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  • Preclinical Development of MGC018, a Duocarmycin-based Antibody-drug Conjugate Targeting B7-H3 for Solid Cancer
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-24
    Juniper A Scribner, Jennifer G Brown, Thomas Son, Michael Chiechi, Pam Li, Sharad Sharma, Hua Li, Anushka De Costa, Ying Li, Yan Chen, Ann Easton, Nicholas C Yee-Toy, Francine Z Chen, Sergey Gorlatov, Bhaswati Barat, Ling Huang, Christina R Wolff, Jeff Hooley, Tim E Hotaling, Timur Gaynutdinov, Valentina Ciccarone, James Tamura, Scott Koenig, Paul A Moore, Ezio Bonvini, Deryk Loo

    B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer, renal cell carcinoma, melanoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer and breast cancer. Over-expression of B7-H3 is associated with disease severity, risk of recurrence and reduced survival. In this

    更新日期:2020-09-24
  • Efficacy, tolerability and pharmacokinetics of combined targeted MEK and dual mTORC1/2 inhibition in a preclinical model of mucosal melanoma.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-21
    Bih-Rong Wei,Shelley B Hoover,Cody J Peer,Jennifer E Dwyer,Hibret A Adissu,Priya Shankarappa,Howard Yang,Maxwell Lee,Tyler J Peat,William D Figg,R Mark Simpson

    Melanomas arising in the mucous membranes are a rare and aggressive subtype. New treatment approaches are needed, yet accumulating sufficient evidence to improve patient outcomes is difficult. Clinical and pathological correlates between human and canine mucosal melanomas (MM) are substantial, and the relatively greater incidence of spontaneous naturally occurring MM in dogs represents a promising

    更新日期:2020-09-22
  • High Tumor Mutational Burden Correlates with Longer Survival in Immunotherapy-Naïve Patients with Diverse Cancers.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-21
    Paul Riviere,Aaron M Goodman,Ryosuke Okamura,Donald A Barkauskas,Theresa J Whitchurch,Suzanna Lee,Noor Khalid,Rachel Collier,Manvita Mareboina,Garrett M Frampton,David Fabrizio,Andrew B Sharabi,Shumei Kato,Razelle Kurzrock

    Higher tumor mutational burden (TMB) has been correlated with response to checkpoint blockade immunotherapy. However, it is unclear whether TMB independently serves as a prognostic biomarker for outcomes in immunotherapy-naïve patients. Here, we evaluated the relationship between TMB and overall survival in 1,415 immunotherapy-naïve patients with diverse advanced malignancies. TMB was studied both

    更新日期:2020-09-22
  • Microparticle Encapsulation of a Prostate-Targeted Biologic for the Treatment of Liver Metastases in a Preclinical Model of Castration-Resistant Prostate Cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-21
    Oliver C Rogers,Lizamma Antony,Oren Levy,Nitin Joshi,Brian W Simons,Susan Dalrymple,Marc Rosen,Andrew Pickering,Haoyue Lan,Heidi Kuang,Sudhir H Ranganath,Lei Zheng,Jeffrey M Karp,S Peter Howard,Samuel R Denmeade,John T Isaacs,W Nathaniel Brennen

    PRX302 is a highly potent mutant bacterial pore-forming biologic protoxin engineered for selective activation by prostate specific antigen (PSA), a serine protease expressed by benign and malignant prostate epithelial cells. Though being developed as a local therapy for benign prostatic hyperplasia and localized prostate cancer, PRX302 cannot be administered systemically as a treatment for metastatic

    更新日期:2020-09-22
  • Synthetic Lethal Metabolic Targeting of Androgen Deprived Prostate Cancer Cells with Metformin.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-17
    Bing Yang,Shivashankar Damodaran,Tariq A Khemees,Mikolaj J Filon,Adam Schultz,Joseph Gawdzik,Tyler Etheridge,Dmitry Malin,Kyle A Richards,Vincent L Cryns,David F Jarrard

    The initiation of androgen deprivation therapy (ADT) induces susceptibilities in prostate cancer (PC) cells that make them vulnerable to synergistic treatment and enhanced cell death. Senescence results in cell cycle arrest, but cells remain viable. In this study, we investigated the mechanisms by which PC cells undergo senescence in response to ADT, and determined whether an FDA approved antidiabetic

    更新日期:2020-09-20
  • Enhanced immunotherapy with LHRH-R targeted lytic peptide in ovarian cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-17
    Mark Seungwook Kim,Shaolin Ma,Anca Chelariu-Raicu,Carola Leuschner,Hector W Alila,Sanghoon Lee,Robert L Coleman,Anil K Sood

    Here, We examined the role of EP-100 (luteinizing hormone-releasing hormone (LHRH) ligand joined to a lytic peptide), improving the efficacy of immune checkpoint blockade. LHRH-R-positive murine ovarian cancer cells (ID8, IG10, IF5, and 2C12) were sensitive to EP-100 and were specifically killed at low micromolar levels through LHRH-R. EP-100 increased PD-L1 levels on murine ovarian cancer cells. In

    更新日期:2020-09-20
  • Dual mechanisms of novel CD73-targeted antibody and antibody-drug conjugate in inhibiting lung tumor growth and promoting antitumor immune-effector function.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-17
    Rui Jin,Liang Liu,Yun Xing,Tao Meng,Lanping Ma,Jinpeng Pei,Ying Cong,Xuesai Zhang,Zhiqiang Ren,Xin Wang,Jingkang Shen,Ker Yu

    While the tyrosine kinase inhibitor (TKI) therapy and immunotherapy have significantly improved lung cancer management, many patients do not benefit or become resistant to treatment, highlighting the need for novel treatments. We found elevated CD73 expression to be prevalent in non-small cell lung cancer (NSCLC) including those harboring the RAS- or RTK (EGFR, EML4-ALK) oncogenes. CD73 expression

    更新日期:2020-09-20
  • Osimertinib, an EGFR tyrosine kinase inhibitor, exerts anti-tumor activity in preclinical NSCLC models harboring the uncommon EGFR mutations G719X or L861Q or S768I.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-17
    Nicolas Floc'h,Sangbin Lim,Sue Bickerton,Afshan Ahmed,Jonathan Orme,Jelena Urosevic,Matthew J Martin,Darren Ae Cross,Byoung Chul Cho,Paul D Smith

    Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations with lower activity against wild-type EGFR and has demonstrated efficacy in NSCLC CNS metastases. The sensitizing mutations, the in-frame deletions in exon 19 and the L858R point mutation

    更新日期:2020-09-20
  • CH7233163 overcomes osimertinib resistant EGFR-Del19/T790M/C797S mutation.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-17
    Kenji Kashima,Hiroki Kawauchi,Hiromi Tanimura,Yukako Tachibana,Takashi Chiba,Takuya Torizawa,Hiroshi Sakamoto

    Osimertinib is the only EGFR-tyrosine kinase inhibitor (TKI) capable of overcoming EGFR-T790M-mutated NSCLC, but osimertinib-resistant EGFR triple mutations (Del19/T790M/C797S or L858R/T790M/C797S) have been reported. Although allosteric EGFR TKIs (eg. EAI-045) which potentially overcome L858R/T790M/C797S have been identified, there are no effective inhibitors against Del19/T790M/C797S. In this study

    更新日期:2020-09-20
  • The Discovery of SWI/SNF Chromatin Remodeling Activity as a Novel and Targetable Dependency in Uveal Melanoma.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-14
    Florencia Rago,GiNell Elliott,Ailing Li,Kathleen Sprouffske,Grainne Kerr,Aurore Desplat,Dorothee Abramowski,Julie T Chen,Ali Farsidjani,Kay X Xiang,Geoffrey Bushold,Yun Feng,Matthew D Shirley,Anka Bric,Anthony Vattay,Henrik Möbitz,Katsumasa Nakajima,Christopher D Adair,Simon Mathieu,Rukundo Ntaganda,Troy Smith,Julien P N Papillon,Audrey Kauffmann,David A Ruddy,Hyo-Eun C Bhang,Deborah Castelletti,Zainab

    Uveal melanoma is a rare and aggressive cancer that originates in the eye. Currently, there are no approved targeted therapies and very few effective treatments for this cancer. Although activating mutations in the G protein alpha subunits, GNAQ and GNA11 , are key genetic drivers of the disease, few additional drug targets have been identified. Recently, studies have identified context-specific roles

    更新日期:2020-09-15
  • Concurrent Targeting of Potential Cancer Stem Cells Regulating Pathways Sensitizes Lung Adenocarcinoma to Standard Chemotherapy.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-14
    Masahiro Shibata,Akira Ooki,Yoshikuni Inokawa,Pritam Sadhukhan,M Talha Ugurlu,Evgeny Izumchenko,Enrico Munari,Giuseppe Bogina,Charles M Rudin,Edward Gabrielson,Anju Singh,Mohammad O Hoque

    Cancer stem cells (CSC) are highly resistant to conventional chemotherapeutic drugs. YAP1 and STAT3 are the two transcription factors that facilitate the therapeutic resistance and expansion of CSCs. The objective of this study was to understand the cross-talk between YAP1 and STAT3 activities and to determine the therapeutic efficacy of targeting dual CSC-regulating pathways (YAP1 and STAT3) combined

    更新日期:2020-09-15
  • An RNA-binding protein, Hu-antigen R, in pancreatic cancer epithelial to mesenchymal transition, metastasis, and cancer stem cells.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-02
    Ruochen Dong,Ping Chen,Kishore Polireddy,Xiaoqing Wu,Tao Wang,Remya Ramesh,Dan A Dixon,Liang Xu,Jeffrey Aubé,Qi Chen

    Pancreatic cancer has poor prognosis and treatment outcomes due to its highly metastatic nature and resistance to current treatments. The RNA binding protein (RBP) Hu-antigen R (HuR) is a central player in posttranscriptional regulation of cancer related gene expression, and contributes to tumorigenesis, tumor growth, metastasis and drug resistance. HuR has been suggested to regulate pancreatic cancer

    更新日期:2020-09-03
  • Menin-mediated repression of glycolysis in combination with autophagy protects colon cancer against small molecule EGFR inhibitors.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-02
    Bryson W Katona,Taylor Hojnacki,Rebecca A Glynn,Kayla E Paulosky,Katherine M Szigety,Yan Cao,Xuyao Zhang,Zijie Feng,Xin He,Jian Ma,Xianxin Hua

    Menin serves both tumor suppressor and promoter roles in a highly tumor-specific manner. In colorectal cancer (CRC) menin is over-expressed and plays a critical role in regulating transcription of SKP2, and combined treatment with a menin inhibitor (MI) and small molecule EGFR inhibitor (EGFRi) leads to synergistic killing of CRC cells. However, the full spectrum of menin function in CRC remains uncertain

    更新日期:2020-09-03
  • LILRB4-Targeting Antibody-Drug Conjugates for the Treatment of Acute Myeloid Leukemia.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-02
    Yasuaki Anami,Mi Deng,Xun Gui,Aiko Yamaguchi,Chisato M Yamazaki,Ningyan Zhang,Chengcheng Zhang,Zhiqiang An,Kyoji Tsuchikama

    Acute myeloid leukemia (AML) is the most common and aggressive blood cancer in adults. In particular, significant unmet medical needs exist for effective treatment strategies for M4 and M5 AML subtypes. Antibody-drug conjugates (ADCs) are a promising drug class for AML therapy, as demonstrated by the FDA-approved anti-CD33 ADC gemutuzumab ozogamicin (Mylotarg®). However, CD33 is expressed in normal

    更新日期:2020-09-03
  • Therapeutic Targeting of Mitochondrial One-Carbon Metabolism in Cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-02
    Aamod S Dekhne,Zhanjun Hou,Aleem Gangjee,Larry H Matherly

    One-carbon (1C) metabolism encompasses folate-mediated 1C transfer reactions and related processes, including nucleotide and amino acid biosynthesis, antioxidant regeneration, and epigenetic regulation. 1C pathways are compartmentalized in the cytosol, mitochondria and nucleus. 1C metabolism in the cytosol has been an important therapeutic target for cancer since the inception of modern chemotherapy

    更新日期:2020-09-03
  • Correction: In Vitro and In Vivo Synergistic Antitumor Activity of the Combination of BKM120 and Erlotinib in Head and Neck Cancer: Mechanism of Apoptosis and Resistance.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Abu Syed Md Anisuzzaman,Abedul Haque,Dongsheng Wang,Mohammad Aminur Rahman,Chao Zhang,Zhengjia Chen,Zhuo Georgia Chen,Dong M Shin,A R M Ruhul Amin

    In the original version of [this article][1] ([1][2]), an IHC image (expression of p-EGFR control) was mistakenly used twice in Fig. 3B. The appropriate BKM panel in the p-EGFR column has replaced the duplicated panel. The error has been corrected in the latest online HTML and PDF versions of the

    更新日期:2020-09-02
  • Blockade of the Short Form of Prolactin Receptor Induces FOXO3a/EIF-4EBP1-Mediated Cell Death in Uterine Cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Yunfei Wen,Ying Wang,Anca Chelariu-Raicu,Elaine Stur,Yuan Liu,Sara Corvigno,Faith Bartsch,Lauren Redfern,Behrouz Zand,Yu Kang,Jinsong Liu,Keith Baggerly,Anil K Sood

    Abnormal activity of human prolactin (PRL) and its membrane-associated receptor (PRLR) contributes to the progression of uterine carcinoma. However, the underlying mechanisms are not well understood, and current means of targeting the PRL/PRLR axis in uterine cancer are limited. Our integrated analyses using The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) databases demonstrated that a

    更新日期:2020-09-02
  • Androgen Receptor Signaling Reduces the Efficacy of Bacillus Calmette-Guérin Therapy for Bladder Cancer via Modulating Rab27b-Induced Exocytosis.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Taichi Mizushima,Guiyang Jiang,Takashi Kawahara,Peng Li,Bin Han,Satoshi Inoue,Hiroki Ide,Ikuma Kato,Mehrsa Jalalizadeh,Etsuko Miyagi,Mitsunori Fukuda,Leonardo O Reis,Hiroshi Miyamoto

    Although intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard for nonsurgical management of non–muscle-invasive bladder cancer, a considerable number of patients exhibit resistance to the adjuvant treatment with unexplained mechanisms. This study aimed to investigate whether and how androgen receptor (AR) signals modulate BCG cytotoxicity in bladder cancer. AR knockdown

    更新日期:2020-09-02
  • Comparison of Panitumumab-IRDye800CW and 5-Aminolevulinic Acid to Provide Optical Contrast in a Model of Glioblastoma Multiforme.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Tiara S Napier,Neha Udayakumar,Aditi H Jani,Yolanda E Hartman,Hailey A Houson,Lindsay Moore,Hope M Amm,Nynke S van den Berg,Anna G Sorace,Jason M Warram

    Maximal safe resection of malignant tissue is associated with improved progression-free survival and better response to radiation and chemotherapy for patients with glioblastoma (GBM). 5-Aminolevulinic acid (5-ALA) is the current FDA-approved standard for intraoperative brain tumor visualization. Unfortunately, autofluorescence in diffuse areas and high fluorescence in dense tissues significantly limit

    更新日期:2020-09-02
  • Statins Reduce Intratumor Cholesterol Affecting Adrenocortical Cancer Growth.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Francesca Trotta,Paola Avena,Adele Chimento,Vittoria Rago,Arianna De Luca,Sara Sculco,Marta C Nocito,Rocco Malivindi,Francesco Fallo,Raffaele Pezzani,Catia Pilon,Francesco M Lasorsa,Simona N Barile,Luigi Palmieri,Antonio M Lerario,Vincenzo Pezzi,Ivan Casaburi,Rosa Sirianni

    Mitotane causes hypercholesterolemia in patients with adrenocortical carcinoma (ACC). We suppose that cholesterol increases within the tumor and can be used to activate proliferative pathways. In this study, we used statins to decrease intratumor cholesterol and investigated the effects on ACC growth related to estrogen receptor α (ERα) action at the nuclear and mitochondrial levels. We first used

    更新日期:2020-09-02
  • A Novel Approach to Safer Glucocorticoid Receptor-Targeted Anti-lymphoma Therapy via REDD1 (Regulated in Development and DNA Damage 1) Inhibition.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Ekaterina A Lesovaya,Alena V Savinkova,Olga V Morozova,Evgeniya S Lylova,Ekaterina M Zhidkova,Evgeny P Kulikov,Kirill I Kirsanov,Anna Klopot,Gleb Baida,Marianna G Yakubovskaya,Leo I Gordon,Ben Readhead,Joel T Dudley,Irina Budunova

    Glucocorticoids are widely used for therapy of hematologic malignancies. Unfortunately, chronic treatment with glucocorticoids commonly leads to adverse effects including skin and muscle atrophy and osteoporosis. We found recently that REDD1 (regulated in development and DNA damage 1) plays central role in steroid atrophy. Here, we tested whether REDD1 suppression makes glucocorticoid-based therapy

    更新日期:2020-09-02
  • Endogenous Retrovirus Transcript Levels Are Associated with Immunogenic Signatures in Multiple Metastatic Cancer Types.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    James T Topham,Emma Titmuss,Erin D Pleasance,Laura M Williamson,Joanna M Karasinska,Luka Culibrk,Michael K C Lee,Shehara Mendis,Robert E Denroche,Gun-Ho Jang,Steve E Kalloger,Hui-Li Wong,Richard A Moore,Andrew J Mungall,Grainne M O'Kane,Jennifer J Knox,Steven Gallinger,Jonathan M Loree,Dixie L Mager,Janessa Laskin,Marco A Marra,Steven J M Jones,David F Schaeffer,Daniel J Renouf

    Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across

    更新日期:2020-09-02
  • Characterization of a Novel FLT3 BiTE Molecule for the Treatment of Acute Myeloid Leukemia.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Bettina Brauchle,Rebecca L Goldstein,Christine M Karbowski,Anja Henn,Chi-Ming Li,Veit L Bücklein,Christina Krupka,Michael C Boyle,Priya Koppikar,Sascha Haubner,Joachim Wahl,Christoph Dahlhoff,Tobias Raum,Matthew J Rardin,Christine Sastri,Dan A Rock,Michael von Bergwelt-Baildon,Brendon Frank,Klaus H Metzeler,Ryan Case,Matthias Friedrich,Mercedesz Balazs,Karsten Spiekermann,Angela Coxon,Marion Subklewe

    Despite advances in the treatment of acute myeloid leukemia (AML), novel therapies are needed to induce deeper and more durable clinical response. Bispecific T-cell Engager (BiTE) molecules, which redirect patient T cells to lyse tumor cells, are a clinically validated modality for hematologic malignancies. Due to broad AML expression and limited normal tissue expression, fms-related tyrosine kinase

    更新日期:2020-09-02
  • A Novel HER2-targeted Antibody-drug Conjugate Offers the Possibility of Clinical Dosing at Trastuzumab-equivalent Exposure Levels.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Robyn M Barfield,Yun Cheol Kim,Stepan Chuprakov,Fangjiu Zhang,Maxine Bauzon,Ayodele O Ogunkoya,Dominick Yeo,Colin Hickle,Mark D Pegram,David Rabuka,Penelope M Drake

    Trastuzumab and the related ADC, ado-trastuzumab emtansine (T-DM1), both target HER2-overexpressing cells. Together, these drugs have treatment indications in both early-stage and metastatic settings for HER2+ breast cancer. T-DM1 retains the antibody functionalities of trastuzumab and adds the potency of a cytotoxic maytansine payload. Interestingly, in the clinic, T-DM1 cannot always replace the

    更新日期:2020-09-02
  • The Role of Specific ATP-Binding Cassette Transporters in the Acquired Resistance to Pyrrolobenzodiazepine Dimer-Containing Antibody-Drug Conjugates.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Simon Corbett,Shiran Huang,Francesca Zammarchi,Philip W Howard,Patrick H van Berkel,John A Hartley

    Antibody–drug conjugates (ADC) containing pyrrolobenzodiazepine (PBD) dimers are being evaluated clinically in both hematologic and solid tumors. These include ADCT-301 (camidanlumab tesirine) and ADCT-402 (loncastuximab tesirine) in pivotal phase II trials that contain the payload tesirine, which releases the PBD dimer warhead SG3199. An important consideration in future clinical development is acquired

    更新日期:2020-09-02
  • Antiproliferative Effects of Monoclonal Antibodies against (Pro)Renin Receptor in Pancreatic Ductal Adenocarcinoma.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Asadur Rahman,Makoto Matsuyama,Akio Ebihara,Yuki Shibayama,Arif Ul Hasan,Hironori Nakagami,Fumiaki Suzuki,Jiao Sun,Tomoe Kobayashi,Hiroki Hayashi,Daisuke Nakano,Hideki Kobara,Tsutomu Masaki,Akira Nishiyama

    We previously reported that silencing of the PRR gene, which encodes the (pro)renin receptor [(P)RR], significantly reduced Wnt/β-catenin–dependent development of pancreatic ductal adenocarcinoma (PDAC). Here, we examined the effects of a panel of blocking mAbs directed against the (P)RR extracellular domain on proliferation of the human PDAC cell lines PK-1 and PANC-1 in vitro and in vivo . We observed

    更新日期:2020-09-02
  • ARX788, a Site-specific Anti-HER2 Antibody-Drug Conjugate, Demonstrates Potent and Selective Activity in HER2-low and T-DM1-resistant Breast and Gastric Cancers.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Lillian Skidmore,Sukumar Sakamuri,Nick A Knudsen,Amha Gebre Hewet,Snezana Milutinovic,Wisam Barkho,Sandra Lyn Biroc,Jessica Kirtley,Robin Marsden,Kristine Storey,Ianina Lopez,Wayne Yu,Shiao-Yan Fang,Sulan Yao,Yi Gu,Feng Tian

    First-generation antibody–drug conjugates (ADC) are heterogeneous mixtures that have shown clinical benefit, but generally exhibited safety issues and a narrow therapeutic window due, in part, to off-target toxicity caused by ADC instability. ARX788 is a next-generation, site-specific anti-HER2 ADC that utilizes a unique nonnatural amino acid–enabled conjugation technology and a noncleavable Amberstatin

    更新日期:2020-09-02
  • Nonclinical Development of Next-generation Site-specific HER2-targeting Antibody-drug Conjugate (ARX788) for Breast Cancer Treatment.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Prathap Nagaraja Shastri,Jingjing Zhu,Lillian Skidmore,Xuejun Liang,Yanping Ji,Yi Gu,Feng Tian,Sulan Yao,Gang Xia

    Conventional antibody–drug conjugates (ADC) utilize native surface-exposed lysines or cysteines on the antibody of interest to conjugate cytotoxic payload. The nonspecific conjugation results in a mixture with variable drug-to-antibody ratios (DAR), conjugation sites, and ADCs that are often unstable in systemic circulation. ARX788 is an ADC consisting of a HER2-targeting antibody site-specifically

    更新日期:2020-09-02
  • PIM Kinase Inhibitors Block the Growth of Primary T-cell Acute Lymphoblastic Leukemia: Resistance Pathways Identified by Network Modeling Analysis.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    James T Lim,Neha Singh,Libia A Leuvano,Valerie S Calvert,Emanuel F Petricoin,David T Teachey,Richard B Lock,Megha Padi,Andrew S Kraft,Sathish K R Padi

    Despite significant progress in understanding the genetic landscape of T-cell acute lymphoblastic leukemia (T-ALL), the discovery of novel therapeutic targets has been difficult. Our results demonstrate that the levels of PIM1 protein kinase is elevated in early T-cell precursor ALL (ETP-ALL) but not in mature T-ALL primary samples. Small-molecule PIM inhibitor (PIMi) treatment decreases leukemia burden

    更新日期:2020-09-02
  • Repurposing the FDA-Approved Antiviral Drug Ribavirin as Targeted Therapy for Nasopharyngeal Carcinoma.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Sakibul Huq,Joshua Casaos,Riccardo Serra,Michael Peters,Yuanxuan Xia,Andy S Ding,Jeff Ehresman,Jayanidhi N Kedda,Manuel Morales,Noah L Gorelick,Tianna Zhao,Wataru Ishida,Alexander Perdomo-Pantoja,Arba Cecia,Chenchen Ji,Ian Suk,David Sidransky,Mariana Brait,Henry Brem,Nicolas Skuli,Betty Tyler

    Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a proclivity for systemic dissemination, leading many patients to present with advanced stage disease and fail available treatments. There is a notable lack of targeted therapies for NPC, despite working knowledge of multiple proteins with integral roles in NPC cancer biology. These proteins include EZH2, Snail, eIF4E, and IMPDH, which

    更新日期:2020-09-02
  • Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Mara Gilardi,Zhiyong Wang,Marco Proietto,Anastasia Chillà,Juan Luis Calleja-Valera,Yusuke Goto,Marco Vanoni,Matthew R Janes,Zbigniew Mikulski,Antonio Gualberto,Alfredo A Molinolo,Napoleone Ferrara,J Silvio Gutkind,Francis Burrows

    Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FTase). FTase catalyzes the posttranslational attachment of farnesyl groups to signaling proteins that are required for localization to cell membranes. Although all RAS isoforms are FTase substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility that HRAS-mutant tumors might be susceptible

    更新日期:2020-09-02
  • Patient Selection Strategies to Maximize Therapeutic Index of Antibody-Drug Conjugates: Prior Approaches and Future Directions.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Marna Williams,Anna Spreafico,Kapil Vashisht,Mary Jane Hinrichs

    Antibody–drug conjugates (ADC) are targeted agents that have shown promise in treating cancer. A central challenge in development of ADCs is the relatively narrow therapeutic index observed in clinical studies. Patient selection strategies based on expression of the target in tumors have the potential to maximize benefit and provide the best chance of clinical success; however, implementation of biomarker-driven

    更新日期:2020-09-02
  • Allosteric Inhibition of ABL Kinases: Therapeutic Potential in Cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    Jill K Jones,Eric M Thompson

    Tyrosine kinase inhibitors have revolutionized the world of cancer treatment in recent years, profoundly improving survival of patients with chronic myeloid leukemia (CML) and beyond. However, off-target toxicities of these inhibitors are well-described, and resistance has become a paramount concern. Novel allosteric inhibitors of the Abelson (ABL) family of tyrosine kinases, including GNF-2, GNF-5

    更新日期:2020-09-02
  • Selected Articles from This Issue
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-09-01
    American Association for Cancer Research

    ### [Skidmore et al. Page 1833][1] ARX788, a site-specific next-generation anti-HER2 ADC, employs an unnatural amino acid to conjugate cytotoxic drug with a highly stable oxime bond, resulting in superior stability and an extended half-life of 12.5 days in mice. In xenograft and PDX animal models,

    更新日期:2020-09-02
  • Antihistamine Drug Ebastine inhibits cancer growth by targeting Polycomb Group Protein EZH2.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-27
    Qiaqia Li,Kilia Y Liu,Qipeng Liu,Guangyu Wang,Weihua Jiang,Qingshu Meng,Yang Yi,Yongyong Yang,Rui Wang,Sen Zhu,Chao Li,Longxiang Wu,Dongyu Zhao,Lin Yan,Lili Zhang,Jung-Sun Kim,Xiongbing Zu,Anthony J Kozielski,Wei Qian,Jenny C Chang,Akash Patnaik,Kaifu Chen,Qi Cao

    Enhancer of Zester Homolog 2 (EZH2), a histone lysine methyltransferase and the catalytic component of Polycomb Repressive Complex 2, has been extensively investigated as a chromatin regulator and a transcriptional suppressor by methylating H3 at lysine 27 (H3K27). EZH2 is upregulated or mutated in most cancers, and its expression levels are negatively associated with clinical outcomes. However, the

    更新日期:2020-08-28
  • Development of anti-CD32b antibodies with enhanced Fc function for the treatment of B and plasma cell malignancies.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Haihui Lu,Ryan D Molony,Dongshu Chen,Sunyoung Jang,Babette Wolf,Stefan Ewert,Meghan Flaherty,Fangmin Xu,Sinan Isim,Yeonju Shim,Christina Dornelas,Nicole Balke,Xavier Charles Leber,Meike Scharenberg,Johanna Koelln,Eugene Choi,Rebecca Ward,Jennifer Johnson,Thomas Calzascia,Isabelle Isnardi,Juliet A Williams,Pieter L Lindenbergh,Niels W C J van de Donk,Tuna Mutis,Heather Huet,Emma Lees,Matthew J Meyer

    The sole inhibitory Fcγ receptor CD32b (FcγRIIb) is expressed throughout B and plasma cell development and on their malignant counterparts. CD32b expression on malignant B cells is known to provide a mechanism of resistance to Rituximab that can be ameliorated with a CD32b-blocking Ab. CD32b therefore represents an attractive tumor antigen for targeting with a monoclonal Ab (mAb). To this end, two

    更新日期:2020-08-27
  • Calcium channel blockers impair the antitumor activity of anti-CD20 monoclonal antibodies by blocking EGR-1 induction.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Ivana Spasevska,Eva Laure Matera,Kamel Chettab,Jade Ville,Marie Potier-Cartereau,Lars Petter Jordheim,Catherine Thieblemont,Denis Sahin,Christian Klein,Charles Dumontet

    Direct cell death induction, in addition to immune effector cell-mediated mechanisms, is one of the key mechanisms of action of anti-CD20 antibodies and yet the signaling pathways implicated remain poorly investigated. Here we show that the transcription factor EGR-1 is rapidly induced by anti-CD20 antibodies and is a key mediator for CD20-induced cell death. EGR-1 induction results from an increased

    更新日期:2020-08-27
  • Nf1 mutant tumors undergo transcriptome and kinome re-modeling after inhibition of either mTOR or MEK.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Daniela Pucciarelli,Steven P Angus,Benjamin Huang,Chi Zhang,Hiroki J Nakaoka,Ganesh Krishnamurthi,Sourav Bandyopadhyay,D Wade Clapp,Kevin Shannon,Gary L Johnson,Jean L Nakamura

    Loss of the tumor suppressor NF1 leads to activation of RAS effector pathways, which are therapeutically targeted by inhibition of mTOR (mTORi) or MEK (MEKi). However, therapeutic inhibition of RAS effectors leads to the development of drug resistance and ultimately disease progression. To investigate molecular signatures in the context of NF1 loss and subsequent acquired drug resistance we analyzed

    更新日期:2020-08-27
  • Paternally Expressed Gene 10 (PEG10) Promotes Growth, Invasion and Survival of Bladder Cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Martin E Gleave,Yoshihisa Kawai,Kenjiro Imada,Shusuke Akamatsu,Fan Zhang,Roland Seiler,Tetsutaro Hayashi,Jeffrey Leong,Eliana Beraldi,Neetu Saxena,Alexander Kretschmer,Htoo Zarni Oo,Alberto Contreras-Sanz,Hideyasu Matsuyama,Dong Lin,Ladan Fazli,Colin C Collins,Alexander W Wyatt,Peter C Black

    Paternally Expressed Gene 10 (PEG10) has been associated with neuroendocrine (NE)-muscle-invasive bladder cancer (MIBC), a subtype of the disease with the poorest survival. In this work, we further characterized the expression pattern of PEG10 in TCGA database of 412 MIBC pateints, and found that, compared to other subtypes, PEG10 mRNA level was enhanced in NE-like MIBC and highly correlats with other

    更新日期:2020-08-27
  • Targeted radionuclide therapy in patient-derived xenografts using 177Lu-EB-RGD.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Liang Zhao,Haojun Chen,Zhide Guo,Kaili Fu,Lanlin Yao,Li Fu,Weixi Guo,Xuejun Wen,Orit Jacobson,Xianzhong Zhang,Long Sun,Hua Wu,Qin Lin,Xiaoyuan Chen

    Currently, most patients with non-small cell lung cancer (NSCLC) are diagnosed in advanced stages with a poor five-year survival rate. Therefore, intensive research aimed at finding novel therapeutic strategies has been ongoing; experimental models that reliably emulate NSCLC disease are greatly needed to predict responses to novel therapeutics. Therefore, we developed patient-derived xenograft models

    更新日期:2020-08-27
  • The dual androgen receptor and glucocorticoid receptor antagonist CB-03-10 as potential treatment for tumors that have acquired GR-mediated resistance to AR blockade.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Caridad Rosette,Frances J Agan,Niccolette Rosette,Alessandro Mazzetti,Luigi Moro,Mara Gerloni

    CB-03-10 (cortexolone 17α-valerate-21-propionate) is a synthetic steroidal compound derived from cortexolone (11-deoxycortisone), an intermediate in cortisol biosynthesis. Characterization of the activity of CB-03-10 and its main related compound CB-03-05 (cortexolone 17α-valerate) included in vitro binding to the androgen and glucocorticoid receptors (AR and GR), antagonism of AR and GR transcriptional

    更新日期:2020-08-27
  • Dysregulation of EAAT2 and VGLUT2 spinal glutamate transports via histone deacetylase 2 (HDAC2) contributes to paclitaxel-induced painful neuropathy.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Xiao-Min Wang,Pan Gu,Leorey Saligan,Michael Iadarola,Lian Kah Ti,Stanley Wong,Chi Wai Cheung

    Effective treatments for chemotherapy-induced peripheral neuropathy (CIPN) remain unavailable. Given the significance of spinal cord glutamate transporters in neuronal plasticity and central sensitization, this study investigated the role of excitatory amino acid transporter 2 (EAAT2) and vesicular-glutamate transporter 2 (VGLUT2) in the development of paclitaxel-induced painful neuropathy. Paclitaxel

    更新日期:2020-08-27
  • Dual epitope targeting and enhanced hexamerization by DR5 antibodies as a novel approach to induce potent anti-tumor activity through DR5 agonism.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Marije B Overdijk,Kristin Strumane,Frank J Beurskens,Antonio Ortiz Buijsse,Claudine Vermot-Desroches,Boris S Vuillermoz,Thessa Kroes,Bart de Jong,Naomi Hoevenaars,Richard G Hibbert,Andreas Lingnau,Ulf Forssmann,Janine Schuurman,Paul W H I Parren,Rob N de Jong,Esther C W Breij

    Higher order DR5 clustering can induce tumor cell death, however therapeutic compounds targeting DR5 have achieved limited clinical efficacy. We describe HexaBody-DR5/DR5, an equimolar mixture of two DR5-specific IgG1 antibodies with an Fc-domain mutation that augments antibody hexamerization after cell surface target binding. The two antibodies do not compete for binding to DR5 as demonstrated using

    更新日期:2020-08-27
  • Pharmacologic Properties and Preclinical Activity of Sasanlimab, A High-Affinity Engineered Anti-Human PD-1 Antibody.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Amir A Al-Khami,Sawsan Youssef,Yasmina Abdiche,HoangKim Nguyen,Joyce Chou,Christopher R Kimberlin,Sherman M Chin,Cris Kamperschroer,Bart Jessen,Brent Kern,Natalija Budimir,Christopher P Dillon,Allison Xu,Jerry D Clark,Jeffrey Chou,Eugenia Kraynov,Arvind Rajpal,John C Lin,Shahram Salek-Ardakani

    Development of antagonistic monoclonal antibodies that specifically target the immune checkpoint receptor, programmed cell death protein 1 (PD-1) is of great interest for cancer immunotherapy. Here we report the biophysical characteristics and non-clinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and

    更新日期:2020-08-27
  • Retargeted and Stealth Modified Oncolytic Measles Viruses for Systemic Cancer Therapy in Measles-Immune Patients.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Eugene S Bah,Rebecca A Nace,Kah Whye Peng,Miguel Ángel Muñoz-Alía,Stephen J Russell

    Measles viruses (MV) are rapidly inactivated by anti-measles neutralizing antibodies which has limited their clinical performance as oncolytic agents. Here, by substituting the H and F surface glycoproteins of MV with those from the homologous canine distemper virus (CDV) and engineering the CDV H attachment protein to target EGF receptor or CD38, we generated a fully retargeted MV capable of resisting

    更新日期:2020-08-27
  • Targeting Multiple EGFR Expressing Tumors with a Highly Potent Tumor-Selective Antibody Drug Conjugate.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Mark G Anderson,Hugh D Falls,Michael J Mitten,Anatol Oleksijew,Kedar S Vaidya,Erwin R Boghaert,Wenqing Gao,Joann P Palma,Diana Cao,Puey-Ling Chia,Thomas John,Hui K Gan,Andrew M Scott,Edward B Reilly

    ABBV-321 (serclutamab talirine), a next-generation epidermal growth factor receptor (EGFR)-targeted antibody-drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity matured AM1 antibody. ABBV-321 follows the development of related EGFR targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated

    更新日期:2020-08-27
  • The novel histone deacetylase inhibitor OBP-801 induces apoptosis in rhabdoid tumors by releasing the silencing of NOXA.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Yohei Sugimoto,Yoshiki Katsumi,Tomoko Iehara,Daisuke Kaneda,Chihiro Tomoyasu,Kazutaka Ouchi,Hideki Yoshida,Mitsuru Miyachi,Shigeki Yagyu,Ken Kikuchi,Kunihiko Tsuchiya,Yasumichi Kuwahara,Toshiyuki Sakai,Hajime Hosoi

    Rhabdoid tumor (RT) is an aggressive, early childhood tumor. Biallelic inactivation of the SMARCB1/INI1 gene is the only common genetic feature in RTs. Loss of SMARCB1 function results in down-regulation of several tumor suppressor genes including p16, p21, and NOXA. The novel histone deacetylase inhibitor OBP-801 induces p21 and has shown efficacy against various cancers. In our study, OBP-801 strongly

    更新日期:2020-08-27
  • Circulating Tumor Cells In Advanced Cervical Cancer: NRG Oncology - Gynecologic Oncology Group Study 240 (NCT 00803062).
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    Krishnansu S Tewari,Michael W Sill,Bradley J Monk,Richard T Penson,David H Moore,Heather A Lankes,Lois M Ramondetta,Lisa M Landrum,Leslie M Randall,Ana Oaknin,Mario M Leitao,Eric L Eisenhauer,Paul DiSilvestro,Linda Van Le,Michael L Pearl,James J Burke,Ritu Salani,Debra L Richardson,Helen E Michael,David W Kindelberger,Michael J Birrer

    Purpose: To isolate circulating tumor cells (CTCs) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival (OS) and progression-free survival (PFS). Experimental Design: 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to

    更新日期:2020-08-27
  • Phase I, pharmacogenomic, drug-interaction study of sorafenib and bevacizumab in combination with paclitaxel in patients with advanced refractory solid tumors.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-26
    E Gabriela Chiorean,Susan M Perkins,Robert M Strother,Anne Younger,Jennifer M Funke,Safi G Shahda,Noah M Hahn,Kumaresan Sandrasegaran,David R Jones,Todd C Skaar,Bryan P Schneider,Christopher J Sweeney,Daniela E Matei

    Vascular endothelial growth factor (VEGF) blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab and paclitaxel in refractory cancer patients. The study had a "3+3" design, using paclitaxel

    更新日期:2020-08-27
  • Expression of the of the androgen receptor governs radiation resistance in a subset of glioblastomas vulnerable to anti-androgen therapy.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-12
    Christian K Werner,Uchechi J Nna,Hanshi Sun,Kari Wilder-Romans,Joseph Dresser,Ayesha U Kothari,Weihua Zhou,Yangyang Yao,Arvind Rao,Stefanie Stallard,Carl Koschmann,Tarik Bor,Waldemar Debinski,Alexander M Hegedus,Meredith A Morgan,Sriram Venneti,Edwina Baskin-Bey,Daniel E Spratt,Howard Colman,Jann N Sarkaria,Arul M Chinnaiyan,Joel R Eisner,Corey Speers,Theodore S Lawrence,Roy E Strowd,Daniel R Wahl

    New approaches are needed to overcome intrinsic therapy resistance in glioblastoma (GBM). Because GBMs exhibit sexual dimorphism and are reported to express steroid hormone receptors, we reasoned that signaling through the androgen receptor (AR) could mediate therapy resistance in GBM, much as it does in AR-positive prostate and breast cancers. We found that nearly half of GBM cell lines, patient-derived

    更新日期:2020-08-14
  • Preclinical Antitumor Activity and Biodistribution of a Novel Anti-GCC Antibody-Drug Conjugate in Patient-Derived Xenografts.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-11
    Adnan O Abu-Yousif,Donna Cvet,Melissa Gallery,Bret M Bannerman,Michelle L Ganno,Michael D Smith,Katharine C Lai,Thomas A Keating,Bradley Stringer,Afrand Kamali,Kurt Eng,Secil Koseoglu,Andy Zhu,Cindy Q Xia,Melissa Saylor Landen,Maria Borland,Robbie Robertson,Jayaprakasam Bolleddula,Mark G Qian,Jennifer Fretland,O Petter Veiby

    Guanylyl cyclase C (GCC) is a unique therapeutic target with expression restricted to the apical side of epithelial cell tight junctions thought to be only accessible by intravenously administered agents on malignant tissues where GCC expression is aberrant. In the present study, we sought to evaluate the therapeutic potential of a second-generation investigational ADC, TAK-164, comprised of a human

    更新日期:2020-08-12
  • Aurora A inhibitor TAS-119 enhances antitumor efficacy of taxanes in vitro and in vivo: preclinical studies as guidance for clinical development and trial design.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-11
    Hiroshi Sootome,Akihiro Miura,Norio Masuko,Takamasa Suzuki,Yoshihiro Uto,Hiroshi Hirai

    TAS-119 is a novel orally active, selective inhibitor of Aurora kinase A identified as a clinical candidate for efficacy testing in combination with taxanes. In vitro, TAS-119 enhanced cell growth inhibition of paclitaxel in multiple human cancer cell lines derived from various tissues, including paclitaxel-resistant cell lines. Interestingly, TAS-119 did not enhance paclitaxel antitumor activity in

    更新日期:2020-08-12
  • Novel, Selective Inhibitors of USP7 Uncover Multiple Mechanisms of Antitumor Activity in Vitro and in Vivo.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-11
    Yamini M Ohol,Michael T Sun,Gene Cutler,Paul R Leger,Dennis X Hu,Berenger Biannic,Payal Rana,Cynthia Cho,Scott Jacobson,Steve T Wong,Jerick Sanchez,Niket Shah,Deepa Pookot,Betty Abraham,Kyle Young,Silpa Suthram,Lisa A Marshall,Delia Bradford,Nathan Kozon,Xinping Han,Akinori Okano,Jack Maung,Christophe Colas,Jacob Schwarz,David Wustrow,Dirk G Brockstedt,Paul D Kassner

    The deubiquitinase USP7 regulates the levels of multiple proteins with roles in cancer progression and immune response. USP7 inhibition may thus decrease oncogene function, increase tumor suppressor function and sensitize tumors to DNA-damaging agents. We have discovered a novel chemical series that potently and selectively inhibits USP7 in biochemical and cellular assays. Our inhibitors reduce the

    更新日期:2020-08-12
  • Discovery of New Targets to Control Metastasis in Pancreatic Cancer by Single-cell Transcriptomics Analysis of Circulating Tumor Cells.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-01
    Spas Dimitrov-Markov,Javier Perales-Patón,Bruno Bockorny,Ana Dopazo,Manuel Muñoz,Natalia Baños,Victoria Bonilla,Camino Menendez,Yolanda Duran,Ling Huang,Sofia Perea,Senthil K Muthuswamy,Fatima Al-Shahrour,Pedro P Lopez-Casas,Manuel Hidalgo

    Metastasis development is the leading cause of cancer-related mortality in pancreatic ductal adenocarcinoma (PDAC) and yet, few preclinical systems to recapitulate its full spreading process are available. Thus, modeling of tumor progression to metastasis is urgently needed. In this work, we describe the generation of highly metastatic PDAC patient-derived xenograft (PDX) mouse models and subsequent

    更新日期:2020-08-04
  • A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in BRAF-Driven Pediatric Low-Grade Glioma Cells.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-01
    Diren Usta,Romain Sigaud,Juliane L Buhl,Florian Selt,Viktoria Marquardt,David Pauck,Jennifer Jansen,Stefan Pusch,Jonas Ecker,Thomas Hielscher,Johanna Vollmer,Alexander C Sommerkamp,Tobias Rubner,Darren Hargrave,Cornelis M van Tilburg,Stefan M Pfister,David T W Jones,Marc Remke,Tilman Brummer,Olaf Witt,Till Milde

    Pilocytic astrocytomas as well as other pediatric low-grade gliomas (pLGG) exhibit genetic events leading to aberrant activation of the MAPK pathway. The most common alterations are KIAA1549:BRAF fusions and BRAFV600E and NF1 mutations. Novel drugs targeting the MAPK pathway (MAPKi) are prime candidates for the treatment of these single-pathway diseases. We aimed to develop an assay suitable for preclinical

    更新日期:2020-08-04
  • NRG1/ERBB3 Pathway Activation Induces Acquired Resistance to XPO1 Inhibitors.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-01
    Takahito M Miyake,Sunila Pradeep,Emine Bayraktar,Elaine Stur,Katelyn F Handley,Sherry Y Wu,Cristian Rodriguez-Aguayo,Ju-Seog Lee,Gabriel Lopez-Berestein,Robert L Coleman,Anil K Sood

    XPO1 inhibitors have shown promise in cancer treatment, but mechanisms of resistance to these drugs are not well understood. In this study, we established selective inhibitors of nuclear export (SINE)-resistant ovarian cancer cell lines from in vivo mouse tumors and determined the mechanisms of adaptive XPO1 inhibitor resistance using protein and genomic arrays. Pathway analyses revealed upregulation

    更新日期:2020-08-04
  • Metabolic Adaptations to MEK and CDK4/6 Cotargeting in Uveal Melanoma.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-01
    Jessica L F Teh,Timothy J Purwin,Anna Han,Vivian Chua,Prem Patel,Usman Baqai,Connie Liao,Nelisa Bechtel,Takami Sato,Michael A Davies,Julio Aguirre-Ghiso,Andrew E Aplin

    Frequent GNAQ and GNA11 mutations in uveal melanoma hyperactivate the MEK–ERK signaling pathway, leading to aberrant regulation of cyclin-dependent kinases (CDK) and cell-cycle progression. MEK inhibitors (MEKi) alone show poor efficacy in uveal melanoma, raising the question of whether downstream targets can be vertically inhibited to provide long-term benefit. CDK4/6 selective inhibitors are FDA-approved

    更新日期:2020-08-04
  • Cross-Resistance Among Next-Generation Antiandrogen Drugs Through the AKR1C3/AR-V7 Axis in Advanced Prostate Cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-01
    Jinge Zhao,Shu Ning,Wei Lou,Joy C Yang,Cameron M Armstrong,Alan P Lombard,Leandro S D'Abronzo,Christopher P Evans,Allen C Gao,Chengfei Liu

    The next-generation antiandrogen drugs, XTANDI (enzalutamide), ZYTIGA (abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend survival times and improve quality of life in patients with advanced prostate cancer. Despite these advances, resistance occurs frequently and there is currently no definitive cure for castration-resistant prostate cancer. Our previous studies identified

    更新日期:2020-08-04
  • Autocrine CCL5 Effect Mediates Trastuzumab Resistance by ERK Pathway Activation in HER2-Positive Breast Cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-01
    Sandra Zazo,Paula González-Alonso,Ester Martín-Aparicio,Cristina Chamizo,Melani Luque,Marta Sanz-Álvarez,Pablo Mínguez,Gonzalo Gómez-López,Ion Cristóbal,Cristina Caramés,Jesús García-Foncillas,Pilar Eroles,Ana Lluch,Oriol Arpí,Ana Rovira,Joan Albanell,Juan Madoz-Gúrpide,Federico Rojo

    HER2-positive breast cancer is currently managed with chemotherapy in combination with specific anti-HER2 therapies, including trastuzumab. However, a high percentage of patients with HER2-positive tumors do not respond to trastuzumab (primary resistance) or either recur (acquired resistance), mostly due to molecular alterations in the tumor that are either unknown or undetermined in clinical practice

    更新日期:2020-08-04
  • EMP2 Is a Novel Regulator of Stemness in Breast Cancer Cells.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-08-01
    Christen Dillard,Meagan Kiyohara,Vei Mah,Sean P McDermott,Dana Bazzoun,Jessica Tsui,Ann M Chan,Ghassan Haddad,Matteo Pellegrini,Yu-Ling Chang,Yahya Elshimali,Yanyuan Wu,Jaydutt V Vadgama,Sara R Kim,Lee Goodglick,Samuel M Law,Deven D Patel,Puneet Dhawan,Neil A O'Brien,Lynn K Gordon,Jonathan Braun,Gary Lazar,Max S Wicha,Madhuri Wadehra

    Little is known about the role of epithelial membrane protein-2 (EMP2) in breast cancer development or progression. In this study, we tested the hypothesis that EMP2 may regulate the formation or self-renewal of breast cancer stem cells (BCSC) in the tumor microenvironment. In silico analysis of gene expression data demonstrated a correlation of EMP2 expression with known metastasis-related genes and

    更新日期:2020-08-04
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