Antitumor Activity of the IGF-1/IGF-2-Neutralizing Antibody Xentuzumab (BI 836845) in Combination with Enzalutamide in Prostate Cancer Models.


:Androgen deprivation therapy and second-generation androgen receptor signaling inhibitors such as enzalutamide are standard treatments for advanced/metastatic prostate cancer. Unfortunately, most men develop resistance and relapse; signaling via insulin-like growth factor (IGF) has been implicated in castration-resistant prostate cancer. We evaluated the antitumor activity of xentuzumab (IGF ligand-neutralizing antibody), alone and in combination with enzalutamide, in prostate cancer cell lines (VCaP, DuCaP, MDA PCa 2b, LNCaP, and PC-3) using established in vitro assays, and in vivo, using LuCaP 96CR, a prostate cancer patient-derived xenograft (PDX) model. Xentuzumab + enzalutamide reduced the viability of phosphatase and tensin homolog (PTEN)-expressing VCaP, DuCaP, and MDA PCa 2b cells more than either single agent, and increased antiproliferative activity and apoptosis induction in VCaP. Xentuzumab or xentuzumab + enzalutamide inhibited IGF type 1 receptor and AKT serine/threonine kinase (AKT) phosphorylation in VCaP, DuCaP, and MDA PCa 2b cells; xentuzumab had no effect on AKT phosphorylation and proliferation in PTEN-null LNCaP or PC-3 cells. Knockdown of PTEN led to loss of antiproliferative activity of xentuzumab and reduced activity of xentuzumab + enzalutamide in VCaP cells. Xentuzumab + enzalutamide inhibited the growth of castration-resistant LuCaP 96CR PDX with acquired resistance to enzalutamide, and improved survival in vivo The data suggest that xentuzumab + enzalutamide combination therapy may overcome castration resistance and could be effective in patients who are resistant to enzalutamide alone. PTEN status as a biomarker of responsiveness to combination therapy needs further investigation.


Mol Cancer Ther


Weyer-Czernilofsky U,Hofmann MH,Friedbichler K,Baumgartinger R,Adam PJ,Solca F,Kraut N,Nguyen HM,Corey E,Liu G,Sprenger CC,Plymate SR,Bogenrieder T




Has Abstract


2020-04-01 00:00:00














  • Metabolomics identifies pyrimidine starvation as the mechanism of 5-aminoimidazole-4-carboxamide-1-β-riboside-induced apoptosis in multiple myeloma cells.

    abstract::To investigate the mechanism by which 5-aminoimidazole-4-carboxamide-1-β-riboside (AICAr) induces apoptosis in multiple myeloma cells, we conducted an unbiased metabolomics screen. AICAr had selective effects on nucleotide metabolism, resulting in an increase in purine metabolites and a decrease in pyrimidine metaboli...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Bardeleben C,Sharma S,Reeve JR,Bassilian S,Frost P,Hoang B,Shi Y,Lichtenstein A

    更新日期:2013-07-01 00:00:00

  • Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma.

    abstract::Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity cou...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Amodio N,Stamato MA,Gullà AM,Morelli E,Romeo E,Raimondi L,Pitari MR,Ferrandino I,Misso G,Caraglia M,Perrotta I,Neri A,Fulciniti M,Rolfo C,Anderson KC,Munshi NC,Tagliaferri P,Tassone P

    更新日期:2016-06-01 00:00:00

  • Induction of Thioredoxin-Interacting Protein by a Histone Deacetylase Inhibitor, Entinostat, Is Associated with DNA Damage and Apoptosis in Esophageal Adenocarcinoma.

    abstract::In 2017, an estimated 17,000 individuals were diagnosed with esophageal adenocarcinoma (EAC), and less than 20% will survive 5 years. Positron emission tomography avidity is indicative of high glucose utilization and is nearly universal in EAC. TXNIP blocks glucose uptake and exhibits proapoptotic functions. Higher ex...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Feingold PL,Surman DR,Brown K,Xu Y,McDuffie LA,Shukla V,Reardon ES,Crooks DR,Trepel JB,Lee S,Lee MJ,Gao S,Xi S,McLoughlin KC,Diggs LP,Beer DG,Nancarrow DJ,Neckers LM,Davis JL,Hoang CD,Hernandez JM,Schrump DS,R

    更新日期:2018-09-01 00:00:00

  • Combined MEK and BCL-2/XL Inhibition Is Effective in High-Grade Serous Ovarian Cancer Patient-Derived Xenograft Models and BIM Levels Are Predictive of Responsiveness.

    abstract::Most patients with late-stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC, making it an attractive therapeutic...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Iavarone C,Zervantonakis IK,Selfors LM,Palakurthi S,Liu JF,Drapkin R,Matulonis UA,Hallberg D,Velculescu VE,Leverson JD,Sampath D,Mills GB,Brugge JS

    更新日期:2019-03-01 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


    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

  • Transcriptional targeting modalities in breast cancer gene therapy using adenovirus vectors controlled by alpha-lactalbumin promoter.

    abstract::The breast-specific antigen alpha-lactalbumin is expressed in >60% of breast cancer tissues. To evaluate the effect of gene therapy for breast cancer by controlling adenovirus replication with human alpha-lactalbumin promoter, we investigated the activity of a 762-bp human alpha-lactalbumin promoter. Alpha-lactalbumin...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Li X,Zhang J,Gao H,Vieth E,Bae KH,Zhang YP,Lee SJ,Raikwar S,Gardner TA,Hutchins GD,VanderPutten D,Kao C,Jeng MH

    更新日期:2005-12-01 00:00:00

  • Bortezomib induces schedule-dependent modulation of gemcitabine pharmacokinetics and pharmacodynamics in non-small cell lung cancer and blood mononuclear cells.

    abstract::Bortezomib combination with gemcitabine/cisplatin in patients with advanced tumors, predominantly non-small cell lung cancer (NSCLC), showed an unexpected transient drop in the deoxycytidine plasma levels, a marker for gemcitabine activity. This study investigates the pharmacokinetic/pharmacodynamic effect of bortezom...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Ceresa C,Giovannetti E,Voortman J,Laan AC,Honeywell R,Giaccone G,Peters GJ

    更新日期:2009-05-01 00:00:00

  • p110α Inhibition Overcomes Stromal Cell-Mediated Ibrutinib Resistance in Mantle Cell Lymphoma.

    abstract::Acquired resistance to cancer drugs is common, also for modern targeted drugs like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, a new drug approved for the treatment of the highly aggressive and relapsing mantle cell lymphoma (MCL). The tumor microenvironment often impacts negatively on drug response. Here, w...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Guan J,Huang D,Yakimchuk K,Okret S

    更新日期:2018-05-01 00:00:00

  • Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer.

    abstract::Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a gastrin-...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Zhang Q,Bhola NE,Lui VW,Siwak DR,Thomas SM,Gubish CT,Siegfried JM,Mills GB,Shin D,Grandis JR

    更新日期:2007-04-01 00:00:00

  • Fasudil inhibits vascular endothelial growth factor-induced angiogenesis in vitro and in vivo.

    abstract::Vascular endothelial growth factor (VEGF)-induced endothelial cell migration is an important component of tumor angiogenesis. Rho and Rho-associated kinase (ROCK) are key regulators of focal adhesion, stress fiber formation, and thus cell motility. Inhibitors of this pathway have been shown to inhibit endothelial cell...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Yin L,Morishige K,Takahashi T,Hashimoto K,Ogata S,Tsutsumi S,Takata K,Ohta T,Kawagoe J,Takahashi K,Kurachi H

    更新日期:2007-05-01 00:00:00

  • The glycotope-specific RAV12 monoclonal antibody induces oncosis in vitro and has antitumor activity against gastrointestinal adenocarcinoma tumor xenografts in vivo.

    abstract::RAV12 is a chimeric antibody that recognizes an N-linked carbohydrate antigen (RAAG12) strongly expressed on multiple solid organ cancers. More than 90% of tumors of colorectal, gastric, and pancreatic origin express RAAG12, and a majority of these tumors exhibit uniform RAAG12 expression. RAV12 exhibits potent cytoto...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Loo D,Pryer N,Young P,Liang T,Coberly S,King KL,Kang K,Roberts P,Tsao M,Xu X,Potts B,Mather JP

    更新日期:2007-03-01 00:00:00

  • U3-1402, a Novel HER3-Targeting Antibody-Drug Conjugate, for the Treatment of Colorectal Cancer.

    abstract::HER3 is overexpressed in several cancers, including colorectal cancer. Although therapies with anti-HER3 antibodies have been investigated, significant clinical benefits have not been reported. U3-1402 is a novel HER3-antibody-drug conjugate (ADC) composed of the HER3 antibody patritumab and a novel topoisomerase I in...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Koganemaru S,Kuboki Y,Koga Y,Kojima T,Yamauchi M,Maeda N,Kagari T,Hirotani K,Yasunaga M,Matsumura Y,Doi T

    更新日期:2019-11-01 00:00:00

  • In vivo optical imaging of human lymphoma xenograft using a library-derived peptidomimetic against alpha4beta1 integrin.

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    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Peng L,Liu R,Andrei M,Xiao W,Lam KS

    更新日期:2008-02-01 00:00:00

  • z-Guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, inhibits angiogenesis in vitro and in vivo.

    abstract::Our previous studies have shown that z-guggulsterone, a constituent of Indian Ayurvedic medicinal plant Commiphora mukul, inhibits the growth of human prostate cancer cells by causing apoptosis. We now report a novel response to z-guggulsterone involving the inhibition of angiogenesis in vitro and in vivo. The z-guggu...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Xiao D,Singh SV

    更新日期:2008-01-01 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


    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

  • Minicircle DNA-Engineered CAR T Cells Suppressed Tumor Growth in Mice.

    abstract::Viral-based chimeric antigen receptor-engineered T (CAR T)-cell manufacturing has potential safety risks and relatively high costs. The nonviral minicircle DNA (mcDNA) is safer for patients, cheaper to produce, and may be a more suitable technique to generate CAR T cells. In this study, we produced mcDNA-based CAR T c...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Han J,Gao F,Geng S,Ye X,Wang T,Du P,Cai Z,Fu Z,Zhao Z,Shi L,Li Q,Cai J

    更新日期:2020-01-01 00:00:00

  • Synergistic antitumor effect of combined use of adenoviral-mediated p53 gene transfer and antisense oligodeoxynucleotide targeting clusterin gene in an androgen-independent human prostate cancer model.

    abstract::Our recent studies showed that antisense oligodeoxynucleotide targeting antiapoptotic gene, clusterin, enhanced apoptosis induced by conventional therapeutic modalities using several prostate cancer models. In this study, to establish a more effective therapeutic strategy against prostate cancer, we investigated the e...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Yamanaka K,Gleave ME,Hara I,Muramaki M,Miyake H

    更新日期:2005-02-01 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


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

    更新日期:2005-06-01 00:00:00

  • Response prediction to a multitargeted kinase inhibitor in cancer cell lines and xenograft tumors using high-content tyrosine peptide arrays with a kinetic readout.

    abstract::Multitargeted kinase inhibitors have shown clinical efficacy in a range of cancer types. However, two major problems associated with these drugs are the low fraction of patients for which these treatments provide initial clinical benefit and the occurrence of resistance during prolonged therapy. Several types of predi...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Versele M,Talloen W,Rockx C,Geerts T,Janssen B,Lavrijssen T,King P,Göhlmann HW,Page M,Perera T

    更新日期:2009-07-01 00:00:00

  • Expression of human glutathione S-transferase P1 mediates the chemosensitivity of osteosarcoma cells.

    abstract::Chemoresistance is a major reason that patients with osteosarcoma fail to achieve a lasting chemotherapy response, and it contributes to disease relapse, progression, and death. Human glutathione S-transferase P1 (GSTP1), a phase II detoxification enzyme, contributes to chemoresistance in many cancers. However, the ro...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Huang G,Mills L,Worth LL

    更新日期:2007-05-01 00:00:00

  • The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and induces apoptosis in human cholangiocarcinoma cells.

    abstract::The expression of cyclooxygenase (COX)-2 is increased in human cancers including cholangiocarcinoma. This study was designed to evaluate the effect and mechanisms of the selective COX-2 inhibitor celecoxib in the growth control of human cholangiocarcinoma cells. Immunohistochemical analysis using human cholangiocarcin...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Wu T,Leng J,Han C,Demetris AJ

    更新日期:2004-03-01 00:00:00

  • DNAzyme technology and cancer therapy: cleave and let die.

    abstract::Novel molecules are constantly being discovered and developed to find better means of managing debilitating and fatal diseases, which include cancer in its multiple forms. Among these molecules, and as a direct consequence of a better understanding of the molecular basis of diseases, are those falling within the class...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章,评审


    authors: Dass CR,Choong PF,Khachigian LM

    更新日期:2008-02-01 00:00:00

  • Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer.

    abstract::Hsp70 is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of Hsp70 has proven relatively challenging, driving interest in alternative approaches. Hsp70 collaborates with the Bcl2-associated athanogene 3 (Bag3) to promote cell survival through mu...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Li X,Colvin T,Rauch JN,Acosta-Alvear D,Kampmann M,Dunyak B,Hann B,Aftab BT,Murnane M,Cho M,Walter P,Weissman JS,Sherman MY,Gestwicki JE

    更新日期:2015-03-01 00:00:00

  • The discovery and mechanism of action of novel tumor-selective and apoptosis-inducing 3,5-diaryl-1,2,4-oxadiazole series using a chemical genetics approach.

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    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Jessen KA,English NM,Yu Wang J,Maliartchouk S,Archer SP,Qiu L,Brand R,Kuemmerle J,Zhang HZ,Gehlsen K,Drewe J,Tseng B,Cai SX,Kasibhatla S

    更新日期:2005-05-01 00:00:00

  • Cotargeting MAPK and PI3K signaling with concurrent radiotherapy as a strategy for the treatment of pancreatic cancer.

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    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Williams TM,Flecha AR,Keller P,Ram A,Karnak D,Galbán S,Galbán CJ,Ross BD,Lawrence TS,Rehemtulla A,Sebolt-Leopold J

    更新日期:2012-05-01 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


    authors: Riffell JL,Jänicke RU,Roberge M

    更新日期:2011-05-01 00:00:00

  • CCR5-Dependent Homing of T Regulatory Cells to the Tumor Microenvironment Contributes to Skin Squamous Cell Carcinoma Development.

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    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: de Oliveira CE,Gasparoto TH,Pinheiro CR,Amôr NG,Nogueira MRS,Kaneno R,Garlet GP,Lara VS,Silva JS,Cavassani KA,Campanelli AP

    更新日期:2017-12-01 00:00:00

  • Biological Role and Therapeutic Targeting of TGF-β3 in Glioblastoma.

    abstract::Transforming growth factor (TGF)-β contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-β1 and TGF-β2 isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma....

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Seystahl K,Papachristodoulou A,Burghardt I,Schneider H,Hasenbach K,Janicot M,Roth P,Weller M

    更新日期:2017-06-01 00:00:00

  • p37 Induces tumor invasiveness.

    abstract::Previous studies have shown a statistically significant correlation between human carcinomas and monoclonal antibody detection of a Mycoplasma hyorhinis-encoded protein known as p37. A potential mechanism of p37 is that it might promote invasion and metastasis. Recombinant p37 enhanced the invasiveness of two prostate...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Ketcham CM,Anai S,Reutzel R,Sheng S,Schuster SM,Brenes RB,Agbandje-McKenna M,McKenna R,Rosser CJ,Boehlein SK

    更新日期:2005-07-01 00:00:00

  • HMG-CoA Reductase Inhibition Delays DNA Repair and Promotes Senescence After Tumor Irradiation.

    abstract::Despite significant advances in combinations of radiotherapy and chemotherapy, altered fractionation schedules and image-guided radiotherapy, many cancer patients fail to benefit from radiation. A prevailing hypothesis is that targeting repair of DNA double strand breaks (DSB) can enhance radiation effects in the tumo...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章


    authors: Efimova EV,Ricco N,Labay E,Mauceri HJ,Flor AC,Ramamurthy A,Sutton HG,Weichselbaum RR,Kron SJ

    更新日期:2018-02-01 00:00:00