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Molecular Cancer Therapeutics

Ursula A Germann, Brinley F Furey, William Markland, Russell R Hoover, Alex M Aronov, Jeffrey J Roix, Micheal Hale, Diane M Boucher, David A Sorrell, Gabriel Martinez-Botella, Matthew Fitzgibbon, Paul Shapiro, Michael J Wick, Ramin Samadani, Kathryn Meshaw, Anna Groover, Gary DeCrescenzo, Mark Namchuk, Caroline M Emery, Saurabh Saha, Dean J Welsch
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...
September 22, 2017: Molecular Cancer Therapeutics
Akinori Morita, Ippei Takahashi, Megumi Sasatani, Shin Aoki, Bing Wang, Shinya Ariyasu, Kaoru Tanaka, Tetsuji Yamaguchi, Akiko Sawa, Yurie Nishi, Tatsuro Teraoka, Shohei Ujita, Yosuke Kawate, Chihiro Yanagawa, Keiji Tanimoto, Atsushi Enomoto, Mitsuru Nenoi, Kenji Kamiya, Yasushi Nagata, Yoshio Hosoi, Toshiya Inaba
Inhibiting p53-dependent apoptosis by inhibitors of p53 is an effective strategy for preventing radiation-induced damage in hematopoietic lineages, while p53 and p21 also play radioprotective roles in the gastrointestinal epithelium. We previously identified some zinc(II) chelators, including 8-quinolinol derivatives that suppress apoptosis in attempts to discover compounds that target the zinc-binding site in p53. We found that 5-chloro-8-quinolinol (5CHQ) has a unique p53-modulating activity that shifts its transactivation from proapoptotic to protective responses including enhancing p21 induction and suppressing PUMA induction...
September 22, 2017: Molecular Cancer Therapeutics
Ran Li, Srinivas Chiguru, Li Li, Dongyoung Kim, Ramraj Velmurugan, David Kim, Siva Charan Devanaboyina, Hong Tian, Alan Schroit, Ralph Mason, Raimund J Ober, E Sally Ward
In response to cellular stress, phosphatidylserine (PS) is exposed on the outer membrane leaflet of tumor blood vessels and cancer cells, motivating the development of PS-specific therapies. The generation of drug-conjugated PS-targeting agents represents an unexplored therapeutic approach, for which anti-tumor effects are critically dependent on efficient internalization and lysosomal delivery of the cytotoxic drug. In the current study, we have generated PS-targeting agents by fusing PS-binding domains to a human IgG1-derived Fc fragment...
September 22, 2017: Molecular Cancer Therapeutics
Osamu Shimomura, Tatsuya Oda, Hiroaki Tateno, Yusuke Ozawa, Sota Kimura, Shingo Sakashita, Masayuki Noguchi, Jun Hirabayashi, Makoto Asashima, Nobuhiro Ohkohchi
Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumour-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin-glycan pairs...
September 22, 2017: Molecular Cancer Therapeutics
Lu Dai, Aiping Bai, Charles D Smith, Paulo C Rodriguez, Fangyou Yu, Zhiqiang Qin
Kaposi's Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several malignancies, including Kaposi's Sarcoma (KS) and primary effusion lymphoma (PEL), which preferentially arise in HIV+ patients and lack effective treatment. Sphingosine kinase 2 (SphK2) is a key factor within sphingolipid metabolism, responsible for the conversion of pro-apoptotic ceramides to anti-apoptotic sphingosine-1-phosphate (S1P). We have previously demonstrated that targeting SphK2 using a novel selective inhibitor, ABC294640, leads to the accumulation of intracellular ceramides and induces apoptosis in KSHV-infected primary endothelial cells and PEL tumor cells but not in uninfected cells...
September 22, 2017: Molecular Cancer Therapeutics
Marguerite L Palisoul, Jeanne M Quinn, Emily Schepers, Ian S Hagemann, Lei Guo, Kelsey Reger, Andrea R Hagemann, Carolyn K McCourt, Premal H Thaker, Matthew A Powell, David G Mutch, Katherine C Fuh
Uterine serous cancer (USC) is aggressive, and the majority of recurrent cases are chemoresistant. Because the receptor tyrosine kinase AXL promotes invasion and metastasis of USC and is implicated in chemoresistance in other cancers, we assessed the role of AXL in paclitaxel resistance in USC, determined the mechanism of action, and sought to restore chemosensitivity by inhibiting AXL in vitro and in vivo. We used small hairpin RNAs and BGB324 to knock down and inhibit AXL. We assessed sensitivity of USC cell lines to paclitaxel and measured paclitaxel intracellular accumulation in vitro in the presence or absence of AXL...
September 13, 2017: Molecular Cancer Therapeutics
Meike Hutt, Lisa Marquardt, Oliver Seifert, Martin Siegemund, Ines Müller, Dagmar Kulms, Klaus Pfizenmaier, Roland E Kontermann
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered as a promising molecule for cancer treatment. However, clinical studies with soluble TRAIL failed to show therapeutic activity, which resulted in subsequent development of more potent TRAIL-based therapeutics. In the present study, we applied defined oligomerization and tumor targeting as strategies to further improve the activity of a single-chain version of TRAIL (scTRAIL). We compared three different formats of epidermal growth factor receptor (EGFR)-targeting dimeric scTRAIL fusion proteins (Diabody (Db)-scTRAIL, scFv-IgE heavy chain domain 2 (EHD2)-scTRAIL, scFv-Fc-scTRAIL) as well as two non-targeted dimeric scTRAIL molecules (EHD2-scTRAIL, Fc-scTRAIL) to reveal the influence of targeting and protein format on anti-tumor activity...
September 13, 2017: Molecular Cancer Therapeutics
Carine Ervolino de Oliveira, Thais Helena Gasparoto, Claudia Ramos Pinheiro, Nádia Ghinelli Amôr, Maria Renata Sales Nogueira, Ramon Kaneno, Gustavo Pompermaier Garlet, Vanessa Soares Lara, João Santana da Silva, Karen Angélica Cavassani, Ana Paula Campanelli
Squamous cell carcinoma (SCC) is one of the most common human cancers worldwide. Recent studies show that regulatory T cells (Tregs) have a critical role in the modulation of an anti- tumor immune response, and consequently the SCC development. Since the accumulation of Tregs at the tumor site is, in part, due to selective recruitment through CCR5 and CCR5-associated chemokines, we investigated the role of CCR5 in the SCC development. Our findings showed that CCR5-deficient mice (CCR5KO) were efficient in controlling papilloma's incidence when compared with wild-type mice...
September 13, 2017: Molecular Cancer Therapeutics
Sri Murugan Poongkavithai Vadevoo, Jung-Eun Kim, Gowri Rangaswamy Gunassekaran, Hyun-Kyung Jung, Lianhua Chi, Dong Eon Kim, Seung-Hyo Lee, Sin-Hyeog Im, Byungheon Lee
Cellular crosstalk between tumors and M2-polarized tumor-associated macrophages (TAMs) favors tumor progression. Upregulation of interleukin 4 receptor (IL4R) is observed in diverse tumors and TAMs. We tested whether an IL4R-targeted pro-apoptotic peptide could inhibit tumor progression. The IL4R-binding peptide (IL4RPep-1) preferentially bound to IL4R-expressing tumor cells and M2-polarized macrophages both in vitro and in 4T1 breast tumors in vivo. To selectively kill IL4R-expressing cells, we designed an IL4R-targeted pro-apoptotic peptide, IL4RPep-1-K, by adding the pro-apoptotic peptide (KLAKLAK)2 to the end of IL4RPep-1...
September 6, 2017: Molecular Cancer Therapeutics
Stefanie Chan, Praveen Sridhar, Rory Kirchner, Ying Jie Lock, Zach Herbert, Silvia Buonamici, Peter Smith, Judy Lieberman, Fabio Petrocca
Prognosis of triple-negative breast cancer (TNBC) remains poor. To identify shared and selective vulnerabilities of basal-like TNBC, the most common TNBC subtype, a directed siRNA lethality screen was performed in 7 human breast cancer cell lines, focusing on 154 previously identified dependency genes of one TNBC line. Thirty common dependency genes were identified, including multiple proteasome and RNA splicing genes, especially those associated with the U4/U6.U5 tri-snRNP complex (e.g., PRPF8, PRPF38A). PRPF8 or PRPF38A knockdown or the splicing modulator E7107 led to widespread intronic retention and altered splicing of transcripts involved in multiple basal-like TNBC dependencies, including protein homeostasis, mitosis and apoptosis...
September 6, 2017: Molecular Cancer Therapeutics
Aimée N Laporte, Neal M Poulin, Jared J Barrott, Xiu Qing Wang, Alireza Lorzadeh, Ryan Vander Werff, Kevin B Jones, T Michael Underhill, Torsten O Nielsen
Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting the causative SS18-SSX fusion oncoprotein are currently available. Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-Seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell cycle arrest, neuronal differentiation and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs...
September 6, 2017: Molecular Cancer Therapeutics
Ronan Le Moigne, Blake T Aftab, Stevan Djakovic, Eugen Dhimolea, Eduardo Valle, Megan Murnane, Emily M King, Ferdie Soriano, Mary-Kamala Menon, Zhi Yong Wu, Stephen T Wong, Grace J Lee, Bing Yao, Arun P Wiita, Christine Lam, Julie Rice, Jinhai Wang, Marta Chesi, P Leif Bergsagel, Marianne Kraus, Christoph Driessen, Szerenke Kiss von Soly, F Michael Yakes, David Wustrow, Laura Shawver, Han-Jie Zhou, Thomas G Martin, Jeffrey L Wolf, Constantine S Mitsiades, Daniel J Anderson, Mark Rolfe
Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system (UPS) and CB-5083, a first in class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematological and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma (MM) cell lines and a number of in vivo MM models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response (UPR) and apoptosis...
September 6, 2017: Molecular Cancer Therapeutics
Jie Du, Jun Shang, Fei Chen, Yushuo Zhang, Narui Yin, Ting Xie, Haowen Zhang, Jiahua Yu, Fenju Liu
Non-homologous end joining (NHEJ) is the major pathway responsible for the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs), and correspondingly regulates the cellular response to IR. Identification of NHEJ inhibitors could substantially enhance the tumor radiosensitivity and improve the therapeutic efficiency of radiotherapy. In present study, we demonstrated a screening for NHEJ inhibitors by using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and high-resolution melting (HRM) analysis...
September 1, 2017: Molecular Cancer Therapeutics
Melissa A Orr-Asman, Zhengtao Chu, Min Jiang, Mariah Worley, Kathleen LaSance, Sheryl E Koch, Vinicius S Carreira, Hanan M Dahche, David R Plas, Kakajan Komurov, Xiaoyang Qi, Carol A Mercer, Lowell B Anthony, Jack Rubinstein, Hala Elnakat Thomas
Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NETs). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNETs) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi) such as CC-223 could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease...
September 1, 2017: Molecular Cancer Therapeutics
Kristina Y Aguilera, Huocong Huang, Wenting Du, Moriah M Hagopian, Zhen Wang, Stefan Hinz, Tae Hyun Hwang, Huamin Wang, Jason B Fleming, Diego H Castrillon, Xiaomei Ren, Ke Ding, Rolf A Brekken
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 pro-tumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells...
September 1, 2017: Molecular Cancer Therapeutics
Agnieszka A Rucki, Qian Xiao, Stephen Muth, Jianlin Chen, Xu Che, Jennifer Kleponis, Rajni Sharma, Robert A Anders, Elizabeth M Jaffee, Lei Zheng
Pancreatic adenocarcinoma (PDA) is one of the most chemotherapy and radiotherapy resistant tumors. The c-Met and Hedgehog (Hh) pathways have been shown previously by our group to be key regulatory pathways in the primary tumor growth and metastases formation. Targeting both the HGF/c-Met and Hh pathways has shown promising results in pre-clinical studies; however, the benefits were not readily translated into to clinical trials with PDA patients. In this study, utilizing mouse models of PDA, we showed that inhibition of either HGF/c-Met or Hh pathways sensitize the PDA tumors to gemcitabine resulting in decreased primary tumor volume as well as significant reduction of metastatic tumor burden...
September 1, 2017: Molecular Cancer Therapeutics
Ana Alcaraz-Sanabria, Cristina Nieto-Jiménez, Verónica Corrales-Sánchez, Leticia Serrano-Oviedo, Fernando Andrés-Pretel, Juan Carlos Montero, Miguel Burgos, Juan Llopis, Eva María Galán-Moya, Atanasio Pandiella, Alberto Ocaña
Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair (HR) 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...
August 28, 2017: Molecular Cancer Therapeutics
Feng Zhou, Michiko Shimoda, Laura Olney, Yuanzhi Lyu, Khiem Tran, Guochun Jiang, Kazushi Nakano, Ryan R Davis, Clifford G Tepper, Emanual Maverakis, Mel Campbell, Yuanpei Li, Satya Dandekar, Yoshihiro Izumiya
Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Currently treatment options for patients with PEL are limited. Oncolytic viruses have been engineered as anti-cancer agents and have recently shown increased therapeutic promise. Similarly, lytic activation of endogenous viruses from latently infected tumor cells can also be applied as a cancer therapy. In theory, such a therapeutic strategy would induce oncolysis by viral replication, while simultaneously stimulating an immune response to viral lytic cycle antigens...
August 28, 2017: Molecular Cancer Therapeutics
Nagako Akeno, Alisa L Reece, Melissa Callahan, Ashley L Miller, Rebecca G Kim, Diana He, Adam Lane, Jonathan S Moulton, Kathryn A Wikenheiser-Brokamp
Lung cancer is the leading cause of cancer deaths with small cell lung cancer (SCLC) as the most aggressive subtype. Preferential occurrence of TP53 missense mutations rather than loss implicates a selective advantage for TP53 mutant expression in SCLC pathogenesis. We show that lung epithelial expression of R270H and R172H (R273H and R175H in humans), common Trp53 mutations in lung cancer, combined with Rb1 loss selectively results in two subtypes of neuroendocrine carcinoma, SCLC and large cell neuroendocrine carcinoma (LCNEC)...
August 28, 2017: Molecular Cancer Therapeutics
Satomi Watanabe, Takeshi Yoshida, Hisato Kawakami, Naoki Takegawa, Junko Tanizaki, Hidetoshi Hayashi, Masayuki Takeda, Kimio Yonesaka, Junji Tsurutani, Kazuhiko Nakagawa
T790M mutation-selective epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) 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 co-oncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced anti-tumor activity in T790M-positive cells...
August 24, 2017: Molecular Cancer Therapeutics
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