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1.
J Clin Invest ; 133(22)2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37725435

RESUMO

Antibody-drug conjugates (ADCs) are a promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer (mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross-linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, and conferred sensitivity were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive (ARPC) prostate cancer models, even with low B7H3 levels. Non-ARPC models, which are currently lacking efficacious treatment, demonstrated the highest replication stress and were most sensitive to treatment. In RB1 WT ARPC tumors, SLFN11 expression or select DNA repair mutations in SLFN11 nonexpressors governed response. Importantly, WT TP53 predicted nonresponsiveness (7 of 8 models). Overall, biomarker-focused selection of models led to high efficacy of in vivo treatment. These data enable a paradigm shift to biomarker-driven trial designs for maximizing clinical benefit of ADC therapies.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias da Próstata , Masculino , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Antineoplásicos/uso terapêutico , Proteínas Nucleares
2.
Mol Cancer Ther ; 19(8): 1649-1659, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32404408

RESUMO

Multiple myeloma is a hematologic cancer that disrupts normal bone marrow function and has multiple lines of therapeutic options, but is incurable as patients ultimately relapse. We developed a novel antibody-drug conjugate (ADC) targeting CS-1, a protein that is highly expressed on multiple myeloma tumor cells. The anti-CS-1 mAb specifically bound to cells expressing CS-1 and, when conjugated to a cytotoxic pyrrolobenzodiazepine payload, reduced the viability of multiple myeloma cell lines in vitro In mouse models of multiple myeloma, a single administration of the CS-1 ADC caused durable regressions in disseminated models and complete regression in a subcutaneous model. In an exploratory study in cynomolgus monkeys, the CS-1 ADC demonstrated a half-life of 3 to 6 days; however, no highest nonseverely toxic dose was achieved, as bone marrow toxicity was dose limiting. Bone marrow from dosed monkeys showed reductions in progenitor cells as compared with normal marrow. In vitro cell killing assays demonstrated that the CS-1 ADC substantially reduced the number of progenitor cells in healthy bone marrow, leading us to identify previously unreported CS-1 expression on a small population of progenitor cells in the myeloid-erythroid lineage. This finding suggests that bone marrow toxicity is the result of both on-target and off-target killing by the ADC.


Assuntos
Anticorpos Monoclonais/química , Antineoplásicos/farmacologia , Benzodiazepinas/química , Imunoconjugados/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas dos Microfilamentos/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Pirróis/química , Animais , Antineoplásicos/química , Apoptose , Proliferação de Células , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Imunoconjugados/química , Macaca fascicularis , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas dos Microfilamentos/imunologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancer Res ; 80(4): 771-783, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31843981

RESUMO

Integrin ß4 (ITGB4) has been shown to play an important role in the regulation of cancer stem cells (CSC). Immune targeting of ITGB4 represents a novel approach to target this cell population, with potential clinical benefit. We developed two immunologic strategies to target ITGB4: ITGB4 protein-pulsed dendritic cells (ITGB4-DC) for vaccination and adoptive transfer of anti-CD3/anti-ITGB4 bispecific antibody (ITGB4 BiAb)-armed tumor-draining lymph node T cells. Two immunocompetent mouse models were utilized to assess the efficacy of these immunotherapies in targeting both CSCs and bulk tumor populations: 4T1 mammary tumors and SCC7 head and neck squamous carcinoma cell line. Immunologic targeting of ITGB4 utilizing either ITGB4-DC or ITGB4 BiAb-T cells significantly inhibited local tumor growth and metastases in both the 4T1 and SCC7 tumor models. Furthermore, the efficacy of both of these ITGB4-targeted immunotherapies was significantly enhanced by the addition of anti-PD-L1. Both ITGB4-targeted immunotherapies induced endogenous T-cell cytotoxicity directed at CSCs as well as non-CSCs, which expressed ITGB4, and immune plasma-mediated killing of CSCs. As a result, ITGB4-targeted immunotherapy reduced not only the number of ITGB4high CSCs in residual 4T1 and SCC7 tumors but also their tumor-initiating capacity in secondary mouse implants. In addition, treated mice demonstrated no apparent toxicity. The specificity of these treatments was demonstrated by the lack of effects observed using ITGB4 knockout 4T1 or ITGB4-negative CT26 colon carcinoma cells. Because ITGB4 is expressed by CSCs across a variety of tumor types, these results support immunologic targeting of ITGB4 as a promising therapeutic strategy.Significance: This study identifies a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients.


Assuntos
Vacinas Anticâncer/administração & dosagem , Imunoterapia Adotiva/métodos , Integrina beta4/metabolismo , Neoplasias/terapia , Células-Tronco Neoplásicas/imunologia , Animais , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Complexo CD3/antagonistas & inibidores , Complexo CD3/imunologia , Vacinas Anticâncer/imunologia , Carcinogênese/imunologia , Linhagem Celular Tumoral/transplante , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Humanos , Integrina beta4/genética , Integrina beta4/imunologia , Linfonodos/citologia , Camundongos , Terapia de Alvo Molecular/métodos , Metástase Neoplásica/imunologia , Metástase Neoplásica/prevenção & controle , Neoplasias/imunologia , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante
6.
J Clin Invest ; 128(2): 805-815, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29337305

RESUMO

Programmed death-1 receptor (PD-L1, B7-H1) and programmed cell death protein 1 (PD-1) pathway blockade is a promising therapy for treating cancer. However, the mechanistic contribution of host and tumor PD-L1 and PD-1 signaling to the therapeutic efficacy of PD-L1 and PD-1 blockade remains elusive. Here, we evaluated 3 tumor-bearing mouse models that differ in their sensitivity to PD-L1 blockade and demonstrated a loss of therapeutic efficacy of PD-L1 blockade in immunodeficient mice and in PD-L1- and PD-1-deficient mice. In contrast, neither knockout nor overexpression of PD-L1 in tumor cells had an effect on PD-L1 blockade efficacy. Human and murine studies showed high levels of functional PD-L1 expression in dendritic cells and macrophages in the tumor microenvironments and draining lymph nodes. Additionally, expression of PD-L1 on dendritic cells and macrophages in ovarian cancer and melanoma patients correlated with the efficacy of treatment with either anti-PD-1 alone or in combination with anti-CTLA-4. Thus, PD-L1-expressing dendritic cells and macrophages may mechanistically shape and therapeutically predict clinical efficacy of PD-L1/PD-1 blockade.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Dendritos/metabolismo , Células Dendríticas/metabolismo , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Feminino , Perfilação da Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Linfonodos/patologia , Macrófagos/metabolismo , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Neoplasias Ovarianas/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Fatores de Tempo , Microambiente Tumoral
7.
Mol Cancer Ther ; 16(8): 1576-1587, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28522587

RESUMO

Antibody-drug conjugates (ADC) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSC), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation. ADCs targeting 5T4 were constructed by site-specifically conjugating the antibody with payloads that possess different mechanisms of action, either a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer or a microtubule-destabilizing tubulysin, so that each ADC had a drug:antibody ratio of 2. The resulting ADCs demonstrated significant target-dependent activity in vitro and in vivo; however, the ADC conjugated with a PBD payload (5T4-PBD) elicited more durable antitumor responses in vivo than the tubulysin conjugate in xenograft models. Likewise, the 5T4-PBD more potently inhibited the growth of 5T4-positive CSCs in vivo, which likely contributed to its superior antitumor activity. Given that the 5T4-PBD possessed both potent antitumor activity as well as anti-CSC activity, and thus could potentially target bulk tumor cells and CSCs in target-positive indications, it was further evaluated in non-GLP rat toxicology studies that demonstrated excellent in vivo stability with an acceptable safety profile. Taken together, these preclinical data support further development of 5T4-PBD, also known as MEDI0641, against 5T4+ cancer indications. Mol Cancer Ther; 16(8); 1576-87. ©2017 AACR.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Benzodiazepinas/uso terapêutico , Imunoconjugados/uso terapêutico , Pirróis/uso terapêutico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacologia , Linhagem Celular Tumoral , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacologia , Masculino , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Pirróis/efeitos adversos , Pirróis/farmacologia , Ratos Sprague-Dawley , Moduladores de Tubulina/efeitos adversos , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Clin Cancer Res ; 23(10): 2516-2527, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-27780858

RESUMO

Purpose: Locoregional recurrence is a frequent treatment outcome for patients with advanced head and neck squamous cell carcinoma (HNSCC). Emerging evidence suggests that tumor recurrence is mediated by a small subpopulation of uniquely tumorigenic cells, that is, cancer stem cells (CSC), that are resistant to conventional chemotherapy, endowed with self-renewal and multipotency.Experimental Design: Here, we evaluated the efficacy of MEDI0641, a novel antibody-drug conjugate targeted to 5T4 and carrying a DNA-damaging "payload" (pyrrolobenzodiazepine) in preclinical models of HNSCC.Results: Analysis of a tissue microarray containing 77 HNSCC with follow-up of up to 12 years revealed that patients with 5T4high tumors displayed lower overall survival than those with 5T4low tumors (P = 0.038). 5T4 is more highly expressed in head and neck CSC (ALDHhighCD44high) than in control cells (non-CSC). Treatment with MEDI0641 caused a significant reduction in the CSC fraction in HNSCC cells (UM-SCC-11B, UM-SCC-22B) in vitro Notably, a single intravenous dose of 1 mg/kg MEDI0641 caused long-lasting tumor regression in three patient-derived xenograft (PDX) models of HNSCC. MEDI0641 ablated CSC in the PDX-SCC-M0 model, reduced it by five-fold in the PDX-SCC-M1, and two-fold in the PDX-SCC-M11 model. Importantly, mice (n = 12) treated with neoadjuvant, single administration of MEDI0641 prior to surgical tumor removal showed no recurrence for more than 200 days, whereas the control group had 7 recurrences (in 12 mice; P = 0.0047).Conclusions: Collectively, these findings demonstrate that an anti-5T4 antibody-drug conjugate reduces the fraction of CSCs and prevents local recurrence and suggest a novel therapeutic approach for patients with HNSCC. Clin Cancer Res; 23(10); 2516-27. ©2016 AACR.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Imunoconjugados/administração & dosagem , Glicoproteínas de Membrana/imunologia , Animais , Benzodiazepinas/administração & dosagem , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Autorrenovação Celular/genética , Autorrenovação Celular/imunologia , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imunoconjugados/imunologia , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Pirróis/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço , Análise Serial de Tecidos , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Neoplasia ; 18(5): 273-281, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27237319

RESUMO

Head and neck squamous cell carcinomas (HNSCC) exhibit a small population of uniquely tumorigenic cancer stem cells (CSC) endowed with self-renewal and multipotency. We have recently shown that IL-6 enhances the survival and tumorigenic potential of head and neck cancer stem cells (i.e. ALDH(high)CD44(high) cells). Here, we characterized the effect of therapeutic inhibition of IL-6 with a novel humanized anti-IL-6 antibody (MEDI5117) using three low-passage patient-derived xenograft (PDX) models of HNSCC. We observed that single agent MEDI5117 inhibited the growth of PDX-SCC-M1 tumors (P < .05). This PDX model was generated from a previously untreated HNSCC. In contrast, MEDI5117 was not effective at reducing overall tumor volume for PDX models representing resistant disease (PDX-SCC-M0, PDX-SCC-M11). Low dose MEDI5117 (3 mg/kg) consistently decreased the fraction of cancer stem cells in PDX models of HNSCC when compared to IgG-treated controls, as follows: PDX-SCC-M0 (P < .001), PDX-SCC-M1 (P < .001), PDX-SCC-M11 (P = .04). Interestingly, high dose MEDI5117 (30 mg/kg) decreased the CSC fraction in the PDX-SCC-M11 model (P = .002), but not in PDX-SCC-M0 and PDX-SCC-M1. MEDI5117 mediated a dose-dependent decrease in the number of orospheres generated by ALDH(high)CD44(high) cells cultured in ultra-low attachment plates (P < .05), supporting an inhibitory effect on head and neck cancer stem cells. Notably, single agent MEDI5117 reduced the overall recurrence rate of PDX-SCC-M0, a PDX generated from the local recurrence of human HNSCC. Collectively, these data demonstrate that therapeutic inhibition of IL-6 with low-dose MEDI5117 decreases the fraction of cancer stem cells, and that adjuvant MEDI5117 inhibits recurrence in preclinical models of HNSCC.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Animais , Biomarcadores , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Modelos Animais de Doenças , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Camundongos , Recidiva , Carcinoma de Células Escamosas de Cabeça e Pescoço , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Front Biosci (Elite Ed) ; 8(1): 181-8, 2016 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-26709654

RESUMO

Cancer stem cells (CSCs) represent a rare subpopulation of tumor cells responsible for tumor initiation and eventual patient relapse. Strong preclinical evidence points to the importance of this population for therapeutic intervention and currently there are several anti-CSC therapies under development. While we begin to advance these therapies into the clinic, there is a need to develop biomarkers to measure both patient response and prognosis. This review will discuss the experimental evidence for the role of CSCs in patient outcomes as well as the need, challenges and the hope that CSC biomarkers may provide.


Assuntos
Biomarcadores Tumorais/metabolismo , Células-Tronco Neoplásicas/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia
11.
World J Stem Cells ; 7(1): 27-36, 2015 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-25621103

RESUMO

The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and cancer stem cell (CSC) models have been proposed as drivers of this heterogeneity. However, the concept of cancer stem cell plasticity and bidirectional conversion between stem and non-stem cells has added additional complexity to these highly studied paradigms and may help explain the tumor heterogeneity observed in solid tumors. The process of cancer stem cell plasticity in which cancer cells harbor the dynamic ability of shifting from a non-CSC state to a CSC state and vice versa may be modulated by specific microenvironmental signals and cellular interactions arising in the tumor niche. In addition to promoting CSC plasticity, these interactions may contribute to the cellular transformation of tumor cells and affect response to chemotherapeutic and radiation treatments by providing CSCs protection from these agents. Herein, we review the literature in support of this dynamic CSC state, discuss the effectors of plasticity, and examine their role in the development and treatment of cancer.

12.
Stem Cells Transl Med ; 2(1): 43-52, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23283488

RESUMO

Although cancer is largely seen as a disease stemming from genetic mutations, evidence has implicated epigenetic regulation of gene expression as a driving force for tumorigenesis. Epigenetic regulation by histone modification, specifically through polycomb group (PcG) proteins such as EZH2 and BMI-1, is a major driver in stem cell biology and is found to be correlated with poor prognosis in many tumor types. This suggests a role for PcG proteins in cancer stem cells (CSCs). We hypothesized that epigenetic modification by EZH2, specifically, helps maintain the CSC phenotype and that in turn this epigenetic modifier can be used as a reporter for CSC activity in an in vitro high-throughput screening assay. CSCs isolated from pancreatic and breast cancer lines had elevated EZH2 levels over non-CSCs. Moreover, EZH2 knockdown by RNA interference significantly reduced the frequency of CSCs in all models tested, confirming the role of EZH2 in maintenance of the CSC population. Interestingly, genes affected by EZH2 loss, and therefore CSC loss, were inversely correlated with genes identified by CSC enrichment, further supporting the function of EZH2 CSC regulation. We translated these results into a novel assay whereby elevated EZH2 staining was used as a reporter for CSCs. Data confirmed that this assay could effectively measure changes, both inhibition and enrichment, in the CSC population, providing a novel approach to look at CSC activity. This assay provides a unique, rapid way to facilitate CSC screening across several tumor types to aid in further CSC-related research.


Assuntos
Biomarcadores Tumorais/metabolismo , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Biomarcadores Tumorais/genética , Neoplasias da Mama , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Histonas/metabolismo , Humanos , Células-Tronco Neoplásicas/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Pancreáticas , Complexo Repressor Polycomb 2/genética , Interferência de RNA , Transcriptoma
13.
J Bone Marrow Res ; 1: 122, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-24772452

RESUMO

BACKGROUND: Human bone marrow derived mesenchymal stem cells (hMSCs) are capable of differentiation into multiple cell lineages and demonstrate a wide variety of use in various therapeutic applications. Only recently has research begun to understand the gene expression profiles of hMSCs and their differentiated counterparts in vivo and ex vivo. PURPOSE: The research presented here aimed at gaining a better understanding of gene expression patterns present during hMSC invasion through a basement membrane. METHODS: Changes in gene expression were evaluated between invasive and non-invasive cells using Agilent's gene expression arrays and Matrigel invasion chambers. The cells were specifically attracted to a defined stem cell media called SCM. RESULTS: A total 435 genes were up-regulated by 2- fold or more in the invasive population of cells and classified into developmental programs and immunological/inflammatory signaling pathways determined by Ingenuity Pathway Analysis (IPA). This list included a variety of regulators of growth and differentiation including NANOG, STAT3 and STAT5A and members of the polycomb repressive complex-2 (PCRC2) EZH2 and SUZ12. The known regulator of inflammation and hypoxia HIF-1α was also increased suggesting that regulation of the microenvironment is important during this process. Finally, the invasion process could be reversed using the STAT3 inhibitor Static. CONCLUSIONS: Overall these data will increase the understanding of the genetic pathways functioning during hMSC invasion and aid in the development of their therapeutic applications.

14.
J Mol Med (Berl) ; 90(7): 791-801, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22660276

RESUMO

Normal development and homeostasis requires a carefully coordinated gene expression program. Appropriate transcriptional regulation is maintained, in part, through epigenetic modifications of both DNA and histones. It is now apparent that the epigenetic landscape is complex and carefully controlled to both silence and activate gene transcription and that these states remain exquisitely poised for reversal. The deregulation of epigenetics in cancer is common and results in both the activation of oncogenes and the silencing of tumor suppressors. A tremendous amount of research corroborates the existence in many tumor types of a cancer stem cell that is both the origin and cell type responsible for resistance of tumors to current therapies. As our understanding of cancer stem cell biology continues, it is apparent that these cells are also under the influence of epigenetic regulation. We will discuss the cancer stem cell hypothesis and the role of epigenetics in both normal and cancer stem cell biology.


Assuntos
Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Células-Tronco/metabolismo , Animais , Metilação de DNA , Humanos , Neoplasias/metabolismo , Neoplasias/terapia , Células-Tronco Neoplásicas/metabolismo
15.
Prostate ; 72(16): 1746-56, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22513891

RESUMO

BACKGROUND: Despite improvements in treatment, prostate cancer (PC) remains the second-leading cause of cancer death in men. Radiotherapy is among the first-line treatments for PC, but a significant number of patients relapse. Recent evidence supports the idea that PC is initiated by a subset of cells, termed cancer stem cells (CSCs). CSCs have also been implicated in radioresistance in various malignancies, but their role in PC has not yet been investigated. METHODS: We compared the relative radiosensitivity of isolated CSCs to the total population of their corresponding cell lines, and examined the relative numbers of CSCs in irradiated cell lines following long-term recovery and in recurrent human PC. RESULTS: Here, we show that while irradiation does not immediately favor increased survival of CSCs, irradiated PC cell lines showed an increase in CSC properties with long-term recovery. These data suggest that, although CSCs are initially damaged by radiation, they possess a greater capacity for recovery and regrowth. CONCLUSIONS: The combination of radiotherapy with a CSC-targeted therapeutic strategy may prevent tumor recurrence.


Assuntos
Células-Tronco Neoplásicas/patologia , Próstata/patologia , Neoplasias da Próstata/patologia , Tolerância a Radiação , Contagem de Células , Linhagem Celular Tumoral , Humanos , Masculino , Células-Tronco Neoplásicas/efeitos da radiação , Próstata/efeitos da radiação , Neoplasias da Próstata/radioterapia
16.
Genomics ; 99(2): 108-17, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22206861

RESUMO

TICs are characterized by their ability to self-renew, differentiate and initiate tumor formation. miRNAs are small noncoding RNAs that bind to mRNAs resulting in regulation of gene expression and biological functions. The role of miRNAs and TICs in cancer progression led us to hypothesize that miRNAs may regulate genes involved in TIC maintenance. Using whole genome miRNA and mRNA expression profiling of TICs from primary prostate cancer cells, we identified a set of up-regulated miRNAs and a set of genes down-regulated in PSs. Inhibition of these miRNAs results in a decrease of prostatosphere formation and an increase in target gene expression. This study uses genome-wide miRNA profiling to analyze expression in TICs. We connect aberrant miRNA expression and deregulated gene expression in TICs. These findings can contribute to a better understanding of the molecular mechanisms governing TIC development/maintenance and the role that miRNAs have in the fundamental biology of TICs.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias da Próstata/patologia , RNA Mensageiro/genética , Esferoides Celulares/metabolismo , Proliferação de Células , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Células Tumorais Cultivadas , Regulação para Cima
17.
Pancreas ; 40(5): 730-9, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21633318

RESUMO

OBJECTIVE: Pancreatic cancer was the fourth leading cause of cancer death in the United States in 2010. Recurrence of disease after resection occurs because of neoplastic cell survival. To better understand these highly aggressive cells, gene expression microarrays were performed. METHODS: Using the established lines HPAC and PANC1 and a Matrigel assay, genome expression arrays were performed to analyze patterns between invasive and total cells. RESULTS: Significant increases in the expression of genes related to DNA repair were observed. A number of the same genes also demonstrated an increase in expression when comparing bulk cells to a putative tumor-initiating cell (TIC) population. The TIC population was isolated using the spheroid technique, and compared with bulk cells, spheroid cells functionally repair breaks in DNA faster after challenge with the drug gemcitabine. Finally, using Oncomine, we observed a significant increase in DNA copy number of BRCA1 and RAD51 in tissue isolated from metastatic pancreatic cancer compared with tissue isolated from the primary site. CONCLUSIONS: From these data, we conclude that the most invasive cells within a pancreatic tumor are able to thrive because of their increased genomic stability. These cells have also been linked to the TIC population in a tumor.


Assuntos
Reparo do DNA/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Bases de Dados Factuais , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Dosagem de Genes , Expressão Gênica , Genes BRCA1 , Instabilidade Genômica , Humanos , Invasividade Neoplásica/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Rad51 Recombinase/genética , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Gencitabina
18.
Mol Cancer ; 10: 40, 2011 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-21501485

RESUMO

BACKGROUND: Polycomb repressive complex 2 (PRC2) mediates gene silencing through histone H3K27 methylation. PRC2 components are over-expressed in metastatic prostate cancer (PC), and are required for cancer stem cell (CSC) self-renewal. 3-Dezaneplanocin-A (DZNeP) is an inhibitor of PRC2 with broad anticancer activity. METHOD: we investigated the effects of DZNeP on cell proliferation, tumorigenicity and invasive potential of PC cell lines (LNCaP and DU145). RESULTS: Exploring GEO and Oncomine databases, we found that specific PRC2 genes (EED, EZH2, SUZ12) predict poor prognosis in PC. Non-toxic DZNeP concentrations completely eradicated LNCaP and DU145 prostatosphere formation, and significantly reduced the expression of CSC markers. At comparable doses, other epigenetic drugs were not able to eradicate CSCs. DZNeP was also able to reduce PC cell invasion. Cells pre-treated with DZNeP were significantly less tumorigenic (LNCaP) and formed smaller tumors (DU145) in immunocompromised mice. CONCLUSION: DZNeP is effective both in vitro and in vivo against PC cells. DZNeP antitumor activity is in part mediated by inhibition of CSC tumorigenic potential.


Assuntos
Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Repressoras/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Metilação/efeitos dos fármacos , Camundongos , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Proteínas do Grupo Polycomb , RNA Mensageiro/genética , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Esferoides Celulares/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Int J Cancer ; 128(8): 1946-54, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20568112

RESUMO

The BMI1 oncogene promotes prostate cancer (PC) progression. High B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) expression predicts poor prognosis in PC patients. Recent evidence suggests that BMI1 may also play a role in docetaxel chemoresistance. However, mechanisms and clinical significance of BMI1-related chemoresistance have not been investigated. For this purpose, BMI1 was silenced in 2 PC cell lines (LNCaP and DU 145). Cell proliferation and apoptosis after docetaxel treatment were measured. Guanine oxidation was assessed by in-cell western. Global gene expression analysis was performed on BMI1 silenced cells. Oncomine database was used to compare in vitro data with gene expression in PC samples. BMI1 silencing had no effect on cell proliferation but significantly enhanced docetaxel-induced antitumor activity. Gene expression analysis demonstrated that BMI1 silencing downregulates a set of antioxidant genes. Docetaxel treatment increased guanine oxidation, whereas the antioxidant N-acetyl cysteine rescued docetaxel-induced cell death. Examination of clinical datasets revealed a positive correlation of BMI1 and antioxidant gene expression. BMI1-controlled antioxidant genes were predictive of poor prognosis in PC patients. In conclusion, BMI1 enhances antioxidant response, thereby allowing PC survival after docetaxel-based chemotherapy. BMI1-controlled antioxidant genes are overexpressed in aggressive PC and should be tested as predictors of chemotherapy failure.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Nucleares/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Taxoides/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Ciclo Celular , Proliferação de Células , Docetaxel , Imunofluorescência , Perfilação da Expressão Gênica , Humanos , Masculino , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Complexo Repressor Polycomb 1 , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/genética , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
20.
Blood ; 117(8): 2396-404, 2011 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-21163924

RESUMO

Modulating aberrant transcription of oncogenes is a relatively unexplored opportunity in cancer therapeutics. In approximately 10% of multiple myelomas, the initiating oncogenic event is translocation of musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a transcriptional activator of key target genes, including cyclinD2. Our prior work showed that MAF is up-regulated in an additional 30% of multiple myeloma cases. The present study describes a common mechanism inducing MAF transcription in both instances. The second mode of MAF transcription occurred in myelomas with multiple myeloma SET domain (MMSET) translocation. MMSET knockdown decreased MAF transcription and cell viability. A small-molecule screen found an inhibitor of mitogen-activated protein kinase kinase (MEK), which activates extracellular signal-regulated kinase (ERK)-MAP kinases, reduced MAF mRNA in cells representing MMSET or MAF subgroups. ERK activates transcription of FOS, part of the AP-1 transcription factor. By chromatin immunoprecipitation, FOS bound the MAF promoter, and MEK inhibition decreased this interaction. MEK inhibition selectively induced apoptosis in MAF-expressing myelomas, and FOS inactivation was similarly toxic. Reexpression of MAF rescued cells from death induced by MMSET depletion, MEK inhibition, or FOS inactivation. The data presented herein demonstrate that the MEK-ERK pathway regulates MAF transcription, providing molecular rationale for clinical evaluation of MEK inhibitors in MAF-expressing myeloma.


Assuntos
Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Proteína Oncogênica v-maf/genética , Proteínas Quinases/uso terapêutico , Apoptose , Regulação da Expressão Gênica , Histona-Lisina N-Metiltransferase/fisiologia , Humanos , Proteínas Repressoras/fisiologia , Transcrição Gênica
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