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1.
Nat Genet ; 39(3): 347-51, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17293865

RESUMO

Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention.


Assuntos
Análise Mutacional de DNA/métodos , Mutação , Neoplasias/genética , Oncogenes , Perfilação da Expressão Gênica , Genoma Humano , Genótipo , Humanos
2.
Clin Cancer Res ; 28(4): 585-593, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34561270

RESUMO

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Humanos , Tolerância Imunológica , Terapia de Imunossupressão , Imunoterapia
3.
Nat Cancer ; 2(12): 1372-1386, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-35121903

RESUMO

Only a subset of recurrent glioblastoma (rGBM) responds to anti-PD-1 immunotherapy. Previously, we reported enrichment of BRAF/PTPN11 mutations in 30% of rGBM that responded to PD-1 blockade. Given that BRAF and PTPN11 promote MAPK/ERK signaling, we investigated whether activation of this pathway is associated with response to PD-1 inhibitors in rGBM, including patients that do not harbor BRAF/PTPN11 mutations. Here we show that immunohistochemistry for ERK1/2 phosphorylation (p-ERK), a marker of MAPK/ERK pathway activation, is predictive of overall survival following adjuvant PD-1 blockade in two independent rGBM patient cohorts. Single-cell RNA-sequencing and multiplex immunofluorescence analyses revealed that p-ERK was mainly localized in tumor cells and that high-p-ERK GBMs contained tumor-infiltrating myeloid cells and microglia with elevated expression of MHC class II and associated genes. These findings indicate that ERK1/2 activation in rGBM is predictive of response to PD-1 blockade and is associated with a distinct myeloid cell phenotype.


Assuntos
Glioblastoma , Glioblastoma/tratamento farmacológico , Humanos , Imunoterapia , Sistema de Sinalização das MAP Quinases , Recidiva Local de Neoplasia/tratamento farmacológico , Fosforilação
4.
Proc Natl Acad Sci U S A ; 104(50): 20007-12, 2007 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-18077431

RESUMO

Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximately 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.


Assuntos
Aberrações Cromossômicas/estatística & dados numéricos , Glioma/genética , Linhagem Celular Tumoral , Interpretação Estatística de Dados , Glioma/patologia , Humanos , Polimorfismo de Nucleotídeo Único , Probabilidade
5.
PLoS Med ; 5(1): e8, 2008 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-18215105

RESUMO

BACKGROUND: There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population. METHODS AND FINDINGS: Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test). CONCLUSIONS: Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development. TRIAL REGISTRATION: http://www.ClinicalTrials.gov (#NCT00047073).


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , PTEN Fosfo-Hidrolase/deficiência , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/fisiologia , Terapia de Salvação , Sirolimo/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Divisão Celular/efeitos dos fármacos , Terapia Combinada , Progressão da Doença , Retroalimentação Fisiológica , Feminino , Glioblastoma/enzimologia , Glioblastoma/genética , Glioblastoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/cirurgia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/fisiologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína S6 Ribossômica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/efeitos adversos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR
6.
Clin Cancer Res ; 13(2 Pt 1): 378-81, 2007 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-17255257

RESUMO

Molecularly targeted therapies are transforming the treatment of cancer. Elucidating the dynamic signaling networks that underlie sensitivity and resistance to these inhibitors is critical for successful clinical application. There is considerable evidence to suggest that constitutively activating mutations in kinases that regulate cellular growth may result in tumor cell "addiction" and favorable response to targeted inhibition. However, there is emerging evidence to suggest that clinical response may also be determined by other changes in the molecular circuitry of cancer cells, such as loss of key tumor-suppressor proteins. Here, we will discuss resistance to epidermal growth factor receptor tyrosine kinase inhibitors in glioblastoma patients that is mediated by loss of the PTEN tumor-suppressor protein.


Assuntos
Neoplasias Encefálicas/metabolismo , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/fisiologia , Glioblastoma/metabolismo , PTEN Fosfo-Hidrolase/fisiologia , Animais , Humanos , Modelos Biológicos , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais
8.
Cancer Discov ; 3(5): 534-47, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23533263

RESUMO

UNLABELLED: Acquired resistance to tyrosine kinase inhibitors (TKI) represents a major challenge for personalized cancer therapy. Multiple genetic mechanisms of acquired TKI resistance have been identified in several types of human cancer. However, the possibility that cancer cells may also evade treatment by co-opting physiologically regulated receptors has not been addressed. Here, we show the first example of this alternate mechanism in brain tumors by showing that EGF receptor (EGFR)-mutant glioblastomas (GBMs) evade EGFR TKIs by transcriptionally de-repressing platelet-derived growth factor receptor ß (PDGFRß). Mechanistic studies show that EGFRvIII signaling actively suppresses PDGFRß transcription in an mTORC1- and extracellular signal-regulated kinase-dependent manner. Genetic or pharmacologic inhibition of oncogenic EGFR renders GBMs dependent on the consequently de-repressed PDGFRß signaling for growth and survival. Importantly, combined inhibition of EGFR and PDGFRß signaling potently suppresses tumor growth in vivo. These data identify a novel, nongenetic TKI resistance mechanism in brain tumors and provide compelling rationale for combination therapy. SIGNIFICANCE: These results provide the fi rst clinical and biologic evidence for receptor tyrosinekinase (RTK) "switching" as a mechanism of resistance to EGFR inhibitors in GBM and provide a molecular explanation of how tumors can become "addicted" to a non amplified, nonmutated, physiologically regulated RTK to evade targeted treatment.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Receptores ErbB/antagonistas & inibidores , Glioblastoma/genética , Inibidores de Proteínas Quinases/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Adulto , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Lapatinib , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos SCID , Mutação , Quinazolinas/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transcrição Gênica , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Cancer Cell ; 16(1): 44-54, 2009 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-19573811

RESUMO

Loss-of-function mutations in the NF1 tumor suppressor result in deregulated Ras signaling and drive tumorigenesis in the familial cancer syndrome neurofibromatosis type I. However, the extent to which NF1 inactivation promotes sporadic tumorigenesis is unknown. Here we report that NF1 is inactivated in sporadic gliomas via two mechanisms: excessive proteasomal degradation and genetic loss. NF1 protein destabilization is triggered by the hyperactivation of protein kinase C (PKC) and confers sensitivity to PKC inhibitors. However, complete genetic loss, which only occurs when p53 is inactivated, mediates sensitivity to mTOR inhibitors. These studies reveal an expanding role for NF1 inactivation in sporadic gliomagenesis and illustrate how different mechanisms of inactivation are utilized in genetically distinct tumors, which consequently impacts therapeutic sensitivity.


Assuntos
Genes Supressores de Tumor , Glioblastoma/genética , Glioma/genética , Mutação , Neurofibromatose 1/genética , Neurofibromina 1/antagonistas & inibidores , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Células 3T3 , Animais , Regulação para Baixo , Genes p53 , Genes ras , Glioblastoma/enzimologia , Glioma/enzimologia , Camundongos , Neurofibromatose 1/metabolismo , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
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