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1.
Mol Cancer Ther ; 20(5): 763-774, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33649102

RESUMO

Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor (AR) pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Among these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of AR signaling. To address this unmet need, we report the discovery of JNJ-63576253, a next-generation AR pathway inhibitor that potently abrogates AR signaling in models of human prostate adenocarcinoma. JNJ-63576253 is advancing as a clinical candidate with potential effectiveness in the subset of patients who do not respond to or are progressing while on second-generation AR-targeted therapeutics.

2.
J Med Chem ; 64(2): 909-924, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33470111

RESUMO

Persistent androgen receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound 4 (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with 4. Subsequent lead optimization of 4 led to amelioration of this pathway and nomination of 5 (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Nitrilos/farmacologia , Picolinas/farmacologia , Piperidinas/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Piridinas/farmacologia , Compostos de Espiro/farmacologia , Antagonistas de Receptores de Andrógenos/farmacocinética , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Biotransformação , Linhagem Celular Tumoral , Cães , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos/genética , Hepatócitos/metabolismo , Humanos , Masculino , Modelos Moleculares , Mutação , Nitrilos/farmacocinética , Nitrilos/uso terapêutico , Picolinas/farmacocinética , Picolinas/uso terapêutico , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/genética , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Compostos de Espiro/farmacocinética , Compostos de Espiro/uso terapêutico , Relação Estrutura-Atividade
3.
Cell Chem Biol ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33086052

RESUMO

Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.

4.
ACS Med Chem Lett ; 7(1): 40-5, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26819663

RESUMO

Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.

5.
Bioorg Med Chem Lett ; 25(14): 2809-12, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25987372
6.
Exp Hematol ; 40(9): 715-723.e6, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22613471

RESUMO

Malignant transformation of normal hematopoietic progenitors is a multistep process that likely requires interaction between collaborating oncogenic signals at critical junctures. For instance, the MLL-AF9 fusion oncogene is thought to contribute to myeloid leukemogenesis by driving a hematopoietic stem cell-like "self-renewal" gene expression signature in committed myeloid progenitors. In addition, insulin-like growth factor (IGF) signaling has been implicated in self-renewal/pluripotency in hematopoietic and embryonic stem cell contexts and supports cell growth/survival by activation of downstream pathways, including phosphatidylinositol 3-kinase/Akt and Ras/Raf/extracellular signal-regulated kinase. We hypothesized that IGF signaling could be an important contributor in the process of cellular transformation and/or clonal propagation. Utilizing an MLL-AF9 mouse bone marrow transplantation model of acute myelogenous leukemia, we discovered that committed myeloid progenitor cells with genetically reduced levels of IGF1R were less susceptible to leukemogenic transformation due, at least in part, to a cell-autonomous defect in clonogenic activity. Rather unexpectedly, genetic deletion of IGF1R by inducible Cre recombinase had no effect on growth/survival of established leukemia cells. These findings suggest that IGF1R signaling contributes to transformation of normal myeloid progenitor cells, but is not required for propagation of the leukemic clone once it has become established. We also show that treatment of mouse MLL-AF9 acute myelogenous leukemia cells with BMS-536924, an IGF1R/insulin receptor-selective tyrosine kinase inhibitor, blocked cell growth, suggesting its efficacy in this model may be due to inhibition of insulin receptor and/or related tyrosine kinases, and raising the possibility that similar IGF1R inhibitors in clinical development may be acting through alternate/related pathways.


Assuntos
Transformação Celular Neoplásica/genética , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Fusão Oncogênica/genética , Receptor IGF Tipo 1/genética , Animais , Benzimidazóis/farmacologia , Western Blotting , Transplante de Medula Óssea , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Feminino , Citometria de Fluxo , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Fusão Oncogênica/metabolismo , Pirazóis/farmacologia , Piridonas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/genética , Análise de Sobrevida , Triazinas/farmacologia
7.
Clin Cancer Res ; 18(6): 1808-17, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22287600

RESUMO

PURPOSE: To improve the significance of insulin-like growth factor-binding protein 5 (IGFBP-5) as a prognostic and potentially predictive marker in patients with breast cancer. EXPERIMENTAL DESIGN: Increased IGFBP-5 expression was identified in MCF-7 cells resistant (MCF-7R4) to the IGF-1R/insulin receptor (InsR) inhibitor BMS-536924 and its role examined by targeted knockdown and overexpression in multiple experimental models. Protein expression of IGFBP-5 was measured by immunohistochemistry in a cohort of 76 patients with breast cancer to examine correlative associations with invasive tumor fraction and outcome. The use of a combined IGFBP-5/IGFBP-4 (BPR) expression ratio was applied to predict anti-IGF-1R/InsR response in a panel of breast cancer lines and outcome in multiple breast tumor cohorts. RESULTS: IGFBP-5 knockdown decreased BMS-536924 resistance in MCF-7R4 cells, whereas IGFBP-5 overexpression in MCF-7 cells conferred resistance. When compared with pathologically normal reduction mammoplasty tissue, IGFBP-5 expression levels were upregulated in both invasive and histologically normal adjacent breast cancer tissue. In both univariate and multivariate modeling, metastasis-free survival, recurrence free survival (RFS), and overall survival (OS) were significantly associated with high IGFBP-5 expression. Prognostic power of IGFBP-5 was further increased with the addition of IGFBP-4 where tumors were ranked based upon IGFBP-5/IGFBP-4 expression ratio (BPR). Multiple breast cancer cohorts confirm that BPR (high vs. low) was a strong predictor of RFS and OS. CONCLUSION: IGFBP-5 expression is a marker of poor outcome in patients with breast cancer. An IGFBP-5/IGFBP-4 expression ratio may serve as a surrogate biomarker of IGF pathway activation and predict sensitivity to anti-IGF-1R targeting.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Piridonas/uso terapêutico
8.
PLoS One ; 7(12): e51189, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23300537

RESUMO

BACKGROUND: Treatment of metastatic prostate cancer (PCa) with single agents has shown only modest efficacy. We hypothesized dual inhibition of different pathways in PCa results in improved tumor inhibition. The Src family kinases (SFK) and insulin-like growth factor-1 (IGF-1) signaling axes are aberrantly activated in both primary PCa and bone metastases and regulate distinct and overlapping functions in PCa progression. We examined the antitumor effects of combined inhibition of these pathways. MATERIALS AND METHODS: Src andIGF-1 receptor (IGF-1R) inhibition was achieved in vitro by short hairpin (sh)RNA and in vitro and in vivo by small molecule inhibitors (dasatinib and BMS-754807, against SFK and IGF-1R/Insulin Receptor(IR), respectively). RESULTS: In vitro, inhibition of IGF-1 signaling affected cell survival and proliferation. SFK blockade alone had modest effects on proliferation, but significantly enhanced the IGF-1R blockade. These findings correlated with a robust inhibition of IGF-1-induced Akt1 phophorylation by dasatinib, whereas Akt2 phosphorylation was SFK independent and only inhibited by BMS-754807. Thus, complete inhibition of both Akt genes, not seen by either drug alone, is likely a major mechanism for the decreased survival of PCa cells. Furthermore, dasatinib and BMS-754807 inhibited in vivo growth of the primary human xenograft MDA PCa 133, with corresponding inhibition of Akt in tumors. Also, both orthotopic and intratibial tumor growth of PC-3 cells were more potently inhibited by dual SFK and IGF-1R/IR blockade compared to either pathway alone, with a corresponding decrease in bone turnover markers. CONCLUSIONS: Dual IGF-1R/IR and SFK inhibition may be a rational therapeutic approach in PCa by blocking both independent and complementary processes critical to tumor growth.


Assuntos
Apoptose/efeitos dos fármacos , Doenças Ósseas/prevenção & controle , Neoplasias da Próstata/prevenção & controle , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor de Insulina/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/antagonistas & inibidores , Animais , Western Blotting , Doenças Ósseas/metabolismo , Doenças Ósseas/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dasatinibe , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoprecipitação , Masculino , Camundongos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Tiazóis/farmacologia , Triazinas/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/metabolismo
9.
Cancer Res ; 71(24): 7597-607, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22042792

RESUMO

Insulin-like growth factor (IGF) signaling has been implicated in the resistance to hormonal therapy in breast cancer. Using a model of postmenopausal, estrogen-dependent breast cancer, we investigated the antitumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor BMS-754807 alone and in combination with letrozole or tamoxifen. BMS-754807 exhibited antiproliferative effects in vitro that synergized strongly in combination with letrozole or 4-hydroxytamoxifen and fulvestrant. Similarly, combined treatment of BMS-754807 with either tamoxifen or letrozole in vivo elicited tumor regressions not achieved by single-agent therapy. Notably, hormonal therapy enhanced the inhibition of IGF-1R/InsR without major side effects in animals. Microarray expression analysis revealed downregulation of cell-cycle control and survival pathways and upregulation of erbB in response to BMS-754807 plus hormonal therapy, particularly tamoxifen. Overall, these results offer a preclinical proof-of-concept for BMS-754807 as an antitumor agent in combination with hormonal therapies in hormone-sensitive breast cancer. Cooperative cell-cycle arrest, decreased proliferation, and enhanced promotion of apoptosis may contribute to antitumor effects to be gauged in future clinical investigations justified by our findings.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Pirazóis/farmacologia , Triazinas/farmacologia , Animais , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Western Blotting , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Estradiol/farmacologia , Estrogênios/metabolismo , Feminino , Fulvestranto , Perfilação da Expressão Gênica , Humanos , Letrozol , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nitrilos/administração & dosagem , Nitrilos/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/antagonistas & inibidores , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Tamoxifeno/administração & dosagem , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia , Triazóis/administração & dosagem , Triazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Mol Cancer Ther ; 10(1): 117-25, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21220496

RESUMO

Preclinical investigations have identified insulin-like growth factor (IGF) signaling as a key mechanism for cancer growth and resistance to clinically useful therapies in multiple tumor types including breast cancer. Thus, agents targeting and blocking IGF signaling have promise in the treatment of solid tumors. To identify possible mechanisms of resistance to blocking the IGF pathway, we generated a cell line that was resistant to the IGF-1R/InsR benzimidazole inhibitors, BMS-554417 and BMS-536924, and compared expression profiles of the parental and resistant cells lines using Affymetrix GeneChip Human Genome U133 arrays. Compared with MCF-7 cells, breast cancer resistance protein (BCRP) expression was increased 9-fold in MCF-7R4, which was confirmed by immunoblotting and was highly statistically significant (P = 7.13E-09). BCRP was also upregulated in an independently derived resistant cell line, MCF-7 924R. MCF-7R4 cells had significantly lower intracellular accumulation of BMS-536924 compared with MCF-7 cells. Expression of BCRP in MCF-7 cells was sufficient to reduce sensitivity to BMS-536924. Furthermore, knockdown of BCRP in MCF-7R4 cells resensitized cells to BMS-536924. Four cell lines selected for resistance to the pyrrolotriazine IGF-1R/InsR inhibitor, BMS-754807, did not have upregulation of BCRP. These data suggest that benzimidazole IGF-1R/InsR inhibitors may select for upregulation and be effluxed by the ATP-binding cassette transporter, BCRP, contributing to resistance. However, pyrrolotriazine IGF-1R/InsR inhibitors do not appear to be affected by this resistance mechanism.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Benzimidazóis/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proteínas de Neoplasias/metabolismo , Piridonas/farmacocinética , Receptores de Somatomedina/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/genética , Benzimidazóis/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Piridonas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Regulação para Cima/efeitos dos fármacos
12.
Prostate ; 71(5): 480-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20878947

RESUMO

BACKGROUND: Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required. METHODS: Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results. RESULTS: As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk. CONCLUSIONS: Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs.


Assuntos
Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/toxicidade , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/farmacocinética , Animais , Cães , Descoberta de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neoplasias da Próstata/metabolismo , Ratos , Ratos Sprague-Dawley
13.
MAbs ; 3(1): 38-48, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21099371

RESUMO

Engineered domains of human fibronectin (Adnectins™) were used to generate a bispecific Adnectin targeting epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor (IGF-IR), two transmembrane receptors that mediate proliferative and survival cell signaling in cancer. Single-domain Adnectins that specifically bind EGFR or IGF-IR were generated using mRNA display with a library containing as many as 10 ( 13) Adnectin variants. mRNA display was also used to optimize lead Adnectin affinities, resulting in clones that inhibited EGFR phosphorylation at 7 to 38 nM compared to 2.6 µM for the parental clone. Individual, optimized, Adnectins specific for blocking either EGFR or IGF-IR signaling were engineered into a single protein (EI-Tandem Adnectin). The EI-Tandems inhibited phosphorylation of EGFR and IGF-IR, induced receptor degradation, and inhibited down-stream cell signaling and proliferation of human cancer cell lines (A431, H292, BxPC3 and RH41) with IC 50 values ranging from 0.1 to 113 nM. Although Adnectins bound to EGFR at a site distinct from those of anti-EGFR antibodies cetuximab, panitumumab and nimotuzumab, like the antibodies, the anti-EGFR Adnectins blocked the binding of EGF to EGFR. PEGylated EI-Tandem inhibited the growth of both EGFR and IGF-IR driven human tumor xenografts, induced degradation of EGFR, and reduced EGFR phosphorylation in tumors. These results demonstrate efficient engineering of bispecific Adnectins with high potency and desired specificity. The bispecificity may improve biological activity compared to monospecific biologics as tumor growth is driven by multiple growth factors. Our results illustrate a technological advancement for constructing multi-specific biologics in cancer therapy.


Assuntos
Receptores ErbB/antagonistas & inibidores , Fibronectinas/química , Fragmentos de Peptídeos/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Receptores ErbB/metabolismo , Feminino , Humanos , Immunoblotting , Cinética , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Panitumumabe , Fragmentos de Peptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Cancer Res ; 71(3): 1060-70, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21148487

RESUMO

The insulin-like growth factor (IGF) 1 receptor (IGF1R) is an important therapeutic target under study in many cancers. Here, we describe a breast cancer model based on expression of the ETV6-NTRK3 (EN) chimeric tyrosine kinase that suggests novel therapeutic applications of IGF1R inhibitors in secretory breast cancers. Originally discovered in congenital fibrosarcomas with t(12;15) translocations, EN was identified subsequently in secretory breast carcinoma (SBC) which represent a variant of invasive ductal carcinoma. Because fibroblast transformation by EN requires the IGF1R axis, we hypothesized a similar dependency may exist in mammary cells and, if so, that IGF1R inhibitors might be useful to block EN-driven breast oncogenesis. In this study, we analyzed EN expressing murine and human mammary epithelial cell lines for transformation properties. Various IGF1R signaling inhibitors, including the dual specificity IGF1R/insulin receptor (INSR) inhibitor BMS-536924, were then tested for effects on three-dimensional Matrigel cell growth, migration, and tumor formation. We found that EN expression increased acinar size and luminal filling in Matrigel cultures and promoted orthotopic tumor growth in mice. Tumors were well differentiated and nonmetastatic, similar to human SBC. The known EN effector pathway, PI3K-Akt, was activated in an IGF1- or insulin-dependent manner. BMS-536924 blocked EN transformation in vitro, whereas BMS-754807, another IGIFR/INSR kinase inhibitor currently in clinical trials, significantly reduced tumor growth in vivo. Importantly, EN model systems mimic the clinical phenotype observed in human SBC. Moreover, EN has a strict requirement for IGF1R or INSR in breast cell transformation. Thus, our findings strongly encourage the evaluation of IGF1R/INSR inhibitors to treat EN-driven breast cancers.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Fusão Oncogênica/biossíntese , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Animais , Benzimidazóis/farmacologia , Neoplasias da Mama/enzimologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Transformação Celular Neoplásica , Transição Epitelial-Mesenquimal , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Camundongos Transgênicos , Terapia de Alvo Molecular , Proteína Oncogênica v-akt/metabolismo , Piridonas/farmacologia , Transdução de Sinais , Transplante Heterólogo
15.
Clin Cancer Res ; 17(8): 2314-27, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21177763

RESUMO

PURPOSE: We previously reported an insulin-like growth factor (IGF) gene expression signature, based on genes induced or repressed by IGF-I, which correlated with poor prognosis in breast cancer. We tested whether the IGF signature was affected by anti-IGF-I receptor (IGF-IR) inhibitors and whether the IGF signature correlated with response to a dual anti-IGF-IR/insulin receptor (InsR) inhibitor, BMS-754807. EXPERIMENTAL DESIGN: An IGF gene expression signature was examined in human breast tumors and cell lines and changes were noted following treatment of cell lines or xenografts with anti-IGF-IR antibodies or tyrosine kinase inhibitors. Sensitivity of cells to BMS-754807 was correlated with levels of the IGF signature. Human primary tumorgrafts were analyzed for the IGF signature and IGF-IR levels and activity, and MC1 tumorgrafts were treated with BMS-754807 and chemotherapy. RESULTS: The IGF gene expression signature was reversed in three different models (cancer cell lines or xenografts) treated with three different anti-IGF-IR therapies. The IGF signature was present in triple-negative breast cancers (TNBC) and TNBC cell lines, which were especially sensitive to BMS-754807, and sensitivity was significantly correlated to the expression of the IGF gene signature. The TNBC primary human tumorgraft MC1 showed high levels of both expression and activity of IGF-IR and IGF gene signature score. Treatment of MC1 with BMS-754807 showed growth inhibition and, in combination with docetaxel, tumor regression occurred until no tumor was palpable. Regression was associated with reduced proliferation, increased apoptosis, and mitotic catastrophe. CONCLUSIONS: These studies provide a clear biological rationale to test anti-IGF-IR/InsR therapy in combination with chemotherapy in patients with TNBC.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Pirazóis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Triazinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Análise por Conglomerados , Docetaxel , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Immunoblotting , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células NIH 3T3 , Pirazóis/administração & dosagem , Receptor ErbB-2/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/antagonistas & inibidores , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxoides/administração & dosagem , Taxoides/farmacologia , Triazinas/administração & dosagem
16.
Cancer Res ; 70(21): 8770-81, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20959493

RESUMO

The insulin-like growth factor-1 receptor (IGF1R) is emerging as a promising therapeutic target in human cancers. In the high-risk childhood sarcomas Ewing family tumor and rhabdomyosarcoma, IGF1R-blocking antibodies show impressive antitumor activity in some but not all patients, and acquired resistance is observed. Because tumor IGF1R mutations are not described, the basis of IGF1R inhibitor resistance remains unknown. We hypothesized that compensatory signaling cascades bypassing targeted IGF1R inhibition might be involved. To test this systematically, we performed small interfering RNA (siRNA) screens in sarcoma cell lines to identify IGF1R pathway components or related protein tyrosine kinase (PTK) networks that modulate the antitumor efficacy of the BMS-536924 IGF1R kinase inhibitor. This strategy revealed (a) that sarcoma cells are exquisitely sensitive to loss of distal rather than proximal IGF1R signaling components, such as ribosomal protein S6 (RPS6); (b) that BMS-536924 fails to block RPS6 activation in resistant sarcoma cell lines; and (c) that siRNA knockdown of the macrophage-stimulating 1 receptor tyrosine kinase (MST1R; also known as RON) restores BMS-536924 efficacy, even in highly drug-resistant cell lines. We confirmed MST1R expression across a broad panel of childhood sarcomas, and found that loss of MST1R by RNA interference blocks downstream RPS6 activation when combined with BMS-536924 in vitro. These findings underscore the importance of fully understanding PTK networks for successful clinical implementation of kinase inhibitor strategies.


Assuntos
RNA Interferente Pequeno/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Proteína S6 Ribossômica/metabolismo , Sarcoma/metabolismo , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Western Blotting , Medula Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Genes Letais , Humanos , Técnicas Imunoenzimáticas , Células-Tronco Mesenquimais/metabolismo , Piridonas/farmacologia , RNA Mensageiro/genética , Receptores Proteína Tirosina Quinases/genética , Receptor IGF Tipo 1/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína S6 Ribossômica/genética , Sarcoma/tratamento farmacológico , Sarcoma/genética , Transdução de Sinais , Células Tumorais Cultivadas
17.
Cancer Res ; 70(18): 7221-31, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20807811

RESUMO

Agents targeting insulin-like growth factor-I receptor (IGF-IR), including antibodies and small-molecule inhibitors, are currently in clinical development for the treatment of cancers including sarcoma. However, development of resistance is a common phenomenon resulting in failures of anticancer therapies. In light of this problem, we developed two resistant models from the rhabdomyosarcoma cell line Rh41: Rh41-807R, with acquired resistance to BMS-754807, a small-molecule dual-kinase inhibitor targeting IGF-IR and insulin receptor (IR), and Rh41-MAB391R, with resistance to MAB391, an IGF-IR-blocking antibody. In addition, tumor xenograft models were established from Rh41 and Rh41-807R cell lines. Gene expression and DNA copy number analyses of these models revealed shared as well as unique acquired resistance mechanisms for the two types of IGF-IR inhibitors. Each resistant model used different signaling pathways as a mechanism for proliferation. Platelet-derived growth factor receptor α (PDGFRα) was amplified, overexpressed, and constitutively activated in Rh41-807R cells and tumors. Knockdown of PDGFRα by small interfering RNA in Rh41-807R resensitized the cells to BMS-754807. Synergistic activities were observed when BMS-754807 was combined with PDGFRα inhibitors in the Rh41-807R model in vitro. In contrast, AXL expression was highly elevated in Rh41-MAB391R but downregulated in Rh41-807R. Notably, BMS-754807 was active in Rh41-MAB391R cells and able to overcome resistance to MAB391, but MAB391 was not active in Rh41-807R cells, suggesting potentially broader clinical activity of BMS-754807. This is the first study to define and compare acquired resistance mechanisms for IGF-IR-targeted therapies. It provides insights into the differential acquired resistance mechanisms for IGF-IR/IR small-molecule inhibitor versus anti-IGF-IR antibody.


Assuntos
Anticorpos Monoclonais/farmacologia , Pirazóis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Rabdomiossarcoma/terapia , Triazinas/farmacologia , Animais , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Receptor IGF Tipo 1/biossíntese , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/imunologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/agonistas , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/biossíntese , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/deficiência , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/genética , Rabdomiossarcoma/imunologia , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Endocr Relat Cancer ; 17(3): 623-36, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20385747

RESUMO

Neuroendocrine (carcinoid) tumors (NETs) are endocrine neoplasms occurring most frequently in gastrointestinal and bronchopulmonary (BP) systems. The majority of patients present with advanced disease for which few treatment options exist. We assessed 104 NETs (74 cases) for biomarkers targeted by anticancer drugs under development for other forms of cancer. Activating mutations were assessed in epidermal growth factor receptor (EGFR), stem cell factor receptor (KIT), and platelet-derived growth factor receptor alpha (PDGFRA), as well as non-response mutations in KRAS. Copy number of EGFR and HER-2/neu was quantified with fluorescence in situ hybridization. Immunohistochemical analyses were performed for EGFR, KIT, PDGFRA, somatostatin receptor subtypes 2A and 5 (SSTR5), vascular endothelial growth factor receptor 1, mammalian target of rapamycin (mTOR), insulin-like growth factor 1 receptor (IGF1R), heat shock protein 90 (Hsp90), and transforming growth factor-beta receptor 1 (TGFBR1). NETs lacked HER2-overexpression predictive of anti-HER2 response and KIT and PDGFRA activating mutations indicative of imatinib sensitivity. High EGFR aneusomy (20% of all cases) and elevated EGFR copy number (39%) were found, but few KRAS mutations associated with non-response to anti-EGFR therapy (3%). Hsp90, TGFBR1, IGF1R, and SSTR5 exhibited highest levels of immunohistochemical staining in the largest percents of tumors. In subsequent in vitro studies, anticancer drug 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) (targeting Hsp90) inhibited proliferation of BP NET lines NCI-H727, NCI-H720, and NCI-H835 with IC(50) values of 70.4, 310, and 788 nM respectively; BMS-754807 (targeting IGF1R/IR) inhibited growth with IC(50) values of 428 nM, 2.8 microM, and 1 microM. At growth-inhibiting concentrations, 17-AAG (24 h) induced loss of EGFR and IGF1R in the IGF1R-expressing NCI-H727 line, and BMS-754807 (24 h) inhibited constitutive IGF1R autophosphorylation. Our results support further research into Hsp90, IGF1R, and EGFR as targets for developing new anticancer therapeutics for some NETs.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoquinonas/farmacologia , Biomarcadores Tumorais/genética , Western Blotting , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Lactamas Macrocíclicas/farmacologia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Reação em Cadeia da Polimerase , Pirazóis/farmacologia , Estudos Retrospectivos , Análise Serial de Tecidos , Triazinas/farmacologia , Adulto Jovem
20.
Cancer Res ; 70(2): 741-51, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20068149

RESUMO

Epidemiologic studies suggest that type 2 diabetes (T2D) increases breast cancer risk and mortality, but there is limited experimental evidence supporting this association. Moreover, there has not been any definition of a pathophysiological pathway that diabetes may use to promote tumorigenesis. In the present study, we used the MKR mouse model of T2D to investigate molecular mechanisms that link T2D to breast cancer development and progression. MKR mice harbor a transgene encoding a dominant-negative, kinase-dead human insulin-like growth factor-I receptor (IGF-IR) that is expressed exclusively in skeletal muscle, where it acts to inactivate endogenous insulin receptor (IR) and IGF-IR. Although lean female MKR mice are insulin resistant and glucose intolerant, displaying accelerated mammary gland development and enhanced phosphorylation of IR/IGF-IR and Akt in mammary tissue, in the context of three different mouse models of breast cancer, these metabolic abnormalities were found to accelerate the development of hyperplastic precancerous lesions. Normal or malignant mammary tissue isolated from these mice exhibited increased phosphorylation of IR/IGF-IR and Akt, whereas extracellular signal-regulated kinase 1/2 phosphorylation was largely unaffected. Tumor-promoting effects of T2D in the models were reversed by pharmacological blockade of IR/IGF-IR signaling by the small-molecule tyrosine kinase inhibitor BMS-536924. Our findings offer compelling experimental evidence that T2D accelerates mammary gland development and carcinogenesis,and that the IR and/or the IGF-IR are major mediators of these effects.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Hiperinsulinismo/metabolismo , Neoplasias Mamárias Experimentais/etiologia , Neoplasias Mamárias Experimentais/metabolismo , Animais , Benzimidazóis/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Feminino , Hiperinsulinismo/sangue , Hiperinsulinismo/patologia , Insulina/sangue , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/sangue , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Transgênicos , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Piridonas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/antagonistas & inibidores , Receptor de Insulina/metabolismo
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