokinase. Here, we study the drug in an in vivo "ontarget" companion dog trial since eBAT effectively kills canine hemangiosarcoma (HSA) and human sarcoma cells in vitro...
February 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28179481/apc-mutations-as-a-potential-biomarker-for-sensitivity-to-tankyrase-inhibitors-in-colorectal-cancer
#7
Noritaka Tanaka, Tetsuo Mashima, Anna Mizutani, Ayana Sato, Aki Aoyama, Bo Gong, Haruka Yoshida, Yukiko Muramatsu, Kento Nakata, Masaaki Matsuura, Ryohei Katayama, Satoshi Nagayama, Naoya Fujita, Yoshikazu Sugimoto, Hiroyuki Seimiya
In most colorectal cancers (CRCs), Wnt/β-catenin signaling is activated by loss-of-function mutations in the adenomatous polyposis coli (APC) gene and plays a critical role in tumorigenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize Axins, a negative regulator of β-catenin, and upregulate β-catenin signaling. Tankyrase inhibitors downregulate β-catenin and are expected to be promising therapeutics for CRC. However, CRC cells are not always sensitive to tankyrase inhibitors, and predictive biomarkers for the drug sensitivity remain elusive...
February 8, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28167506/lipid-nanoparticle-mediated-delivery-of-anti-mir-17-family-oligonucleotide-suppresses-hepatocellular-carcinoma-growth
#8
Xinqiang Huang, Jill Magnus, Vivek Kaimal, Priya Karmali, Jian Li, Marlena Walls, Rene Prudente, Eric Sung, Mehran Sorourian, Robin Lee, Scott Davis, Xia Yang, Heather Estrella, Edmund C Lee, B Nelson Chau, Adam Pavlicek, Sonya Zabludoff
Hepatocellular carcinoma (HCC) is one of the most common human malignancies with poor prognosis and urgent unmet medical need. Aberrant expression of multiple members of the microRNA-17 (miR-17) family are frequently observed in HCC and their overexpression promotes tumorigenic properties of HCC cells. However, whether pharmacological inhibition of the miR-17 family inhibits HCC growth remains unknown. In the present study, we validated that the miR-17 family was up-regulated in a subset of HCC tumors and cell lines and its inhibition by a tough decoy inhibitor suppressed growth of Hep3B and HepG2 cells, which overexpress the miR-17 family...
February 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28167505/acquired-resistance-to-the-hsp90-inhibitor-ganetespib-in-kras-mutant-nsclc-is-mediated-via-reactivation-of-the-erk-p90rsk-mtor-signaling-network
#9
Suman Chatterjee, Eric H-B Huang, Ian Christie, Brenda F Kurland, Timothy F Burns
Approximately 25% of non-small cell lung cancer (NSCLC) patients have KRAS mutations and no effective therapeutic strategy exists for these patients. The use of Heat shock protein 90 (Hsp90) inhibitors in KRAS mutant NSCLC appeared to be a promising approach since these inhibitors target many KRAS downstream effectors, however, limited clinical efficacy has been observed due to resistance. Here, we examined the mechanism(s) of acquired resistance to the Hsp90 inhibitor, ganetespib, and identified novel and rationally devised Hsp90 inhibitor combinations which may prevent and overcome resistance to Hsp90 inhibitors...
February 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28167504/inhibition-of-isoprenylcysteine-carboxylmethyltransferase-induces-cell-cycle-arrest-and-apoptosis-through-p21-and-p21-regulated-bnip3-induction-in-pancreatic-cancer
#10
Kanjoormana Aryan Manu, Tin Fan Chai, Jing Tsong Teh, Wan Long Zhu, Patrick J Casey, Mei Wang
Pancreatic cancer remains one of the most difficult to treat human cancers despite recent advances in targeted therapy. Inhibition of Isoprenylcysteine carboxylmethyltransferase (ICMT), an enzyme that post-translationally modifies a group of proteins including several small GTPases, suppresses proliferation of some human cancer cells. However, the efficacy of ICMT inhibition on human pancreatic cancer has not been evaluated. In this study we have evaluated a panel of human pancreatic cancer cell lines and identified those that are sensitive to ICMT inhibition...
February 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28148716/a-prodrug-of-two-approved-drugs-cisplatin-and-chlorambucil-for-chemo-war-against-cancer
#11
Rakesh K Pathak, Ru Wen, Nagesh Kolishetti, Shanta Dhar
Cancer cells maintain normal mitochondrial glutathione as one of the defense mechanisms to inhibit mitochondrial membrane polarization and hence apoptosis. A combinational therapeutic modality Platin-Cbl, a prodrug of Food and Drug Administration (FDA) approved chemotherapeutic agents, cisplatin and chlorambucil (Cbl), was synthesized and characterized to explore the potential of this compound to initiate chemo war on cancer cells using the active drugs, cisplatin and Cbl, when delivered to the cellular power house mitochondrion using a targeted nanoparticle (NP) designed to get associated with this organelle...
February 1, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28148715/the-exportin-1-inhibitor-selinexor-exerts-superior-anti-tumor-activity-when-combined-with-t-cell-checkpoint-inhibitors
#12
Matthew R Farren, Rebecca C Hennessey, Reena Shakya, Omar Elnaggar, Gregory Young, Kari Kendra, Yosef Landesman, Sivan Elloul, Marsha Crochiere, Boris Klebanov, Trinayan Kashyap, Christin E Burd, Gregory B Lesinski
Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound targeting exportin-1, has previously been shown to inhibit melanoma cell growth in vivo. We hypothesized that combining selinexor with antibodies that block or disrupt T cell checkpoint molecule signaling would exert superior anti-melanoma activity. In vitro, selinexor increased PD-1 and CTLA4 gene expression in leukocytes and induced PD L1 gene expression in human melanoma cell lines. Mice bearing syngeneic B16F10 melanoma tumors demonstrated a significant reduction in tumor growth rate in response to the combination of selinexor and anti-PD-1 or anti-PD-L1 antibodies (p<0...
February 1, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28148714/clinical-dosing-regimen-of-selinexor-maintains-normal-immune-homeostasis-and-t-cell-effector-function-in-mice-implications-for-combination-with-immunotherapy
#13
Paul M Tyler, Mariah M Servos, Romy C de Vries, Boris Klebanov, Trinayan Kashyap, Sharon Sacham, Yosef Landesman, Michael Dougan, Stephanie K Dougan
Selinexor (KPT-330) is a first in class nuclear transport inhibitor currently in clinical trials as an anti-cancer agent. To determine how selinexor might impact anti-tumor immunity, we analyzed immune homeostasis in mice treated with selinexor and found disruptions in T cell development, a progressive loss of CD8 T cells and increases in inflammatory monocytes. Antibody production in response to immunization was mostly normal. Precursor populations in bone marrow and thymus were unaffected by selinexor, suggesting that normal immune homeostasis could recover...
February 1, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28138037/insulin-mediated-signaling-facilitates-resistance-to-pdgfr-inhibition-in-proneural-hpdgfb-driven-gliomas
#14
Damian A Almiron Bonnin, Cong Ran, Matthew C Havrda, Huan Liu, Yasuyuki Hitoshi, Zhonghua Zhang, Chao Cheng, Matthew Ung, Mark A Israel
Despite abundant evidence implicating receptor tyrosine kinases (RTKs), including the platelet-derived growth factor receptor (PDGFR), in the pathogenesis of glioblastoma (GBM), the clinical use of RTK inhibitors in this disease has been greatly compromised by the rapid emergence of therapeutic resistance. To study the resistance of proneural gliomas that are driven by a PDGFR regulated pathway to targeted tyrosine kinase inhibitors (TKIs), we utilized a mouse model of proneural glioma in which mice develop tumors that become resistant to PDGFR inhibition...
January 30, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28138036/suppression-of-the-growth-and-invasion-of-human-head-and-neck-squamous-cell-carcinomas-via-regulating-stat3-signaling-and-mir-21-%C3%AE-catenin-axis-with-hjc0152
#15
Yu Wang, Sinan Wang, Yansheng Wu, Yu Ren, Zhaoqing Li, Xiaofeng Yao, Chao Zhang, Na Ye, Chao Jing, Jiabin Dong, Kailiang Zhang, Shanshan Sun, Minghui Zhao, Wenyu Guo, Xin Qu, Yu Qiao, Haiying Chen, Linhgping Kong, Rui Jin, Xudong Wang, Lun Zhang, Jia Zhou, Qiang Shen, Xuan Zhou
Signal transducer and activator of transcription 3 (STAT3) is involved in the tumor growth and metastasis of human head and neck squamous cell carcinoma (HNSCC) and is therefore a target with therapeutic potential. In this study, we show that HJC0152, a recently developed anticancer agent and a STAT3 signaling inhibitor, exhibits promising antitumor effects against HNSCC both in vitro and in vivo via inactivating STAT3 and downstream microRNA-21/β-catenin axis. HJC0152 treatment efficiently suppressed HNSCC cell proliferation, arrested the cell cycle at the G0/G1 phase, induced apoptosis, and reduced cell invasion in both SCC25 and CAL27 cell lines...
January 30, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28138035/co-targeting-hgf-cmet-signaling-with-mek-inhibitors-in-metastatic-uveal-melanoma
#16
Hanyin Cheng, Vivian Chua, Connie Liao, Timothy J Purwin, Mizue Terai, Ken Kageyama, Michael A Davies, Takami Sato, Andrew E Aplin
Metastatic uveal melanoma (UM) patients usually die within one year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in UM patients. Our previous work showed that HGF signaling elicits resistance to MEK inhibitors in metastatic UM. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and BMF, contributes to HGF-mediated resistance to MEK inhibitors...
January 30, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28138034/azd6738-a-novel-oral-inhibitor-of-atr-induces-synthetic-lethality-with-atm-deficiency-in-gastric-cancer-cells
#17
Ahrum Min, Seock-Ah Im, Hyemin Jang, Seongyeong Kim, Miso Lee, Debora Keunyoung Kim, Yaewon Yang, Hee-Jun Kim, Kyung-Hun Lee, Jin Won Kim, Tae-Yong Kim, Do-Youn Oh, Jeff Brown, Alan Lau, Mark J O Connor, Yung-Jue Bang
Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect (HRD). The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer. In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3-dependent apoptosis. In contrast, SNU-484 cells with functional ATM were not sensitive to AZD6738...
January 30, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28138033/targeted-treatment-of-metastatic-breast-cancer-by-plk1-sirna-delivered-by-an-antioxidant-nanoparticle-platform
#18
Jingga Morry, Worapol Ngamcherdtrakul, Shenda Gu, Moataz Reda, David J Castro, Thanapon Sangvanich, Joe W Gray, Wassana Yantasee
Metastatic breast cancer is developed in about 20-30% of newly diagnosed early stage breast cancer patients despite treatments. Herein, we report a novel nanoparticle platform with intrinsic anti-metastatic properties for the targeted delivery of Polo-like kinase 1 siRNA (siPLK1). We first evaluated it in a triple negative breast cancer (TNBC) model, which shows high metastatic potential. PLK1 was identified as the top therapeutic target for TNBC cells and tumor initiating cells in a kinome-wide screen. The platform consists of a 50-nm mesoporous silica nanoparticle (MSNP) core coated layer-by-layer with bioreducible cross-linked PEI and PEG polymers, conjugated with an antibody for selective uptake into cancer cells...
January 30, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28138032/ras-mek-signaling-mediates-a-critical-chk1-dependent-dna-damage-response-in-cancer-cells
#19
Ho-June Lee, Yi Cao, Victoria Pham, Elizabeth Blackwood, Catherine Wilson, Marie Evangelista, Christiaan Klijn, David Stokoe, Jeff Settleman
Cancer cell line profiling to identify previously unrecognized kinase dependencies revealed a novel non-mutational dependency on the DNA damage response checkpoint kinase Chk1. While Chk1 is a promising therapeutic target in p53-deficient cancers, we found that Ras-MEK signaling engages Chk1 in a subset of osteosarcoma, ovarian, and breast cancer cells to enable their survival upon DNA damage, irrespective of p53 mutation status. Mechanistically, Ras-MEK signaling drives Chk1 expression, and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage...
January 30, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28138031/anti-kit-monoclonal-antibody-treatment-enhances-the-anti-tumor-activity-of-immune-checkpoint-inhibitors-by-reversing-tumor-induced-immunosuppression
#20
Andrew J Garton, Scott Seibel, Lori Lopresti-Morrow, Linda Crew, Neal Janson, Sreekala Mandiyan, E Sergio Trombetta, Shannon Pankratz, Theresa M LaVallee, Richard Gedrich
The receptor tyrosine kinase KIT is an established oncogenic driver of tumor growth in certain tumor types including gastrointestinal stromal tumors (GIST), in which constitutively active mutant forms of KIT represent an actionable target for small molecule tyrosine kinase inhibitors. There is also considerable potential for KIT to influence tumor growth indirectly based on its expression and function in cell types of the innate immune system, most notably mast cells. We have evaluated syngeneic mouse tumor models for anti-tumor effects of an inhibitory KIT monoclonal antibody (mAb), dosed either alone or in combination with immune checkpoint inhibitors...
January 30, 2017: Molecular Cancer Therapeutics
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