33 results on '"Wongvipat J"'
Search Results
2. Timing of treatment shapes the path to androgen receptor signaling inhibitor resistance in prostate cancer.
- Author
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Lee E, Zhang Z, Chen CC, Choi D, Rivera ACA, Linton E, Ho YJ, Love J, LaClair J, Wongvipat J, and Sawyers CL
- Abstract
There is optimism that cancer drug resistance can be addressed through appropriate combination therapy, but success requires understanding the growing complexity of resistance mechanisms, including the evolution and population dynamics of drug-sensitive and drug-resistant clones over time. Using DNA barcoding to trace individual prostate tumor cells in vivo , we find that the evolutionary path to acquired resistance to androgen receptor signaling inhibition (ARSI) is dependent on the timing of treatment. In established tumors, resistance occurs through polyclonal adaptation of drug-sensitive clones, despite the presence of rare subclones with known, pre-existing ARSI resistance. Conversely, in an experimental setting designed to mimic minimal residual disease, resistance occurs through outgrowth of pre-existing resistant clones and not by adaptation. Despite these different evolutionary paths, the underlying mechanisms responsible for resistance are shared across the two evolutionary paths. Furthermore, mixing experiments reveal that the evolutionary path to adaptive resistance requires cooperativity between subclones. Thus, despite the presence of pre-existing ARSI-resistant subclones, acquired resistance in established tumors occurs primarily through cooperative, polyclonal adaptation of drug-sensitive cells. This tumor ecosystem model of resistance has new implications for developing effective combination therapy.
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- 2024
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3. Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer.
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Zhang Z, Karthaus WR, Lee YS, Gao VR, Wu C, Russo JW, Liu M, Mota JM, Abida W, Linton E, Lee E, Barnes SD, Chen HA, Mao N, Wongvipat J, Choi D, Chen X, Zhao H, Manova-Todorova K, de Stanchina E, Taplin ME, Balk SP, Rathkopf DE, Gopalan A, Carver BS, Mu P, Jiang X, Watson PA, and Sawyers CL
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- Animals, Cancer-Associated Fibroblasts drug effects, Cancer-Associated Fibroblasts metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation genetics, Cells, Cultured, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic drug effects, Humans, Kaplan-Meier Estimate, Male, Mice, SCID, Neuregulin-1 metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms prevention & control, Tumor Microenvironment drug effects, Xenograft Model Antitumor Assays methods, Androgen Antagonists pharmacology, Drug Resistance, Neoplasm genetics, Neuregulin-1 genetics, Prostatic Neoplasms genetics, Tumor Microenvironment genetics
- Abstract
Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies., Competing Interests: Declaration of Interests C.L.S. and J.W. are co-inventors of enzalutamide and apalutamide and may be entitled to royalties. C.L.S. serves on the Board of Directors of Novartis and is a co-founder of ORIC Pharmaceuticals. He is a science advisor to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra, and PMV. W.A. reports consulting for Clovis Oncology, Janssen, MORE Health, and ORIC Pharmaceuticals, and received honoraria from CARET and travel accommodations from GlaxoSmith Kline, Clovis Oncology, and ORIC Pharmaceuticals. D.E.R. reports having consulting or advisory role (uncompensated) from Genentech/Roche, Janssen Oncology, and TRACON Pharma, and received research funding from: AstraZeneca (Inst); Celgene (Inst); Ferring (Inst); Genentech/Roche (Inst); Janssen Oncology (Inst); Medivation/Astellas/Pfizer (Inst); Millennium (Inst); Novartis (Inst); Taiho Pharmaceutical (Inst); Takeda (Inst); TRACON Pharma (Inst). W.R.K. is a coinventor on patent WO2012168930A2 filed by Koninklijke Nederlandse Akademie Van Wetenschappen that covers organoid technology., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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4. Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation.
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Zhang Z, Zhou C, Li X, Barnes SD, Deng S, Hoover E, Chen CC, Lee YS, Zhang Y, Wang C, Metang LA, Wu C, Tirado CR, Johnson NA, Wongvipat J, Navrazhina K, Cao Z, Choi D, Huang CH, Linton E, Chen X, Liang Y, Mason CE, de Stanchina E, Abida W, Lujambio A, Li S, Lowe SW, Mendell JT, Malladi VS, Sawyers CL, and Mu P
- Subjects
- Animals, Apoptosis, Biomarkers, Tumor genetics, Cell Proliferation, Chromatin metabolism, DNA Helicases genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Gene Expression Regulation, Neoplastic, High-Throughput Screening Assays, Humans, Male, Mice, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology, Receptors, Androgen genetics, Transcription Factors metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Androgen Antagonists pharmacology, Chromatin genetics, DNA Helicases antagonists & inhibitors, DNA-Binding Proteins antagonists & inhibitors, Drug Resistance, Neoplasm genetics, Prostatic Neoplasms, Castration-Resistant drug therapy, RNA, Small Interfering genetics, Receptors, Androgen chemistry
- Abstract
Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms., Competing Interests: Declaration of Interests C.L.S. and J.W. are co-inventors of enzalutamide and apalutamide and may be entitled to royalties. C.L.S. serves on the Board of Directors of Novartis and is a co-founder of ORIC Pharm. He is a science advisor to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra, and PMV. He was a co-founder of Seragon, purchased by Genentech/Roche in 2014. S.W.L. is a founder and member of the scientific advisory board of ORIC Pharmaceuticals, Blueprint Medicines, and Mirimus, Inc.; he is also on the scientific advisory board of PMV Pharmaceuticals, Constellation Pharmaceuticals, and Petra Pharmaceuticals. W.A. reports consulting for Clovis Oncology, Janssen, MORE Health, and ORIC Pharmaceuticals. He received honoraria from CARET and travel accommodations from GlaxoSmith Kline, Clovis Oncology, and ORIC Pharmaceuticals. C.E.M is a co-founder and board member for Biotia and Onegevity Health, as well as an advisor for Genpro and Karius., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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5. GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance.
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Lee E, Wongvipat J, Choi D, Wang P, Lee YS, Zheng D, Watson PA, Gopalan A, and Sawyers CL
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- Benzamides, Cell Line, Tumor, Chromatin metabolism, DNA, Neoplasm metabolism, Humans, Male, Nitriles, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin pharmacology, Prostatic Neoplasms genetics, Protein Binding drug effects, Transcription, Genetic drug effects, Androgen Antagonists pharmacology, Drug Resistance, Neoplasm drug effects, Neoplasm Proteins metabolism, Prostatic Neoplasms metabolism, Receptors, Androgen metabolism
- Abstract
Genomic amplification of the androgen receptor ( AR ) is an established mechanism of antiandrogen resistance in prostate cancer. Here, we show that the magnitude of AR signaling output, independent of AR genomic alteration or expression level, also contributes to antiandrogen resistance, through upregulation of the coactivator GREB1 . We demonstrate 100-fold heterogeneity in AR output within human prostate cancer cell lines and show that cells with high AR output have reduced sensitivity to enzalutamide. Through transcriptomic and shRNA knockdown studies, together with analysis of clinical datasets, we identify GREB1 as a gene responsible for high AR output. We show that GREB1 is an AR target gene that amplifies AR output by enhancing AR DNA binding and promoting EP300 recruitment. GREB1 knockdown in high AR output cells restores enzalutamide sensitivity in vivo . Thus, GREB1 is a candidate driver of enzalutamide resistance through a novel feed forward mechanism., Competing Interests: EL, DC, PW, YL, DZ, PW, AG No competing interests declared, JW co-inventor of enzalutamide, CS Senior Editor eLife; Board of Directors of Novartis; co-founder of ORIC Pharm; co-inventor of enzalutamide and apalutamide; Science advisor to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra and PMV; co-founder of Seragon, purchased by Genentech/Roche in 2014., (© 2019, Lee et al.)
- Published
- 2019
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6. COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors.
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Xie Y, Cao Z, Wong EW, Guan Y, Ma W, Zhang JQ, Walczak EG, Murphy D, Ran L, Sirota I, Wang S, Shukla S, Gao D, Knott SR, Chang K, Leu J, Wongvipat J, Antonescu CR, Hannon G, Chi P, and Chen Y
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- Adenovirus E1A Proteins genetics, Adenovirus E1A Proteins metabolism, Animals, Carrier Proteins genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Extracellular Signal-Regulated MAP Kinases genetics, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, MAP Kinase Signaling System genetics, Melanoma drug therapy, Melanoma genetics, Melanoma pathology, Mice, Mice, SCID, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-ets genetics, Transcription Factors genetics, Transcription Factors metabolism, Transcriptome genetics, Ubiquitin-Protein Ligases genetics, Xenograft Model Antitumor Assays, Carrier Proteins metabolism, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, MAP Kinase Signaling System drug effects, Melanoma metabolism, Mutation, Proto-Oncogene Proteins c-ets metabolism, Transcriptome drug effects, Ubiquitin-Protein Ligases metabolism, Vemurafenib pharmacology
- Abstract
Aberrant activation of MAPK signaling leads to the activation of oncogenic transcriptomes. How MAPK signaling is coupled with the transcriptional response in cancer is not fully understood. In 2 MAPK-activated tumor types, gastrointestinal stromal tumor and melanoma, we found that ETV1 and other Pea3-ETS transcription factors are critical nuclear effectors of MAPK signaling that are regulated through protein stability. Expression of stabilized Pea3-ETS factors can partially rescue the MAPK transcriptome and cell viability after MAPK inhibition. To identify the players involved in this process, we performed a pooled genome-wide RNAi screen using a fluorescence-based ETV1 protein stability sensor and identified COP1, DET1, DDB1, UBE3C, PSMD4, and COP9 signalosome members. COP1 or DET1 loss led to decoupling between MAPK signaling and the downstream transcriptional response, where MAPK inhibition failed to destabilize Pea3 factors and fully inhibit the MAPK transcriptome, thus resulting in decreased sensitivity to MAPK pathway inhibitors. We identified multiple COP1 and DET1 mutations in human tumors that were defective in the degradation of Pea3-ETS factors. Two melanoma patients had de novo DET1 mutations arising after vemurafenib treatment. These observations indicate that MAPK signaling-dependent regulation of Pea3-ETS protein stability is a key signaling node in oncogenesis and therapeutic resistance to MAPK pathway inhibition.
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- 2018
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7. Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance.
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Shukla S, Cyrta J, Murphy DA, Walczak EG, Ran L, Agrawal P, Xie Y, Chen Y, Wang S, Zhan Y, Li D, Wong EWP, Sboner A, Beltran H, Mosquera JM, Sher J, Cao Z, Wongvipat J, Koche RP, Gopalan A, Zheng D, Rubin MA, Scher HI, Chi P, and Chen Y
- Subjects
- Animals, Heterografts, Humans, Male, Mice, Mice, SCID, Prostatic Neoplasms, Castration-Resistant pathology, Trypsin Inhibitor, Kazal Pancreatic biosynthesis, Drug Resistance, Neoplasm physiology, Gene Expression Regulation, Neoplastic physiology, Hepatocyte Nuclear Factor 1-alpha metabolism, Hepatocyte Nuclear Factor 4 metabolism, Prostatic Neoplasms, Castration-Resistant metabolism
- Abstract
Prostate cancer exhibits a lineage-specific dependence on androgen signaling. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. We describe an aberrant gastrointestinal-lineage transcriptome expressed in ∼5% of primary prostate cancer that is characterized by abbreviated response to androgen-deprivation therapy and in ∼30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A. Cistrome and chromatin analyses revealed that HNF4G is a pioneer factor that generates and maintains enhancer landscape at gastrointestinal-lineage genes, independent of androgen-receptor signaling. In HNF4G/HNF1A-double-negative prostate cancer, exogenous expression of HNF4G at physiologic levels recapitulates the gastrointestinal transcriptome, chromatin landscape, and leads to relative castration resistance., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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8. Deletion of 3p13-14 locus spanning FOXP1 to SHQ1 cooperates with PTEN loss in prostate oncogenesis.
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Hieronymus H, Iaquinta PJ, Wongvipat J, Gopalan A, Murali R, Mao N, Carver BS, and Sawyers CL
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- Animals, Carrier Proteins genetics, Forkhead Transcription Factors genetics, Humans, Male, Mechanistic Target of Rapamycin Complex 1 genetics, Mechanistic Target of Rapamycin Complex 1 metabolism, Mice, PTEN Phosphohydrolase genetics, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Prostate metabolism, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Repressor Proteins genetics, Carrier Proteins metabolism, Forkhead Transcription Factors metabolism, PTEN Phosphohydrolase metabolism, Repressor Proteins metabolism
- Abstract
A multigenic locus at 3p13-14, spanning FOXP1 to SHQ1, is commonly deleted in prostate cancer and lost broadly in a range of cancers but has unknown significance to oncogenesis or prognosis. Here, we report that FOXP1-SHQ1 deletion cooperates with PTEN loss to accelerate prostate oncogenesis and that loss of component genes correlates with prostate, breast, and head and neck cancer recurrence. We demonstrate that Foxp1-Shq1 deletion accelerates prostate tumorigenesis in mice in combination with Pten loss, consistent with the association of FOXP1-SHQ1 and PTEN loss observed in human cancers. Tumors with combined Foxp1-Shq1 and Pten deletion show increased proliferation and anaplastic dedifferentiation, as well as mTORC1 hyperactivation with reduced Akt phosphorylation. Foxp1-Shq1 deletion restores expression of AR target genes repressed in tumors with Pten loss, circumventing PI3K-mediated repression of the androgen axis. Moreover, FOXP1-SHQ1 deletion has prognostic relevance, with cancer recurrence associated with combined loss of PTEN and FOXP1-SHQ1 genes.
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- 2017
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9. Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer.
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Shah N, Wang P, Wongvipat J, Karthaus WR, Abida W, Armenia J, Rockowitz S, Drier Y, Bernstein BE, Long HW, Freedman ML, Arora VK, Zheng D, and Sawyers CL
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- Animals, Azepines, Benzamides, Cell Line, Tumor, Chromatin Immunoprecipitation methods, Clustered Regularly Interspaced Short Palindromic Repeats, Drug Resistance, Neoplasm drug effects, Heterografts, Humans, Male, Metabolism, Inborn Errors metabolism, Mice, Nitriles, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin pharmacology, Receptors, Androgen metabolism, Receptors, Glucocorticoid deficiency, Sequence Analysis, Signal Transduction drug effects, Triazoles, Androgen Antagonists pharmacology, Drug Resistance, Neoplasm physiology, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms pathology, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism
- Abstract
In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.
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- 2017
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10. ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis.
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Bose R, Karthaus WR, Armenia J, Abida W, Iaquinta PJ, Zhang Z, Wongvipat J, Wasmuth EV, Shah N, Sullivan PS, Doran MG, Wang P, Patruno A, Zhao Y, Zheng D, Schultz N, and Sawyers CL
- Subjects
- Androgens metabolism, Animals, Cell Line, Tumor, Genes genetics, Humans, Male, Mice, Prostate metabolism, Protein Stability, Receptors, Androgen metabolism, Repressor Proteins deficiency, Repressor Proteins metabolism, Serine Endopeptidases deficiency, Serine Endopeptidases metabolism, Signal Transduction, Transcriptional Regulator ERG deficiency, Transcriptional Regulator ERG metabolism, Transcriptome genetics, Tumor Suppressor Proteins metabolism, Up-Regulation, Carcinogenesis genetics, Mutation, Prostate pathology, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Proto-Oncogene Proteins c-ets metabolism, Repressor Proteins genetics
- Abstract
Half of all prostate cancers are caused by the TMPRSS2-ERG gene-fusion, which enables androgens to drive expression of the normally silent E26 transformation-specific (ETS) transcription factor ERG in prostate cells. Recent genomic landscape studies of such cancers have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF. Here we show these ERF mutations cause decreased protein stability and mostly occur in tumours without ERG upregulation. ERF loss recapitulates the morphological and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor transcriptional repertoire, and ERF has tumour suppressor activity in the same genetic background of Pten loss that yields oncogenic activity by ERG. In the more common scenario of ERG upregulation, chromatin immunoprecipitation followed by sequencing indicates that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites both in normal and in cancerous prostate cells. Consistent with a competition model, ERF overexpression blocks ERG-dependent tumour growth, and ERF loss rescues TMPRSS2-ERG-positive prostate cancer cells from ERG dependency. Collectively, these data provide evidence that the oncogenicity of ERG is mediated, in part, by competition with ERF and they raise the larger question of whether other gain-of-function oncogenic transcription factors might also inactivate endogenous tumour suppressors.
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- 2017
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11. Androgen Receptor Upregulation Mediates Radioresistance after Ionizing Radiation.
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Spratt DE, Evans MJ, Davis BJ, Doran MG, Lee MX, Shah N, Wongvipat J, Carnazza KE, Klee GG, Polkinghorn W, Tindall DJ, Lewis JS, and Sawyers CL
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- Animals, Blotting, Western, Cell Line, Tumor, Comet Assay, Fluorescent Antibody Technique, Humans, Luminescent Measurements, Male, Mice, Mice, SCID, Prostatic Neoplasms metabolism, Real-Time Polymerase Chain Reaction, Up-Regulation, Xenograft Model Antitumor Assays, Prostatic Neoplasms radiotherapy, Radiation Tolerance physiology, Receptors, Androgen biosynthesis
- Abstract
Clinical trials have established the benefit of androgen deprivation therapy (ADT) combined with radiotherapy in prostate cancer. ADT sensitizes prostate cancer to radiotherapy-induced death at least in part through inhibition of DNA repair machinery, but for unknown reasons, adjuvant ADT provides further survival benefits. Here, we show that androgen receptor (AR) expression and activity are durably upregulated following radiotherapy in multiple human prostate cancer models in vitro and in vivo. Moreover, the degree of AR upregulation correlates with survival in vitro and time to tumor progression in animal models. We also provide evidence of AR pathway upregulation, measured by a rise in serum levels of AR-regulated hK2 protein, in nearly 20% of patients after radiotherapy. Furthermore, these men were three-fold more likely to experience subsequent biochemical failure. Collectively, these data demonstrate that radiotherapy can upregulate AR signaling after therapy to an extent that negatively affects disease progression and/or survival., (©2015 American Association for Cancer Research.)
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- 2015
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12. Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ.
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Schwartz S, Wongvipat J, Trigwell CB, Hancox U, Carver BS, Rodrik-Outmezguine V, Will M, Yellen P, de Stanchina E, Baselga J, Scher HI, Barry ST, Sawyers CL, Chandarlapaty S, and Rosen N
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Cycle drug effects, Cell Line, Tumor, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Neoplasm Transplantation, Neoplasms genetics, Neoplasms pathology, Signal Transduction drug effects, Aniline Compounds pharmacology, Chromones pharmacology, Neoplasms drug therapy, PTEN Phosphohydrolase genetics, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors pharmacology, Thiazoles pharmacology
- Abstract
In PTEN-mutated tumors, we show that PI3Kα activity is suppressed and PI3K signaling is driven by PI3Kβ. A selective inhibitor of PI3Kβ inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3Kβ only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3Kα and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3Kα and PI3Kβ. In PTEN-deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions., (Copyright © 2015 Elsevier Inc. All rights reserved.)
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- 2015
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13. Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling.
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Wanjala J, Taylor BS, Chapinski C, Hieronymus H, Wongvipat J, Chen Y, Nanjangud GJ, Schultz N, Xie Y, Liu S, Lu W, Yang Q, Sander C, Chen Z, Sawyers CL, and Carver BS
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- Animals, Cell Line, Tumor, Cell Proliferation drug effects, DNA Copy Number Variations, Gene Amplification, Gene Expression Profiling, Genetic Heterogeneity, Genome, Humans, MAP Kinase Signaling System, Male, Mice, Mice, Transgenic, Neoplasms, Experimental, Protein Kinase Inhibitors pharmacology, PTEN Phosphohydrolase genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Proto-Oncogene Proteins c-met genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Copy-number alterations (CNA) are among the most common molecular events in human prostate cancer genomes and are associated with worse prognosis. Identification of the oncogenic drivers within these CNAs is challenging due to the broad nature of these genomic gains or losses which can include large numbers of genes within a given region. Here, we profiled the genomes of four genetically engineered mouse prostate cancer models that reflect oncogenic events common in human prostate tumors, with the goal of integrating these data with human prostate cancer datasets to identify shared molecular events. Met was amplified in 67% of prostate tumors from Pten p53 prostate conditional null mice and in approximately 30% of metastatic human prostate cancer specimens, often in association with loss of PTEN and TP53. In murine tumors with Met amplification, Met copy-number gain and expression was present in some cells but not others, revealing intratumoral heterogeneity. Forced MET overexpression in non-MET-amplified prostate tumor cells activated PI3K and MAPK signaling and promoted cell proliferation and tumor growth, whereas MET kinase inhibition selectively impaired the growth of tumors with Met amplification. However, the impact of MET inhibitor therapy was compromised by the persistent growth of non-Met-amplified cells within Met-amplified tumors. These findings establish the importance of MET in prostate cancer progression but reveal potential limitations in the clinical use of MET inhibitors in late-stage prostate cancer., (©2014 American Association for Cancer Research.)
- Published
- 2015
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14. Annotating STEAP1 regulation in prostate cancer with 89Zr immuno-PET.
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Doran MG, Watson PA, Cheal SM, Spratt DE, Wongvipat J, Steckler JM, Carrasquillo JA, Evans MJ, and Lewis JS
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- Animals, Antigens, Neoplasm genetics, Antigens, Neoplasm physiology, Cell Line, Tumor, Cell Proliferation drug effects, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Mice, Oxidoreductases genetics, Oxidoreductases physiology, Positron-Emission Tomography, Radioisotopes, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals pharmacokinetics, Tissue Distribution, Zirconium, Antigens, Neoplasm biosynthesis, Immunoconjugates cerebrospinal fluid, Immunoconjugates pharmacokinetics, Oxidoreductases biosynthesis, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms metabolism
- Abstract
Unlabelled: Antibodies and antibody-drug conjugates targeting the cell surface protein 6 transmembrane epithelial antigen of prostate 1 (STEAP1) are in early clinical development for the treatment of castration-resistant prostate cancer (PCa). In general, antigen expression directly affects the bioactivity of therapeutic antibodies, and the biologic regulation of STEAP1 is unusually complicated in PCa. Paradoxically, STEAP1 can be induced or repressed by the androgen receptor (AR) in different human PCa models, while also expressed in AR-null PCa. Consequently, there is an urgent need to translate diagnostic strategies to establish which regulatory mechanism predominates in patients to situate the appropriate therapy within standard of care therapies inhibiting AR., Methods: To this end, we prepared and evaluated (89)Zr-labeled MSTP2109A ((89)Zr-2109A), a radiotracer for PET derived from a fully humanized monoclonal antibody to STEAP1 in preclinical PCa models., Results: (89)Zr-2109A specifically localized to the STEAP1-positive human PCa models CWR22Pc, 22Rv1, and PC3. Moreover, (89)Zr-2109A sensitively measured treatment-induced changes (∼66% decline) in STEAP1 expression in CWR22PC in vitro and in vivo, a model we showed to express STEAP1 in an AR-dependent manner., Conclusion: These findings highlight the ability of immuno-PET with (89)Zr-2109A to detect acute changes in STEAP1 expression and argue for an expansion of ongoing efforts to image PCa patients with (89)Zr-2109A to maximize the clinical benefit associated with antibodies or antibody-drug conjugates to STEAP1., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)
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- 2014
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15. MAGI-2 scaffold protein is critical for kidney barrier function.
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Balbas MD, Burgess MR, Murali R, Wongvipat J, Skaggs BJ, Mundel P, Weins A, and Sawyers CL
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- Animals, Cell Proliferation, Epithelial Cells metabolism, Epithelial Cells pathology, Immunohistochemistry, Inflammation pathology, Kidney metabolism, Kidney Glomerulus blood supply, Kidney Glomerulus metabolism, Kidney Glomerulus pathology, Kidney Glomerulus ultrastructure, Membrane Proteins metabolism, Mice, Knockout, Neoplasm Proteins metabolism, Nerve Tissue Proteins metabolism, Podocytes metabolism, Podocytes pathology, Proteinuria metabolism, Proteinuria pathology, Survival Analysis, Up-Regulation, Adaptor Proteins, Signal Transducing metabolism, Guanylate Kinases metabolism, Kidney pathology
- Abstract
MAGUK Inverted 2 (MAGI-2) is a PTEN-interacting scaffold protein implicated in cancer on the basis of rare, recurrent genomic translocations and deletions in various tumors. In the renal glomerulus, MAGI-2 is exclusively expressed in podocytes, specialized cells forming part of the glomerular filter, where it interacts with the slit diaphragm protein nephrin. To further explore MAGI-2 function, we generated Magi-2-KO mice through homologous recombination by targeting an exon common to all three alternative splice variants. Magi-2 null mice presented with progressive proteinuria as early as 2 wk postnatally, which coincided with loss of nephrin expression in the glomeruli. Magi-2-null kidneys revealed diffuse podocyte foot process effacement and focal podocyte hypertrophy by 3 wk of age, as well as progressive podocyte loss. By 5.5 wk, coinciding with a near-complete loss of podocytes, Magi-2-null mice developed diffuse glomerular extracapillary epithelial cell proliferations, and died of renal failure by 3 mo of age. As confirmed by immunohistochemical analysis, the proliferative cell populations in glomerular lesions were exclusively composed of activated parietal epithelial cells (PECs). Our results reveal that MAGI-2 is required for the integrity of the kidney filter and podocyte survival. Moreover, we demonstrate that PECs can be activated to form glomerular lesions resembling a noninflammatory glomerulopathy with extensive extracapillary proliferation, sometimes resembling crescents, following rapid and severe podocyte loss.
- Published
- 2014
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16. Identification of multipotent luminal progenitor cells in human prostate organoid cultures.
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Karthaus WR, Iaquinta PJ, Drost J, Gracanin A, van Boxtel R, Wongvipat J, Dowling CM, Gao D, Begthel H, Sachs N, Vries RGJ, Cuppen E, Chen Y, Sawyers CL, and Clevers HC
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- Androgens metabolism, Humans, Male, Stem Cells cytology, Stem Cells metabolism, Organ Culture Techniques, Organoids, Prostate cytology
- Abstract
The prostate gland consists of basal and luminal cells arranged as pseudostratified epithelium. In tissue recombination models, only basal cells reconstitute a complete prostate gland, yet murine lineage-tracing experiments show that luminal cells generate basal cells. It has remained challenging to address the molecular details of these transitions and whether they apply to humans, due to the lack of culture conditions that recapitulate prostate gland architecture. Here, we describe a 3D culture system that supports long-term expansion of primary mouse and human prostate organoids, composed of fully differentiated CK5+ basal and CK8+ luminal cells. Organoids are genetically stable, reconstitute prostate glands in recombination assays, and can be experimentally manipulated. Single human luminal and basal cells give rise to organoids, yet luminal-cell-derived organoids more closely resemble prostate glands. These data support a luminal multilineage progenitor cell model for prostate tissue and establish a robust, scalable system for mechanistic studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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17. Organoid cultures derived from patients with advanced prostate cancer.
- Author
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Gao D, Vela I, Sboner A, Iaquinta PJ, Karthaus WR, Gopalan A, Dowling C, Wanjala JN, Undvall EA, Arora VK, Wongvipat J, Kossai M, Ramazanoglu S, Barboza LP, Di W, Cao Z, Zhang QF, Sirota I, Ran L, MacDonald TY, Beltran H, Mosquera JM, Touijer KA, Scardino PT, Laudone VP, Curtis KR, Rathkopf DE, Morris MJ, Danila DC, Slovin SF, Solomon SB, Eastham JA, Chi P, Carver B, Rubin MA, Scher HI, Clevers H, Sawyers CL, and Chen Y
- Subjects
- Heterografts, Humans, Male, Neoplasm Metastasis pathology, Pharmacology methods, Tumor Suppressor Proteins metabolism, Culture Techniques, Organoids pathology, Prostatic Neoplasms pathology
- Abstract
The lack of in vitro prostate cancer models that recapitulate the diversity of human prostate cancer has hampered progress in understanding disease pathogenesis and therapy response. Using a 3D organoid system, we report success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells. The first seven fully characterized organoid lines recapitulate the molecular diversity of prostate cancer subtypes, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss. Whole-exome sequencing shows a low mutational burden, consistent with genomics studies, but with mutations in FOXA1 and PIK3R1, as well as in DNA repair and chromatin modifier pathways that have been reported in advanced disease. Loss of p53 and RB tumor suppressor pathway function are the most common feature shared across the organoid lines. The methodology described here should enable the generation of a large repertoire of patient-derived prostate cancer lines amenable to genetic and pharmacologic studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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18. Cabozantinib resolves bone scans in tumor-naïve mice harboring skeletal injuries.
- Author
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Doran MG, Spratt DE, Wongvipat J, Ulmert D, Carver BS, Sawyers CL, and Evans MJ
- Subjects
- Anilides therapeutic use, Animals, Axitinib, Crizotinib, Fluorine Radioisotopes pharmacokinetics, Imidazoles administration & dosage, Imidazoles therapeutic use, Indazoles administration & dosage, Indazoles therapeutic use, Mice, Positron-Emission Tomography methods, Protein Kinase Inhibitors therapeutic use, Pyrazoles administration & dosage, Pyrazoles therapeutic use, Pyridines therapeutic use, Technetium Tc 99m Medronate pharmacokinetics, Tomography, Emission-Computed, Single-Photon methods, Anilides administration & dosage, Bone Regeneration drug effects, Fractures, Bone diagnostic imaging, Fractures, Bone drug therapy, Protein Kinase Inhibitors administration & dosage, Pyridines administration & dosage, Radiopharmaceuticals pharmacokinetics
- Abstract
The receptor tyrosine kinase inhibitor cabozantinib (XL184, BMS-907351 Cometriq) has displayed impressive clinical activity against several indications, culminating in its recent approval for medullary thyroid cancer. Among malignancies with tropism for the bone (prostate, breast), one striking feature of early clinical reports about this drug has been the rapid and complete resolution of bone scans, a phenomenon almost never observed even among therapies already shown to confer survival benefit. In castration-resistant prostate cancer, not all conventional response indicators change as dramatically posttreatment, raising the possibility that cabozantinib may impair the ability of bone-seeking radionuclides to integrate within the remodeling bone. To test this hypothesis, we surgically induced bone remodeling via physical insult in non-tumor-bearing mice and performed 18F-sodium fluoride (18F-NaF) positron emission tomographic (PET) and technetium 99m-methylene diphosphonate (99mTc-MDP) single-photon emission computed tomographic (SPECT) scans pre- and posttreatment with cabozantinib and related inhibitors. A consistent reduction in the accumulation of either radiotracer at the site of bone remodeling was observed in animals treated with cabozantinib. Given that cabozantinib is known to inhibit several receptor tyrosine kinases, we drugged animals with various permutations of more selective inhibitors to attempt to refine the molecular basis of bone scan resolution. Neither the vascular endothelial growth factor receptor (VEGFR) inhibitor axitinib, the MET inhibitor crizotinib, nor the combination was capable of inhibiting 18F-NaF accumulation at known bioactive doses. In summary, although the mechanism by which cabozantinib suppresses radionuclide incorporation into foci undergoing bone remodeling remains unknown, that this phenomenon occurs in tumor-naïve models indicates that caution should be exercised in interpreting the clinical significance of this event.
- Published
- 2014
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19. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade.
- Author
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Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, Shah N, Cai L, Efstathiou E, Logothetis C, Zheng D, and Sawyers CL
- Subjects
- Animals, Benzamides, Disease Models, Animal, Gene Expression Regulation, Heterografts, Humans, Male, Mice, Neoplasm Transplantation, Nitriles, Phenylthiohydantoin therapeutic use, Receptors, Androgen metabolism, Transcriptome, Androgen Antagonists therapeutic use, Androgen Receptor Antagonists therapeutic use, Drug Resistance, Neoplasm, Phenylthiohydantoin analogs & derivatives, Prostatic Neoplasms drug therapy, Receptors, Glucocorticoid metabolism
- Abstract
The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here, we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug-resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance, whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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20. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss.
- Author
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Chen Y, Chi P, Rockowitz S, Iaquinta PJ, Shamu T, Shukla S, Gao D, Sirota I, Carver BS, Wongvipat J, Scher HI, Zheng D, and Sawyers CL
- Subjects
- Animals, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Chromatin Immunoprecipitation, DNA-Binding Proteins metabolism, Disease Models, Animal, Histones metabolism, Humans, Lysine metabolism, Male, Mice, Oncogene Proteins metabolism, PTEN Phosphohydrolase metabolism, Phenotype, Principal Component Analysis, Prostate metabolism, Prostate pathology, Prostatic Neoplasms genetics, Signal Transduction genetics, Transcription Factors metabolism, Transcriptional Regulator ERG, Transcriptome genetics, Cell Transformation, Neoplastic pathology, Genes genetics, PTEN Phosphohydrolase deficiency, Prostatic Neoplasms pathology, Proto-Oncogene Proteins c-ets metabolism, Receptors, Androgen genetics, Receptors, Androgen metabolism
- Abstract
Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN-deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.
- Published
- 2013
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21. Overcoming mutation-based resistance to antiandrogens with rational drug design.
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Balbas MD, Evans MJ, Hosfield DJ, Wongvipat J, Arora VK, Watson PA, Chen Y, Greene GL, Shen Y, and Sawyers CL
- Subjects
- Androgen Antagonists chemistry, Cell Line, Drug Resistance, Neoplasm genetics, Humans, Male, Molecular Dynamics Simulation, Prostatic Neoplasms drug therapy, Androgen Antagonists therapeutic use, Drug Design, Mutation
- Abstract
The second-generation antiandrogen enzalutamide was recently approved for patients with castration-resistant prostate cancer. Despite its success, the duration of response is often limited. For previous antiandrogens, one mechanism of resistance is mutation of the androgen receptor (AR). To prospectively identify AR mutations that might confer resistance to enzalutamide, we performed a reporter-based mutagenesis screen and identified a novel mutation, F876L, which converted enzalutamide into an AR agonist. Ectopic expression of AR F876L rescued the growth inhibition of enzalutamide treatment. Molecular dynamics simulations performed on antiandrogen-AR complexes suggested a mechanism by which the F876L substitution alleviates antagonism through repositioning of the coactivator recruiting helix 12. This model then provided the rationale for a focused chemical screen which, based on existing antiandrogen scaffolds, identified three novel compounds that effectively antagonized AR F876L (and AR WT) to suppress the growth of prostate cancer cells resistant to enzalutamide. DOI:http://dx.doi.org/10.7554/eLife.00499.001.
- Published
- 2013
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22. Annotating MYC status with 89Zr-transferrin imaging.
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Holland JP, Evans MJ, Rice SL, Wongvipat J, Sawyers CL, and Lewis JS
- Subjects
- Animals, Deferoxamine, Male, Mice, Mice, Transgenic, Radioisotopes, Radiopharmaceuticals, Receptors, Transferrin metabolism, Transplantation, Heterologous, Positron-Emission Tomography methods, Prostatic Intraepithelial Neoplasia diagnostic imaging, Prostatic Neoplasms diagnostic imaging, Proto-Oncogene Proteins c-myc metabolism, Transferrin, Zirconium
- Abstract
A noninvasive technology that quantitatively measures the activity of oncogenic signaling pathways could have a broad impact on cancer diagnosis and treatment with targeted therapies. Here we describe the development of (89)Zr-desferrioxamine-labeled transferrin ((89)Zr-transferrin), a new positron emission tomography (PET) radiotracer that binds the transferrin receptor 1 (TFRC, CD71) with high avidity. The use of (89)Zr-transferrin produces high-contrast PET images that quantitatively reflect treatment-induced changes in MYC-regulated TFRC expression in a MYC-driven prostate cancer xenograft model. Moreover, (89)Zr-transferrin imaging can detect the in situ development of prostate cancer in a transgenic MYC prostate cancer model, as well as in prostatic intraepithelial neoplasia (PIN) before histological or anatomic evidence of invasive cancer. These preclinical data establish (89)Zr-transferrin as a sensitive tool for noninvasive measurement of oncogene-driven TFRC expression in prostate and potentially other cancers, with prospective near-term clinical application.
- Published
- 2012
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23. ARN-509: a novel antiandrogen for prostate cancer treatment.
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Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher HI, Smith-Jones P, Klang M, Smith ND, De Stanchina E, Wu N, Ouerfelli O, Rix PJ, Heyman RA, Jung ME, Sawyers CL, and Hager JH
- Subjects
- Androgen Antagonists pharmacokinetics, Anilides pharmacokinetics, Anilides therapeutic use, Animals, Antineoplastic Agents, Hormonal blood, Antineoplastic Agents, Hormonal pharmacokinetics, Benzamides, Cell Line, Tumor, Cell Proliferation drug effects, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Mice, Nitriles pharmacokinetics, Nitriles therapeutic use, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin blood, Phenylthiohydantoin pharmacokinetics, Phenylthiohydantoin therapeutic use, Rats, Receptors, Androgen drug effects, Thiohydantoins blood, Thiohydantoins chemical synthesis, Thiohydantoins pharmacokinetics, Tosyl Compounds pharmacokinetics, Tosyl Compounds therapeutic use, Xenograft Model Antitumor Assays, Androgen Antagonists therapeutic use, Antineoplastic Agents, Hormonal therapeutic use, Prostatic Neoplasms drug therapy, Thiohydantoins therapeutic use
- Abstract
Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.
- Published
- 2012
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24. Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen.
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Evans MJ, Smith-Jones PM, Wongvipat J, Navarro V, Kim S, Bander NH, Larson SM, and Sawyers CL
- Subjects
- Androgen Antagonists pharmacology, Androgens pharmacology, Animals, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacokinetics, Antigens, Surface immunology, Antigens, Surface metabolism, Benzamides, Cell Line, Tumor, Copper Radioisotopes pharmacokinetics, Dihydrotestosterone pharmacology, Gene Expression Regulation, Neoplastic drug effects, Glutamate Carboxypeptidase II immunology, Glutamate Carboxypeptidase II metabolism, Heterocyclic Compounds, 1-Ring chemistry, Humans, Immunoblotting, Male, Mice, Mice, SCID, Neoplasms, Experimental genetics, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Nitriles, Orchiectomy, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin pharmacology, Prostate-Specific Antigen genetics, Prostate-Specific Antigen metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Radiopharmaceuticals immunology, Radiopharmaceuticals pharmacokinetics, Receptors, Androgen metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Transplantation, Heterologous, Antigens, Surface genetics, Glutamate Carboxypeptidase II genetics, Positron-Emission Tomography methods, Prostatic Neoplasms genetics, Receptors, Androgen genetics, Signal Transduction genetics
- Abstract
Despite encouraging clinical results with next generation drugs (MDV3100 and abiraterone) that inhibit androgen receptor (AR) signaling in patients with castration-resistant prostate cancer (CRPC), responses are variable and short-lived. There is an urgent need to understand the basis of resistance to optimize their future use. We reasoned that a radiopharmaceutical that measures intratumoral changes in AR signaling could substantially improve our understanding of AR pathway directed therapies. Expanding on previous observations, we first show that prostate-specific membrane antigen (PSMA) is repressed by androgen treatment in multiple models of AR-positive prostate cancer in an AR-dependent manner. Conversely, antiandrogens up-regulate PSMA expression. These expression changes, including increased PSMA expression in response to treatment with the antiandrogen MDV3100, can be quantitatively measured in vivo in human prostate cancer xenograft models through PET imaging with a fully humanized, radiolabeled antibody to PSMA, (64)Cu-J591. Collectively, these results establish that relative changes in PSMA expression levels can be quantitatively measured using a human-ready imaging reagent and could serve as a biomarker of AR signaling to noninvasively evaluate AR activity in patients with CRPC.
- Published
- 2011
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25. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.
- Author
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Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, Arora VK, Le C, Koutcher J, Scher H, Scardino PT, Rosen N, and Sawyers CL
- Subjects
- Androgen Antagonists pharmacology, Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Feedback, Physiological, Gene Expression Regulation, Neoplastic, Genes, Reporter, Humans, Magnetic Resonance Imaging, Male, Mice, Mice, Knockout, Mice, SCID, Mice, Transgenic, Nuclear Proteins metabolism, PTEN Phosphohydrolase genetics, Phosphoinositide-3 Kinase Inhibitors, Phosphoprotein Phosphatases metabolism, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, RNA Interference, Receptor, ErbB-2 antagonists & inhibitors, Receptor, ErbB-2 metabolism, Receptor, ErbB-3 antagonists & inhibitors, Receptor, ErbB-3 metabolism, Receptors, Androgen drug effects, Time Factors, Transcription, Genetic, Transfection, Tumor Burden drug effects, Xenograft Model Antitumor Assays, PTEN Phosphohydrolase deficiency, Phosphatidylinositol 3-Kinase metabolism, Prostatic Neoplasms enzymology, Receptors, Androgen metabolism, Signal Transduction drug effects
- Abstract
Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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26. MYC cooperates with AKT in prostate tumorigenesis and alters sensitivity to mTOR inhibitors.
- Author
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Clegg NJ, Couto SS, Wongvipat J, Hieronymus H, Carver BS, Taylor BS, Ellwood-Yen K, Gerald WL, Sander C, and Sawyers CL
- Subjects
- Animals, Apoptosis drug effects, Disease Models, Animal, Disease Progression, Enzyme Activation drug effects, Humans, Male, Mice, Mice, Transgenic, Neoplasm Invasiveness, Phenotype, Precancerous Conditions pathology, Prostate drug effects, Prostate pathology, Prostatic Intraepithelial Neoplasia enzymology, Prostatic Intraepithelial Neoplasia pathology, Prostatic Neoplasms pathology, Protein Binding drug effects, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Signal Transduction drug effects, TOR Serine-Threonine Kinases metabolism, Precancerous Conditions enzymology, Prostatic Neoplasms enzymology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-myc metabolism, TOR Serine-Threonine Kinases antagonists & inhibitors
- Abstract
MYC and phosphoinositide 3-kinase (PI3K)-pathway deregulation are common in human prostate cancer. Through examination of 194 human prostate tumors, we observed statistically significant co-occurrence of MYC amplification and PI3K-pathway alteration, raising the possibility that these two lesions cooperate in prostate cancer progression. To investigate this, we generated bigenic mice in which both activated human AKT1 and human MYC are expressed in the prostate (MPAKT/Hi-MYC model). In contrast to mice expressing AKT1 alone (MPAKT model) or MYC alone (Hi-MYC model), the bigenic phenotype demonstrates accelerated progression of mouse prostate intraepithelial neoplasia (mPIN) to microinvasive disease with disruption of basement membrane, significant stromal remodeling and infiltration of macrophages, B- and T-lymphocytes, similar to inflammation observed in human prostate tumors. In contrast to the reversibility of mPIN lesions in young MPAKT mice after treatment with mTOR inhibitors, Hi-MYC and bigenic MPAKT/Hi-MYC mice were resistant. Additionally, older MPAKT mice showed reduced sensitivity to mTOR inhibition, suggesting that additional genetic events may dampen mTOR dependence. Since increased MYC expression is an early feature of many human prostate cancers, these data have implications for treatment of human prostate cancers with PI3K-pathway alterations using mTOR inhibitors.
- Published
- 2011
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27. ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours.
- Author
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Chi P, Chen Y, Zhang L, Guo X, Wongvipat J, Shamu T, Fletcher JA, Dewell S, Maki RG, Zheng D, Antonescu CR, Allis CD, and Sawyers CL
- Subjects
- Animals, Benzamides, Binding Sites, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Line, Tumor, Cell Survival drug effects, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins genetics, Disease Progression, Enhancer Elements, Genetic genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic genetics, Humans, Imatinib Mesylate, Interstitial Cells of Cajal metabolism, Interstitial Cells of Cajal pathology, Mice, Mutant Proteins genetics, Mutant Proteins metabolism, Mutation, NIH 3T3 Cells, Oncogenes genetics, Piperazines pharmacology, Protein Stability, Proto-Oncogene Proteins c-kit genetics, Pyrimidines pharmacology, Signal Transduction, Transcription Factors antagonists & inhibitors, Transcription Factors genetics, Cell Lineage, Cell Transformation, Neoplastic, DNA-Binding Proteins metabolism, Gastrointestinal Stromal Tumors metabolism, Gastrointestinal Stromal Tumors pathology, Oncogenes physiology, Proto-Oncogene Proteins c-kit metabolism, Transcription Factors metabolism
- Abstract
Gastrointestinal stromal tumour (GIST) is the most common human sarcoma and is primarily defined by activating mutations in the KIT or PDGFRA receptor tyrosine kinases. KIT is highly expressed in interstitial cells of Cajal (ICCs)-the presumed cell of origin for GIST-as well as in haematopoietic stem cells, melanocytes, mast cells and germ cells. Yet, families harbouring germline activating KIT mutations and mice with knock-in Kit mutations almost exclusively develop ICC hyperplasia and GIST, suggesting that the cellular context is important for KIT to mediate oncogenesis. Here we show that the ETS family member ETV1 is highly expressed in the subtypes of ICCs sensitive to oncogenic KIT mediated transformation, and is required for their development. In addition, ETV1 is universally highly expressed in GISTs and is required for growth of imatinib-sensitive and resistant GIST cell lines. Transcriptome profiling and global analyses of ETV1-binding sites suggest that ETV1 is a master regulator of an ICC-GIST-specific transcription network mainly through enhancer binding. The ETV1 transcriptional program is further regulated by activated KIT, which prolongs ETV1 protein stability and cooperates with ETV1 to promote tumorigenesis. We propose that GIST arises from ICCs with high levels of endogenous ETV1 expression that, when coupled with an activating KIT mutation, drives an oncogenic ETS transcriptional program. This differs from other ETS-dependent tumours such as prostate cancer, melanoma and Ewing sarcoma where genomic translocation or amplification drives aberrant ETS expression. It also represents a novel mechanism of oncogenic transcription factor activation.
- Published
- 2010
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28. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor.
- Author
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Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A, Kim K, and Sawyers CL
- Subjects
- Amino Acid Sequence, Androgen Receptor Antagonists, Androgens pharmacology, Animals, Castration, Cell Line, Tumor, Disease Models, Animal, Exons genetics, Humans, Male, Mice, Molecular Sequence Data, Protein Structure, Tertiary genetics, RNA, Messenger biosynthesis, Sequence Analysis, Protein, Alternative Splicing, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Receptors, Androgen genetics, Receptors, Androgen metabolism
- Abstract
Androgen receptor (AR) splice variants lacking the ligand binding domain (ARVs), originally isolated from prostate cancer cell lines derived from a single patient, are detected in normal and malignant human prostate tissue, with the highest levels observed in late stage, castration-resistant prostate cancer. The most studied variant (called AR-V7 or AR3) activates AR reporter genes in the absence of ligand and therefore, could play a role in castration resistance. To explore the range of potential ARVs, we screened additional human and murine prostate cancer models using conventional and next generation sequencing technologies and detected several structurally diverse AR isoforms. Some, like AR-V7/AR3, display gain of function, whereas others have dominant interfering activity. We also find that ARV expression increases acutely in response to androgen withdrawal, is suppressed by testosterone, and in some models, is coupled to full-length AR (AR-FL) mRNA production. As expected, constitutively active, ligand-independent ARVs such as AR-V7/AR3 are sufficient to confer anchorage-independent (in vitro) and castration-resistant (in vivo) growth. Surprisingly, this growth is blocked by ligand binding domain-targeted antiandrogens, such as MDV3100, or by selective siRNA silencing of AR-FL, indicating that the growth-promoting effects of ARVs are mediated through AR-FL. These data indicate that the increase in ARV expression in castrate-resistant prostate cancer is an acute response to castration rather than clonal expansion of castration or antiandrogen-resistant cells expressing gain of function ARVs, and furthermore, they provide a strategy to overcome ARV function in the clinic.
- Published
- 2010
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29. Development of a second-generation antiandrogen for treatment of advanced prostate cancer.
- Author
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Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, and Sawyers CL
- Subjects
- Androgen Antagonists metabolism, Androgen Antagonists pharmacokinetics, Androgen Antagonists pharmacology, Anilides metabolism, Anilides pharmacology, Animals, Antineoplastic Agents metabolism, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Benzamides, Biological Availability, Cell Line, Tumor, Cell Nucleus metabolism, Cell Proliferation drug effects, DNA metabolism, Drug Screening Assays, Antitumor, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Mice, Nitriles metabolism, Nitriles pharmacology, Phenylthiohydantoin metabolism, Phenylthiohydantoin pharmacokinetics, Phenylthiohydantoin pharmacology, Phenylthiohydantoin therapeutic use, Prostatic Neoplasms pathology, Receptors, Androgen chemistry, Receptors, Androgen genetics, Receptors, Androgen metabolism, Tosyl Compounds metabolism, Tosyl Compounds pharmacology, Transcription, Genetic drug effects, Xenograft Model Antitumor Assays, Androgen Antagonists therapeutic use, Antineoplastic Agents therapeutic use, Phenylthiohydantoin analogs & derivatives, Prostatic Neoplasms drug therapy
- Abstract
Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.
- Published
- 2009
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30. Transgenic mouse model for rapid pharmacodynamic evaluation of antiandrogens.
- Author
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Ellwood-Yen K, Wongvipat J, and Sawyers C
- Subjects
- Animals, Female, Luciferases genetics, Male, Mice, Mice, Transgenic, Nitriles, Receptors, Androgen genetics, Tosyl Compounds, Androgen Antagonists pharmacology, Anilides pharmacology, Neoplasms, Hormone-Dependent drug therapy, Prostatic Neoplasms drug therapy, Receptors, Androgen physiology
- Abstract
Persistent androgen receptor signaling has been implicated as a critical factor in prostate cancer progression even at the hormone-refractory stage and provides strong rationale for developing novel androgen receptor antagonists. Traditional models for in vivo evaluation of antiandrogens are cumbersome because they rely on physiologic end points, such as the size of androgen-dependent tissues. Here, we describe a transgenic mouse (ARR2 Pb-Lux) that expresses luciferase specifically in the prostate in an androgen-dependent fashion. This signal is reduced by castration or by treatment with bicalutamide and can be quantified through noninvasive bioluminescent imaging. ARR2 Pb-Lux mice provide a novel method for rapid pharmacodynamic evaluation of novel pharmacologic compounds designed to inhibit androgen receptor signaling.
- Published
- 2006
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31. Context-dependent hormone-refractory progression revealed through characterization of a novel murine prostate cancer cell line.
- Author
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Watson PA, Ellwood-Yen K, King JC, Wongvipat J, Lebeau MM, and Sawyers CL
- Subjects
- Animals, Castration, Disease Progression, Gene Expression Regulation, Neoplastic, Genetic Engineering, Humans, Male, Mammary Neoplasms, Experimental metabolism, Mammary Neoplasms, Experimental pathology, Mice, Mice, Transgenic, Prostatic Neoplasms genetics, Proto-Oncogene Proteins c-myc genetics, Stem Cells cytology, Stem Cells metabolism, Tumor Cells, Cultured, Androgens physiology, Neoplasms, Hormone-Dependent genetics, Neoplasms, Hormone-Dependent metabolism, Neoplasms, Hormone-Dependent pathology, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Proto-Oncogene Proteins c-myc physiology, Receptors, Androgen metabolism
- Abstract
Insights into the molecular basis of hormone-refractory prostate cancer have principally relied on human prostate cancer cell lines, all of which were derived from patients who had already failed hormonal therapy. Recent progress in developing genetically engineered mouse prostate cancer models provides an opportunity to isolate novel cell lines from animals never exposed to hormone ablation, avoiding any potential bias conferred by the selective pressure of the castrate environment. Here we report the isolation of such a cell line (Myc-CaP) from a c-myc transgenic mouse with prostate cancer. Myc-CaP cells have an amplified androgen receptor gene despite no prior exposure to androgen withdrawal and they retain androgen-dependent transgene expression as well as androgen-dependent growth in soft agar and in mice. Reexpression of c-Myc from a hormone-independent promoter rescues growth in androgen-depleted agar but not in castrated mice, showing a clear distinction between the molecular requirements for hormone-refractory growth in vitro versus in vivo. Myc-CaP cells represent a unique reagent for dissecting discreet steps in hormone-refractory prostate cancer progression and show the general utility of using genetically engineered mouse models for establishing new prostate cancer cell lines.
- Published
- 2005
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32. HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability.
- Author
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Mellinghoff IK, Vivanco I, Kwon A, Tran C, Wongvipat J, and Sawyers CL
- Subjects
- Animals, COS Cells, Chlorocebus aethiops, DNA, Neoplasm metabolism, ErbB Receptors physiology, Humans, Male, Protein Serine-Threonine Kinases physiology, Proto-Oncogene Proteins physiology, Proto-Oncogene Proteins c-akt, RNA, Small Interfering pharmacology, Receptor, ErbB-2 antagonists & inhibitors, Signal Transduction, Transfection, Tumor Cells, Cultured, Prostatic Neoplasms metabolism, Pyrimidines pharmacology, Pyrroles pharmacology, Receptor, ErbB-2 physiology, Receptors, Androgen metabolism
- Abstract
Given the role of the EGFR/HER2 family of tyrosine kinases in breast cancer, we dissected the molecular basis of EGFR/HER2 kinase signaling in prostate cancer. Using the small molecule dual EGFR/HER2 inhibitor PKI-166, we show that the biologic effects of EGFR/HER-2 pathway inhibition are caused by reduced AR transcriptional activity. Additional genetic and pharmacologic experiments show that this modulation of AR function is mediated by the HER2/ERBB3 pathway, not by EGFR. This HER2/ERBB3 signal stabilizes AR protein levels and optimizes binding of AR to promoter/enhancer regions of androgen-regulated genes. Surprisingly, the downstream signaling pathway responsible for these effects appears to involve kinases other than Akt. These data suggest that the HER2/ERBB3 pathway is a critical target in hormone-refractory prostate cancer.
- Published
- 2004
- Full Text
- View/download PDF
33. Myc-driven murine prostate cancer shares molecular features with human prostate tumors.
- Author
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Ellwood-Yen K, Graeber TG, Wongvipat J, Iruela-Arispe ML, Zhang J, Matusik R, Thomas GV, and Sawyers CL
- Subjects
- Androgens metabolism, Animals, Gene Expression Profiling, Gene Expression Regulation, Neoplastic physiology, Genes, myc genetics, Homeodomain Proteins metabolism, Humans, Male, Mice, Mice, Transgenic, Neovascularization, Pathologic, Orchiectomy, Prostatic Intraepithelial Neoplasia physiopathology, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-pim-1, Transcription Factors metabolism, Adenocarcinoma physiopathology, Genes, myc physiology, Prostate physiopathology, Prostatic Neoplasms physiopathology
- Abstract
Increased Myc gene copy number is observed in human prostate cancer. To define Myc's functional role, we generated transgenic mice expressing human c-Myc in the mouse prostate. All mice developed murine prostatic intraepithelial neoplasia followed by invasive adenocarcinoma. Microarray-based expression profiling identified a Myc prostate cancer expression signature, which included the putative human tumor suppressor NXK3.1. Human prostate tumor databases revealed modules of human genes that varied in concert with the Myc prostate cancer signature. This module includes the Pim-1 kinase, a gene known to cooperate with Myc in tumorigenesis, and defines a subset of human, "Myc-like" human cancers. This approach illustrates how genomic technologies can be applied to mouse cancer models to guide evaluation of human tumor databases.
- Published
- 2003
- Full Text
- View/download PDF
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