EGF Receptor and mTORC1 Are Novel Therapeutic Targets in Nonseminomatous Germ Cell Tumors.

Abstract:

:Germ cell tumors (GCT) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and nonseminoma forms of GCT exhibit distinct differentiation states, clinical behavior, and response to treatment; however, the molecular mechanisms of GCT differentiation are not fully understood. We tested whether the activity of the mTORC1 and MAPK pathways were differentially active in the two classes of GCT. Here we show that nonseminomatous germ cell tumors (NSGCT, including embryonal carcinoma, yolk sac tumor, and choriocarcinoma) from both children and adults display activation of the mTORC1 pathway, while seminomas do not. In seminomas, high levels of REDD1 may negatively regulate mTORC1 activity. In NSGCTs, on the other hand, EGF and FGF2 ligands can stimulate mTORC1 and MAPK signaling, and members of the EGF and FGF receptor families are more highly expressed. Finally, proliferation of NSGCT cells in vitro and in vivo is significantly inhibited by combined treatment with the clinically available agents erlotinib and rapamycin, which target EGFR and mTORC1 signaling, respectively. These results provide an understanding of the signaling network that drives GCT growth and a rationale for therapeutic targeting of GCTs with agents that antagonize the EGFR and mTORC1 pathways. Mol Cancer Ther; 17(5); 1079-89. ©2018 AACR.

journal_name

Mol Cancer Ther

authors

Chen KS,Fustino NJ,Shukla AA,Stroup EK,Budhipramono A,Ateek C,Stuart SH,Yamaguchi K,Kapur P,Frazier AL,Lum L,Looijenga LHJ,Laetsch TW,Rakheja D,Amatruda JF

doi

10.1158/1535-7163.MCT-17-0137

subject

Has Abstract

pub_date

2018-05-01 00:00:00

pages

1079-1089

issue

5

eissn

1535-7163

issn

1538-8514

pii

1535-7163.MCT-17-0137

journal_volume

17

pub_type

杂志文章
  • Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes.

    abstract::Cationic liposomes have been used for targeted drug delivery to tumor blood vessels, via mechanisms that are not fully elucidated. Doxorubicin (Dox)-loaded liposomes were prepared that incorporate a cationic lipid; 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), along with a small amount of porphyrin-phospholipid (P...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0276

    authors: Luo D,Geng J,Li N,Carter KA,Shao S,Atilla-Gokcumen GE,Lovell JF

    更新日期:2017-11-01 00:00:00

  • Therapeutic Potential of Focal Adhesion Kinase Inhibition in Small Cell Lung Cancer.

    abstract::Small cell lung cancer (SCLC) has a poor prognosis. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase regulating cell proliferation, survival, migration, and invasion, which is overexpressed and/or activated in several cancers, including SCLC. We wanted to determine whether FAK contributes to SCLC aggressi...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-18-0328

    authors: Aboubakar Nana F,Lecocq M,Ladjemi MZ,Detry B,Dupasquier S,Feron O,Massion PP,Sibille Y,Pilette C,Ocak S

    更新日期:2019-01-01 00:00:00

  • KD5170, a novel mercaptoketone-based histone deacetylase inhibitor, exerts antimyeloma effects by DNA damage and mitochondrial signaling.

    abstract::Histone deacetylase inhibitors have emerged as promising anticancer drugs. Using an unbiased ultrahigh throughput screening system, a novel mercaptoketone-based histone deacetylase inhibitor series was identified that was optimized to the lead compound, KD5170. KD5170 inhibited the proliferation of myeloma cell lines ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-08-0183

    authors: Feng R,Ma H,Hassig CA,Payne JE,Smith ND,Mapara MY,Hager JH,Lentzsch S

    更新日期:2008-06-01 00:00:00

  • 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors.

    abstract::There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-pa...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-15-0598

    authors: Onion D,Argent RH,Reece-Smith AM,Craze ML,Pineda RG,Clarke PA,Ratan HL,Parsons SL,Lobo DN,Duffy JP,Atherton JC,McKenzie AJ,Kumari R,King P,Hall BM,Grabowska AM

    更新日期:2016-04-01 00:00:00

  • Heregulin-ErbB3-Driven Tumor Growth Persists in PI3 Kinase Mutant Cancer Cells.

    abstract::PI3K is frequently mutated in cancer and plays an important role in cell growth and survival. Heregulin (HRG)-mediated autocrine or paracrine signaling through the receptor tyrosine kinase ErbB3 potently activates the PI3K/AKT pathway and has been shown to mediate resistance to a wide variety of anticancer agents. Alt...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-15-0075

    authors: Yarar D,Lahdenranta J,Kubasek W,Nielsen UB,MacBeath G

    更新日期:2015-09-01 00:00:00

  • The nonsteroidal anti-inflammatory drug tolfenamic acid inhibits BT474 and SKBR3 breast cancer cell and tumor growth by repressing erbB2 expression.

    abstract::Tolfenamic acid (TA) is a nonsteroidal anti-inflammatory drug that inhibits pancreatic cancer cell and tumor growth through decreasing expression of specificity protein (Sp) transcription factors. TA also inhibits growth of erbB2-overexpressing BT474 and SKBR3 breast cancer cells; however, in contrast to pancreatic ca...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-08-1097

    authors: Liu X,Abdelrahim M,Abudayyeh A,Lei P,Safe S

    更新日期:2009-05-01 00:00:00

  • Diallyl trisulfide increases the effectiveness of TRAIL and inhibits prostate cancer growth in an orthotopic model: molecular mechanisms.

    abstract::Recent studies have shown that naturally occurring compounds can enhance the efficacy of chemotherapeutic drugs. The objectives of this study were to investigate the molecular mechanisms by which diallyl trisulfide (DATS) enhanced the therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand (TR...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-08-0216

    authors: Shankar S,Chen Q,Ganapathy S,Singh KP,Srivastava RK

    更新日期:2008-08-01 00:00:00

  • Antitumor activity and immune response induction of a dual agonist of Toll-like receptors 7 and 8.

    abstract::Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptors 7 and 8 (TLR7 and TLR8). We have reported a novel class of synthetic oligoribonucleotides, referred to as stabilized immune-modulatory RNA compounds, which act as agonists of TLR7, TLR8, or both TLR7 and TLR8 depending on the sequence com...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-1198

    authors: Wang D,Precopio M,Lan T,Yu D,Tang JX,Kandimalla ER,Agrawal S

    更新日期:2010-06-01 00:00:00

  • BH3-only proteins Mcl-1 and Bim as well as endonuclease G are targeted in spongistatin 1-induced apoptosis in breast cancer cells.

    abstract::Spongistatin 1, a marine experimental substance with chemotherapeutic potential, induces apoptosis and inhibits clonogenic survival of MCF-7 cells. Regarding the apoptotic signaling pathways of spongistatin 1, we present two major facts. Firstly, spongistatin 1-induced cell death, mainly caspase-independent, involves ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-08-1179

    authors: Schneiders UM,Schyschka L,Rudy A,Vollmar AM

    更新日期:2009-10-01 00:00:00

  • Topoisomerase poisons differentially activate DNA damage checkpoints through ataxia-telangiectasia mutated-dependent and -independent mechanisms.

    abstract::Camptothecin and Adriamycin are clinically important inhibitors for topoisomerase (Topo) I and Topo II, respectively. The ataxia-telangiectasia mutated (ATM) product is essential for ionizing radiation-induced DNA damage responses, but the role of ATM in Topo poisons-induced checkpoints remains unresolved. We found th...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Siu WY,Lau A,Arooz T,Chow JP,Ho HT,Poon RY

    更新日期:2004-05-01 00:00:00

  • Antimitotic effect of the retinoid 4-oxo-fenretinide through inhibition of tubulin polymerization: a novel mechanism of retinoid growth-inhibitory activity.

    abstract::The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), a metabolite of fenretinide (4-HPR) present in plasma of 4-HPR-treated patients, is very effective in inducing growth inhibition and apoptosis in several cancer cell lines. 4-Oxo-4-HPR and 4-HPR have different mechanisms of action because 4-oxo-4-HPR, unl...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0798

    authors: Appierto V,Tiberio P,Cavadini E,Casalini P,Cappelletti G,Formelli F

    更新日期:2009-12-01 00:00:00

  • The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo.

    abstract::A novel oral Hsp90 inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC(50) values on three of the Hsp90 isoforms (Hsp90α, Hsp90β, and GRP94) and 320 nanomolar IC(50) value on the fourth (TRAP-1), with selectivity against unrelated en...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-11-0667

    authors: Menezes DL,Taverna P,Jensen MR,Abrams T,Stuart D,Yu GK,Duhl D,Machajewski T,Sellers WR,Pryer NK,Gao Z

    更新日期:2012-03-01 00:00:00

  • Targeting Tumor Neoangiogenesis via Targeted Adenoviral Vector to Achieve Effective Cancer Gene Therapy for Disseminated Neoplastic Disease.

    abstract::The application of cancer gene therapy has heretofore been restricted to local, or locoregional, neoplastic disease contexts. This is owing to the lack of gene transfer vectors, which embody the requisite target cell selectivity in vivo required for metastatic disease applications. To this end, we have explored novel ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-19-0768

    authors: Lee M,Lu ZH,Li J,Kashentseva EA,Dmitriev IP,Mendonca SA,Curiel DT

    更新日期:2020-03-01 00:00:00

  • The natural inhibitor of DNA topoisomerase I, camptothecin, modulates HIF-1α activity by changing miR expression patterns in human cancer cells.

    abstract::DNA topoisomerase I (Top1) inhibition by camptothecin derivatives can impair the hypoxia-induced cell transcriptional response. In the present work, we determined molecular aspects of the mechanism of camptothecin's effects on hypoxia-inducible factor-1α (HIF-1α) activity in human cancer cells. In particular, we provi...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-13-0729

    authors: Bertozzi D,Marinello J,Manzo SG,Fornari F,Gramantieri L,Capranico G

    更新日期:2014-01-01 00:00:00

  • In vitro cytotoxicity of carcinoma cells with 111In-labeled antibodies to HER-2.

    abstract::Antibodies conjugated to radionuclides emitting low-energy electrons, which include Auger electrons and some conversion electrons, were recently shown to efficiently kill cells bearing a high density of the antigen recognized. The primary purpose of this study was to determine if such killing could be obtained with an...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-04-0340

    authors: Michel RB,Andrews PM,Castillo ME,Mattes MJ

    更新日期:2005-06-01 00:00:00

  • BCH-1868 [(-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-yl-methyl) tetrahydrofuran]: a cyclic nucleoside phosphonate with antitumor activity.

    abstract::Nucleoside phosphonates are widely used therapeutic agents with a broad spectrum of antiviral activity. However, only a few of them are reported to have antitumor activity. In this study, we show that a tetrahydrofuran phosphonate analogue of guanosine, (-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-ylmethyl) tetrahydr...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Leblond L,Attardo G,Hamelin B,Bouffard DY,Nguyen-Ba N,Gourdeau H

    更新日期:2002-07-01 00:00:00

  • Targeting blockage of STAT3 in hepatocellular carcinoma cells augments NK cell functions via reverse hepatocellular carcinoma-induced immune suppression.

    abstract::STAT3 is an important transcriptional factor for cell growth, differentiation, and apoptosis. Although evidence suggests a positive role for STAT3 in cancer, the inhibitory effects of tumor STAT3 on natural killer (NK) cell functions in human hepatocellular carcinoma are unclear. In this study, we found that blocking ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-12-1087

    authors: Sun X,Sui Q,Zhang C,Tian Z,Zhang J

    更新日期:2013-12-01 00:00:00

  • Determinants of mitotic catastrophe on abrogation of the G2 DNA damage checkpoint by UCN-01.

    abstract::Genotoxic stress such as ionizing radiation halts entry into mitosis by activation of the G(2) DNA damage checkpoint. The CHK1 inhibitor 7-hydroxystaurosporine (UCN-01) can bypass the checkpoint and induce unscheduled mitosis in irradiated cells. Precisely, how cells behave following checkpoint abrogation remains to b...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-10-0809

    authors: On KF,Chen Y,Ma HT,Chow JP,Poon RY

    更新日期:2011-05-01 00:00:00

  • Caspase-3-dependent mitotic checkpoint inactivation by the small-molecule inducers of mitotic slippage SU6656 and geraldol.

    abstract::Microtubule-targeting cancer drugs such as paclitaxel block cell-cycle progression at mitosis by prolonged activation of the mitotic checkpoint. Cells can spontaneously escape mitotic arrest and enter interphase without chromosome segregation by a process termed mitotic slippage that involves the degradation of cyclin...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-10-0909

    authors: Riffell JL,Jänicke RU,Roberge M

    更新日期:2011-05-01 00:00:00

  • An Antibody-Drug Conjugate Targeting MUC1-Associated Carbohydrate CA6 Shows Promising Antitumor Activities.

    abstract::Glycosylation is a complex multienzyme-related process that is frequently deregulated in cancer. Aberrant glycosylation can lead to the generation of novel tumor surface-specific glycotopes that can be targeted by antibodies. Murine DS6 mAb (muDS6) was generated from serous ovary adenocarcinoma immunization. It recogn...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-19-0826

    authors: Nicolazzi C,Caron A,Tellier A,Trombe M,Pinkas J,Payne G,Carrez C,Guérif S,Maguin M,Baffa R,Fassan M,Adam J,Mangatal-Wade L,Blanc V

    更新日期:2020-08-01 00:00:00

  • The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs survival in non-small cell lung cancer model mice.

    abstract::Activation of anaplastic lymphoma receptor tyrosine kinase (ALK) is involved in the pathogenesis of several carcinomas, including non-small cell lung cancer (NSCLC). Echinoderm microtubule-associated protein like 4 (EML4)-ALK, which is derived from the rearrangement of ALK and EML4 genes, has been validated as a thera...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-13-0395

    authors: Mori M,Ueno Y,Konagai S,Fushiki H,Shimada I,Kondoh Y,Saito R,Mori K,Shindou N,Soga T,Sakagami H,Furutani T,Doihara H,Kudoh M,Kuromitsu S

    更新日期:2014-02-01 00:00:00

  • Oncostatin M induces growth arrest of mammary epithelium via a CCAAT/enhancer-binding protein delta-dependent pathway.

    abstract::Oncostatin M (OSM), an interleukin 6-type cytokine, induces sustained up-regulation of CCAAT/enhancer-binding protein (C/EBP) delta mRNA and protein in nonneoplastic HC11 mouse mammary epithelial cells. This up-regulation is dependent on signaling by phospho-Stat3 (signal transducers and activators of transcription). ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Hutt JA,DeWille JW

    更新日期:2002-06-01 00:00:00

  • The G-rich promoter and G-rich coding sequence of basic fibroblast growth factor are the targets of thalidomide in glioma.

    abstract::Thalidomide is considered to be a potent antiangiogenic and immunomodulatory drug for cancer therapy. Earlier clinical studies have found that patients responding to this drug often had high plasma levels of basic fibroblast growth factor (bFGF). This cytokine is a proangiogenic factor overexpressed in many tumors and...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-07-2398

    authors: Mei SC,Wu RT

    更新日期:2008-08-01 00:00:00

  • Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547.

    abstract::The challenge of developing effective pharmacodynamic biomarkers for preclinical and clinical testing of FGFR signaling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables ac...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-16-0297

    authors: Delpuech O,Rooney C,Mooney L,Baker D,Shaw R,Dymond M,Wang D,Zhang P,Cross S,Veldman-Jones M,Wilson J,Davies BR,Dry JR,Kilgour E,Smith PD

    更新日期:2016-11-01 00:00:00

  • Proof-of-principle: oncogenic beta-catenin is a valid molecular target for the development of pharmacological inhibitors.

    abstract::Activation of beta-catenin is a critical step in the pathogenesis of many common human cancers and is the initiating event in adenocarcinoma of the colon. Because activation of beta-catenin provides a gain-of-function, it is tempting to speculate that specific pharmacological inhibition of activated beta-catenin might...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Kim JS,Crooks H,Foxworth A,Waldman T

    更新日期:2002-12-01 00:00:00

  • Algorithmic guided screening of drug combinations of arbitrary size for activity against cancer cells.

    abstract::The standard treatment for most advanced cancers is multidrug therapy. Unfortunately, combinations in the clinic often do not perform as predicted. Therefore, to complement identifying rational drug combinations based on biological assumptions, we hypothesized that a functional screen of drug combinations, without lim...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-08-0937

    authors: Zinner RG,Barrett BL,Popova E,Damien P,Volgin AY,Gelovani JG,Lotan R,Tran HT,Pisano C,Mills GB,Mao L,Hong WK,Lippman SM,Miller JH

    更新日期:2009-03-01 00:00:00

  • Synergistic enhancement of TRAIL- and tumor necrosis factor alpha-induced cell death by a phenoxazine derivative.

    abstract::2-Amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one (Phx-1) has been developed as a novel phenoxazine derivative having an anticancer activity on a variety of cancer cell lines as well as transplanted tumors in mice with minimal toxicity to normal cells. We examined the effects of Phx-1 on Jurkat cells, a ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0067

    authors: Hara K,Okamoto M,Aki T,Yagita H,Tanaka H,Mizukami Y,Nakamura H,Tomoda A,Hamasaki N,Kang D

    更新日期:2005-07-01 00:00:00

  • Acquired Resistance Mechanisms to Combination Met-TKI/EGFR-TKI Exposure in Met-Amplified EGFR-TKI-Resistant Lung Adenocarcinoma Harboring an Activating EGFR Mutation.

    abstract::Met-amplified EGFR-tyrosine kinase inhibitor (TKI)-resistant non-small cell lung cancer (NSCLC) harboring an activating EGFR mutation is responsive to concurrent EGFR-TKI and Met-TKI treatment in a preclinical model. Here, we determined that Met-amplified gefitinib-resistant cells acquire dual resistance to inhibition...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-16-0313

    authors: Yamaoka T,Ohmori T,Ohba M,Arata S,Kishino Y,Murata Y,Kusumoto S,Ishida H,Shirai T,Hirose T,Ohnishi T,Sasaki Y

    更新日期:2016-12-01 00:00:00

  • Suppression of the malignant phenotype in human pancreatic cancer cells by the overexpression of manganese superoxide dismutase.

    abstract::Cells contain a large number of antioxidants to prevent or repair the damage caused by reactive oxygen species. One component of the antioxidant system, manganese superoxide dismutase (MnSOD), is localized in the mitochondria, and the levels of this protein have been previously shown to inversely correlate with pancre...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Weydert C,Roling B,Liu J,Hinkhouse MM,Ritchie JM,Oberley LW,Cullen JJ

    更新日期:2003-04-01 00:00:00

  • Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1-Stat3.

    abstract::Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma, indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (γ-secretase inhibitor) PF-03084...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0001

    authors: Wu CX,Xu A,Zhang CC,Olson P,Chen L,Lee TK,Cheung TT,Lo CM,Wang XQ

    更新日期:2017-08-01 00:00:00