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1.
Sci Adv ; 6(17): eaaz3221, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32494639

RESUMO

Mutations in isocitrate dehydrogenase (IDH) genes occur in multiple cancer types, lead to global changes in the epigenome, and drive tumorigenesis. Yet, effective strategies targeting solid tumors harboring IDH mutations remain elusive. Here, we demonstrate that IDH-mutant gliomas and cholangiocarcinomas display elevated DNA damage. Using multiple in vitro and preclinical animal models of glioma and cholangiocarcinoma, we developed treatment strategies that use a synthetic lethality approach targeting the reduced DNA damage repair conferred by mutant IDH using poly(adenosine 5'-diphosphate) ribose polymerase inhibitors (PARPis). The therapeutic effects are markedly enhanced by cotreatment with concurrent, localized radiation therapy. PARPi-buttressed multimodality therapies may represent a readily applicable approach that is selective for IDH-mutant tumor cells and has potential to improve outcomes in multiple cancers.

2.
Nat Commun ; 10(1): 943, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808951

RESUMO

Mutational inactivation of ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in large subsets of malignant glioma. Yet the pathogenic consequences of ATRX deficiency remain unclear, as do tractable mechanisms for its therapeutic targeting. Here we report that ATRX loss in isogenic glioma model systems induces replication stress and DNA damage by way of G-quadruplex (G4) DNA secondary structure. Moreover, these effects are associated with the acquisition of disease-relevant copy number alterations over time. We then demonstrate, both in vitro and in vivo, that ATRX deficiency selectively enhances DNA damage and cell death following chemical G4 stabilization. Finally, we show that G4 stabilization synergizes with other DNA-damaging therapies, including ionizing radiation, in the ATRX-deficient context. Our findings reveal novel pathogenic mechanisms driven by ATRX deficiency in glioma, while also pointing to tangible strategies for drug development.


Assuntos
Neoplasias Encefálicas/genética , Quadruplex G , Glioma/genética , Proteína Nuclear Ligada ao X/deficiência , Proteína Nuclear Ligada ao X/genética , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Dano ao DNA , Replicação do DNA , DNA de Neoplasias/química , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Técnicas de Silenciamento de Genes , Instabilidade Genômica , Glioma/metabolismo , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Mutação
3.
Neoplasia ; 19(2): 75-83, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28038320

RESUMO

Mutation of the PARK2 gene can promote both Parkinson's Disease and cancer, yet the underlying mechanisms of how PARK2 controls cellular physiology is incompletely understood. Here, we show that the PARK2 tumor suppressor controls the apoptotic regulator BCL-XL and modulates programmed cell death. Analysis of approximately 10,000 tumor genomes uncovers a striking pattern of mutual exclusivity between PARK2 genetic loss and amplification of BCL2L1, implicating these genes in a common pathway. PARK2 directly binds to and ubiquitinates BCL-XL. Inactivation of PARK2 leads to aberrant accumulation of BCL-XL both in vitro and in vivo, and cancer-specific mutations in PARK2 abrogate the ability of the ubiquitin E3 ligase to target BCL-XL for degradation. Furthermore, PARK2 modulates mitochondrial depolarization and apoptosis in a BCL-XL-dependent manner. Thus, like genes at the nodal points of growth arrest pathways such as p53, the PARK2 tumor suppressor is able to exert its antiproliferative effects by regulating both cell cycle progression and programmed cell death.


Assuntos
Apoptose , Neoplasias/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteína bcl-X/metabolismo , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Mitocôndrias/metabolismo , Mutação , Neoplasias/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteólise , Ubiquitina-Proteína Ligases/genética , Proteína bcl-X/genética
4.
Protein Eng Des Sel ; 27(10): 317-24, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25095796

RESUMO

Activated leukocyte cell adhesion molecule (ALCAM) is an immunoglobulin superfamily cell adhesion molecule that is aberrantly expressed in a wide variety of human tumors, including melanoma, prostate cancer, breast cancer, colorectal carcinoma, bladder cancer and pancreatic adenocarcinoma. This wide spectrum of human malignancies makes ALCAM a prospective pan-cancer immunoPET target to aid in detection and diagnosis in multiple malignancies. In this study, we assess site-specific versus non-site-specific conjugation strategies for (64)Cu-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) immunoPET imaging of a fully human ALCAM cys-diabody (cDb) with a reduced linker length that retains its bivalent binding ability. ALCAM constructs with linker lengths of eight, five and three amino acids were produced to make true non-covalent site-specifically modified cDbs. Characterization by gel electrophoresis, size exclusion chromatography, flow cytometry and mass spectrometry of the various constructs was performed. To demonstrate the increased utility of targeting multiple malignancies expressing ALCAM, we compare the targeting of the site-specific versus non-site-specific conjugated cDbs to the human colorectal cancer xenograft LS174T. Interestingly, the conjugation strategy not only affects tumor targeting but also hepatic and renal uptake/clearance.


Assuntos
Molécula de Adesão de Leucócito Ativado/química , Neoplasias Colorretais/diagnóstico por imagem , Cobre , Compostos Heterocíclicos com 1 Anel , Imuno-Histoquímica/métodos , Tomografia por Emissão de Pósitrons/métodos , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/química , Neoplasias Colorretais/metabolismo , Humanos , Imagem Molecular/métodos , Ratos , Distribuição Tecidual
5.
Oncotarget ; 5(16): 6976-82, 2014 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-25138050

RESUMO

PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers. Despite its frequent inactivation, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo. PTPRD is located on chromosome 9p, as is CDKN2A, and the two loci are frequently deleted together. Here, we show that co-deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis. Interestingly,heterozygous loss of Ptprd was sufficient to promote tumorigenesis in our model, suggesting that Ptprd may be a haploinsufficient tumor suppressor. The loss of Ptprd resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas. In total, we reveal that Ptprd is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/deficiência , Sarcoma/genética , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Técnicas de Genotipagem , Humanos , Perda de Heterozigosidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Sarcoma/metabolismo
6.
Proc Natl Acad Sci U S A ; 111(22): 8149-54, 2014 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-24843164

RESUMO

PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear. Here, using genomic analysis and a glioma mouse model, we demonstrate that loss of Ptprd accelerates tumor formation and define the oncogenic context in which Ptprd loss acts. Specifically, we show that in human GBMs, heterozygous loss of PTPRD is the predominant type of lesion and that loss of PTPRD and the CDKN2A/p16(INK4A) tumor suppressor frequently co-occur. Accordingly, heterozygous loss of Ptprd cooperates with p16 deletion to drive gliomagenesis in mice. Moreover, loss of the Ptprd phosphatase resulted in phospho-Stat3 accumulation and constitutive activation of Stat3-driven genetic programs. Surprisingly, the consequences of Ptprd loss are maximal in the heterozygous state, demonstrating a tight dependence on gene dosage. Ptprd loss did not increase cell proliferation but rather altered pathways governing the macrophage response. In total, we reveal that PTPRD is a bona fide tumor suppressor, pinpoint PTPRD loss as a cause of aberrant STAT3 activation in gliomas, and establish PTPRD loss, in the setting of CDKN2A/p16(INK4A) deletion, as a driver of glioma progression.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/metabolismo , Proliferação de Células , Galinhas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/fisiologia , Genes Supressores de Tumor/fisiologia , Glioblastoma/imunologia , Glioblastoma/patologia , Heterozigoto , Humanos , Camundongos , Camundongos Knockout , Transplante de Neoplasias , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Microambiente Tumoral/imunologia
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