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1.
Cancer Discov ; 14(5): 752-765, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38227896

RESUMO

A substantial fraction of cancers evade immune detection by silencing Stimulator of Interferon Genes (STING)-Interferon (IFN) signaling. Therapeutic reactivation of this program via STING agonists, epigenetic, or DNA-damaging therapies can restore antitumor immunity in multiple preclinical models. Here we show that adaptive induction of three prime exonuclease 1 (TREX1) restrains STING-dependent nucleic acid sensing in cancer cells via its catalytic function in degrading cytosolic DNA. Cancer cell TREX1 expression is coordinately induced with STING by autocrine IFN and downstream STAT1, preventing signal amplification. TREX1 inactivation in cancer cells thus unleashes STING-IFN signaling, recruiting T and natural killer (NK) cells, sensitizing to NK cell-derived IFNγ, and cooperating with programmed cell death protein 1 blockade in multiple mouse tumor models to enhance immunogenicity. Targeting TREX1 may represent a complementary strategy to induce cytosolic DNA and amplify cancer cell STING-IFN signaling as a means to sensitize tumors to immune checkpoint blockade (ICB) and/or cell therapies. SIGNIFICANCE: STING-IFN signaling in cancer cells promotes tumor cell immunogenicity. Inactivation of the DNA exonuclease TREX1, which is adaptively upregulated to limit pathway activation in cancer cells, recruits immune effector cells and primes NK cell-mediated killing. Targeting TREX1 has substantial therapeutic potential to amplify cancer cell immunogenicity and overcome ICB resistance. This article is featured in Selected Articles from This Issue, p. 695.


Assuntos
Exodesoxirribonucleases , Proteínas de Membrana , Fosfoproteínas , Transdução de Sinais , Exodesoxirribonucleases/genética , Camundongos , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Humanos , Animais , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neoplasias/imunologia , Neoplasias/genética , Neoplasias/tratamento farmacológico , Interferons/metabolismo , Linhagem Celular Tumoral , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo
2.
Case Rep Surg ; 2023: 9279934, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37469658

RESUMO

Introduction: Pseudoangiomatous stromal hyperplasia (PASH) presenting as gigantomastia is rare in pregnancy but can result in severe clinical consequences for both mother and fetus. Case Presentation. A 43-year-old female with a history of biopsy-proven bilateral PASH presented at 22 3/7 weeks gestation with massive bilateral breast enlargement that was symptomatic. After multidisciplinary care, she underwent bilateral mastectomies and delivered at term with no additional complications. Conclusion: Pregnant women who undergo mastectomies for PASH-induced gigantomastia during their second trimesters will likely recover quickly, and fetal risks are low. Given the rarity of this breast entity, management guidelines are sparse. Our case report is an effort to comprehensively review this condition and share the clinical recommendations made by our institution's multidisciplinary team.

3.
Cancer Cell ; 40(10): 1128-1144.e8, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-36150391

RESUMO

KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2'3'-cyclic GMP-AMP (2'3'-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that transient MPS1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.


Assuntos
Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Decitabina , Genes ras , Humanos , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
4.
Ann Surg Oncol ; 28(5): 2589-2598, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33078312

RESUMO

BACKGROUND: With more effective screening and treatment strategies, there is debate over whether surgical axillary staging should be deescalated for patients with small favorable breast cancers, such as tubular carcinoma (TC). PATIENTS AND METHODS: We identified patients with TC [defined as > 90% tubular tubules (angulated, not multilayered)] and known surgical axillary staging from our institutional database (2000-2018). Using the National Cancer Database (NCDB) (2004-2015), we identified patients with TC, ductal carcinoma in situ (DCIS), and pT1 estrogen receptor (ER)-positive invasive ductal carcinoma (IDC). We determined the rates of lymph node (LN) metastases, and the 5- and 10-year overall survival (OS) for patients with LN-negative versus LN-positive disease using the Kaplan-Meier method and propensity match analysis. RESULTS: In our institutional cohort, we identified 112 patients with T1 TC; only one (0.9%) patient had nodal involvement. In the NCDB cohort, we identified 6938 patients with T1 TC; 323 (4.7%) patients had axillary LN disease. The rate of axillary LN involvement for TC was comparable to that identified for patients with DCIS (4.2%), and much lower than that found for patients with grade I-III, T1, ER-positive IDC (20.5%), and patients with grade I, T1, ER-positive IDC (14.4%). There was no difference in 5-year (94.6% versus 95.4%, p = 0.67) and 10-year (83.9% versus 85.2%, p = 0.98) OS between TC patients with or without LN involvement. Kaplan-Meier survival curves even after propensity score matching suggest that tubular histology is independently associated with improved survival. CONCLUSIONS: T1 TC is an excellent starting point for deescalation of surgical axillary staging.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Axila/patologia , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Intraductal não Infiltrante/cirurgia , Humanos , Linfonodos/patologia , Linfonodos/cirurgia , Estadiamento de Neoplasias , Estudos Retrospectivos
5.
Clin Cancer Res ; 26(10): 2393-2403, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32034078

RESUMO

PURPOSE: Evaluating drug responses using primary patient-derived cells ex vivo represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in HER2 mutant non-small cell lung cancer (NSCLC) patient xenograft-derived organotypic spheroids (XDOTS) using a short-term ex vivo system. EXPERIMENTAL DESIGN: We generated two HER2-mutant NSCLC PDX models [DFCI359 (HER2 exon19 755_757LREdelinsRP) and DFCI315 (HER2 exon20 V777_G778insGSP)] and used the PDX tumors to generate XDOTS. Tumor spheroids were grown in a microfluidic device and treated ex vivo with neratinib-based drug combinations. Live/dead quantification was performed by dual-labeling deconvolution fluorescence microscopy. The most efficacious ex vivo combination was subsequently validated in vivo using the DFCI359 and DFCI315 PDXs and a HER2 YVMA genetically engineered mouse model. RESULTS: Both neratinib and afatinib, but not gefitinib, induced cell death in DFCI359 XDOTS. The combinations of neratinib/trastuzumab and neratinib/temsirolimus enhanced the therapeutic benefit of neratinib alone in DFCI315 and DFCI359. The combination of neratinib and trastuzumab in vivo was more effective compared with single-agent neratinib or trastuzumab and was associated with more robust inhibition of HER2 and downstream signaling. CONCLUSIONS: The XDOTS platform can be used to evaluate therapies and therapeutic combinations ex vivo using PDX tumors. This approach may accelerate the identification and clinical development of therapies for targets with no or few existing models and/or therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Receptor ErbB-2/genética , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Quinolinas/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Esferoides Celulares , Trastuzumab/administração & dosagem , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Res ; 80(1): 44-56, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31662325

RESUMO

Triple-negative breast cancer (TNBC) is a heterogeneous disease enriched for mutations in PTEN and dysregulation of innate immune signaling. Here, we demonstrate that Rab7, a recently identified substrate of PTEN phosphatase activity, is also a substrate of the innate immune signaling kinases TANK-binding kinase 1 (TBK1)/IκB kinase ε (IKKε) on the same serine-72 (S72) site. An unbiased search for novel TBK1/IKKε substrates using stable isotope labeling with amino acids in cell culture phosphoproteomic analysis identified Rab7-S72 as a top hit. PTEN-null TNBC cells expressing a phosphomimetic version of Rab7-S72 exhibited diffuse cytosolic Rab7 localization and enhanced innate immune signaling, in contrast to a kinase-resistant version, which localized to active puncta that promote lysosomal-mediated stimulator of interferon genes (STING) degradation. Thus, convergence of PTEN loss and TBK1/IKKε activation on Rab7-S72 phosphorylation limited STING turnover and increased downstream production of IRF3 targets including CXCL10, CCL5, and IFNß. Consistent with this data, PTEN-null TNBC tumors expressed higher levels of STING, and PTEN-null TNBC cell lines were hyperresponsive to STING agonists. Together, these findings begin to uncover how innate immune signaling is dysregulated downstream of TBK1/IKKε in a subset of TNBCs and reveals previously unrecognized cross-talk with STING recycling that may have implications for STING agonism in the clinic. SIGNIFICANCE: These findings identify Rab7 as a substrate for TBK1 for regulation of innate immune signaling, thereby providing important insight for strategies aimed at manipulating the immune response to enhance therapeutic efficacy in TNBC.


Assuntos
Quinase I-kappa B/metabolismo , Imunidade Inata , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Proteínas rab de Ligação ao GTP/metabolismo , Mama/imunologia , Mama/patologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Proteínas de Membrana/agonistas , Proteínas de Membrana/metabolismo , Mutagênese Sítio-Dirigida , Mutação , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação/genética , Fosforilação/imunologia , Proteólise , Serina/genética , Serina/metabolismo , Transdução de Sinais/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/imunologia , proteínas de unión al GTP Rab7
8.
Ann Surg Oncol ; 22(12): 3861-5, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25783678

RESUMO

BACKGROUND: In postmenopausal women with hormone receptor (HR)-positive breast cancer, neoadjuvant endocrine therapy (ET) provides effective downstaging of tumor for improved surgical outcome and offers an important advantage of assessing tumor endocrine responsiveness for individualized therapy in the adjuvant setting. Although approximately 60 % of breast cancers in premenopausal women are HR positive, the role of neoadjuvant ET in this population is not well defined. METHODS: We identified 162 patients with stage I-III estrogen receptor-positive breast cancer treated with neoadjuvant ET between 2003 and 2012. Of this group, 17 patients were premenopausal. Data included patient/tumor characteristics, surgical, systemic, and radiation treatment received, and outcomes. Descriptive statistics were used for data summary. RESULTS: The cohort included 17 patients with a mean age of 46.2 years (range 39-53 years). Patients were treated with a combination of gonadotrophic-releasing hormone agonist with either an aromatase inhibitor (n = 14) or tamoxifen (n = 3) for 4-6 months. Among the premenopausal patients, six underwent breast-conserving therapy, with 3 of 6 (50.0 %) having positive margins. Adjuvant chemotherapy was recommended for 13 (76.5 %), and adjuvant radiotherapy was recommended for 13 (76.5 %). Of the 17 premenopausal women, 11 had a clinical response based on response evaluation criteria in solid tumors (RECIST) of a decrease in tumor size of 30 % (64.7 %); this is similar to that of postmenopausal women, where 85 of 145 (58.6 %) patients showed a clinical response. CONCLUSION: As with all neoadjuvant systemic interventions, we identified those with disease that did and did not respond to ET, emphasizing the heterogeneity of HR-positive breast cancers. The response rate of premenopausal women to neoadjuvant ET is similar to that of postmenopausal women.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Pré-Menopausa , Adulto , Anastrozol , Neoplasias da Mama/química , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/química , Carcinoma Lobular/cirurgia , Quimioterapia Adjuvante , Feminino , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Letrozol , Pessoa de Meia-Idade , Terapia Neoadjuvante , Nitrilas/administração & dosagem , Receptores de Estrogênio/análise , Critérios de Avaliação de Resposta em Tumores Sólidos , Tamoxifeno/administração & dosagem , Triazóis/administração & dosagem
9.
J Clin Invest ; 124(12): 5411-23, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25365225

RESUMO

Triple-negative breast cancers (TNBCs) are a heterogeneous set of cancers that are defined by the absence of hormone receptor expression and HER2 amplification. Here, we found that inducible IκB kinase-related (IKK-related) kinase IKBKE expression and JAK/STAT pathway activation compose a cytokine signaling network in the immune-activated subset of TNBC. We found that treatment of cultured IKBKE-driven breast cancer cells with CYT387, a potent inhibitor of TBK1/IKBKE and JAK signaling, impairs proliferation, while inhibition of JAK alone does not. CYT387 treatment inhibited activation of both NF-κB and STAT and disrupted expression of the protumorigenic cytokines CCL5 and IL-6 in these IKBKE-driven breast cancer cells. Moreover, in 3D culture models, the addition of CCL5 and IL-6 to the media not only promoted tumor spheroid dispersal but also stimulated proliferation and migration of endothelial cells. Interruption of cytokine signaling by CYT387 in vivo impaired the growth of an IKBKE-driven TNBC cell line and patient-derived xenografts (PDXs). A combination of CYT387 therapy with a MEK inhibitor was particularly effective, abrogating tumor growth and angiogenesis in an aggressive PDX model of TNBC. Together, these findings reveal that IKBKE-associated cytokine signaling promotes tumorigenicity of immune-driven TNBC and identify a potential therapeutic strategy using clinically available compounds.


Assuntos
Neoplasias da Mama/metabolismo , Quimiocina CCL5/metabolismo , Quinase I-kappa B/metabolismo , Interleucina-6/metabolismo , Proteínas de Neoplasias/metabolismo , Transdução de Sinais , Animais , Benzamidas/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quimiocina CCL5/genética , Feminino , Humanos , Quinase I-kappa B/genética , Interleucina-6/genética , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas de Neoplasias/genética , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Cancer Discov ; 4(4): 452-65, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24444711

RESUMO

Although the roles of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, the inhibition of which are likely to be necessary for effective KRAS-directed therapy. Here, we show that the IκB kinase (IKK)-related kinases Tank-binding kinase-1 (TBK1) and IKKε promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKKε inhibitor. CYT387 treatment ablates RAS-associated cytokine signaling and impairs Kras-driven murine lung cancer growth. Combined CYT387 treatment and MAPK pathway inhibition induces regression of aggressive murine lung adenocarcinomas driven by Kras mutation and p53 loss. These observations reveal that TBK1/IKKε promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKKε, Janus-activated kinase (JAK), and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS.


Assuntos
Comunicação Autócrina , Benzamidas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas ras/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Quimiocina CCL5/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas I-kappa B/metabolismo , Interleucina-6/metabolismo , Camundongos , Neoplasias Experimentais , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo
11.
Proc Natl Acad Sci U S A ; 100(26): 15601-6, 2003 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-14671316

RESUMO

In addition to causing regression of the Mullerian duct in the male embryo, Mullerian Inhibiting Substance (MIS) inhibits the growth of epithelial ovarian cancer cells, which are known to be of Mullerian origin. Because the uterine cervix is derived from the same Mullerian duct precursor as the epithelium of the ovary, we tested the hypothesis that cervical cancer cells might also respond to MIS. A number of cervical cancer cell lines express the MIS type II receptor, and MIS inhibits the growth of both human papilloma virus-transformed and non-human papilloma virus-transformed cervical cell lines, with a more dramatic effect seen in the latter. As in the ovarian cancer cell line OVCAR8, suppression of growth of the C33A cervical cancer cell line by MIS is associated with induction of the p16 tumor suppressor protein. However, in contrast to OVCAR8 cells, induction of p130 and p107 appears to play an important role in the inhibition of growth of C33A cells by MIS. Finally, normal cervical tissue expresses the MIS type II receptor in vivo, supporting the idea that MIS could be a targeted therapy for cervical cancer.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Divisão Celular/efeitos dos fármacos , Glicoproteínas/metabolismo , Proteínas Nucleares/fisiologia , Fosfoproteínas/fisiologia , Proteínas , Hormônios Testiculares/metabolismo , Animais , Hormônio Antimülleriano , Western Blotting , Células COS , Proteínas de Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Transformada , Colo do Útero/citologia , Colo do Útero/efeitos dos fármacos , Chlorocebus aethiops , Quinases Ciclina-Dependentes/genética , Feminino , Humanos , Ductos Paramesonéfricos , Ratos , Proteína do Retinoblastoma/fisiologia , Proteína p107 Retinoblastoma-Like , Proteína p130 Retinoblastoma-Like , Transdução de Sinais/efeitos dos fármacos , Transfecção , Células Tumorais Cultivadas , Neoplasias do Colo do Útero
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