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1.
Cell ; 186(25): 5620-5637.e16, 2023 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-38065082

RESUMO

Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments.


Assuntos
Neoplasias Colorretais , Instabilidade de Microssatélites , Microambiente Tumoral , Humanos , Instabilidade Cromossômica/genética , Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica , Quinases Ativadas por p21/genética , Filogenia , Mutação , Progressão da Doença , Prognóstico
2.
Mol Cancer ; 20(1): 85, 2021 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-34092233

RESUMO

BACKGROUND: While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy. METHODS: Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAFwt and BRAFmut melanoma and analyzed in reference to patient data. RESULTS: RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8+ cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40+SOX10+ melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB. CONCLUSIONS: Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone. TRIAL REGISTRATION: NCT01205815 (Sept 17, 2010).


Assuntos
Antineoplásicos/farmacologia , Antígenos CD40/biossíntese , Glicina/análogos & derivados , Inibidores de Checkpoint Imunológico/farmacologia , Melanoma/patologia , Sulfonas/farmacologia , Proteínas ras/antagonistas & inibidores , Animais , Feminino , Glicina/farmacologia , Humanos , Masculino , Melanoma/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases raf/antagonistas & inibidores
3.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069042

RESUMO

OBJECTIVES: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. METHODS: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. RESULTS: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. CONCLUSION: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Inibidores de Checkpoint Imunológico , Animais , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Granulócitos/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Morfolinas/administração & dosagem , Paclitaxel/administração & dosagem , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Pirimidinas/administração & dosagem , Quinazolinas/administração & dosagem , Tiazóis/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento , Triazinas/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos
4.
BMC Cancer ; 17(1): 434, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28633655

RESUMO

BACKGROUND: Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Local treatment of the intraocular disease is usually effective if diagnosed early; however advanced Rb can metastasize through routes that involve invasion of the choroid, sclera and optic nerve or more broadly via the ocular vasculature. Metastatic Rb patients have very high mortality rates. While current therapy for Rb is directed toward blocking tumor cell division and tumor growth, there are no specific treatments targeted to block Rb metastasis. Two such targets are matrix metalloproteinases-2 and -9 (MMP-2, -9), which degrade extracellular matrix as a prerequisite for cellular invasion and have been shown to be involved in other types of cancer metastasis. Cancer Clinical Trials with an anti-MMP-9 therapeutic antibody were recently initiated, prompting us to investigate the role of MMP-2, -9 in Rb metastasis. METHODS: We compare MMP-2, -9 activity in two well-studied Rb cell lines: Y79, which exhibits high metastatic potential and Weri-1, which has low metastatic potential. The effects of inhibitors of MMP-2 (ARP100) and MMP-9 (AG-L-66085) on migration, angiogenesis, and production of immunomodulatory cytokines were determined in both cell lines using qPCR, and ELISA. Cellular migration and potential for invasion were evaluated by the classic wound-healing assay and a Boyden Chamber assay. RESULTS: Our results showed that both inhibitors had differential effects on the two cell lines, significantly reducing migration in the metastatic Y79 cell line and greatly affecting the viability of Weri-1 cells. The MMP-9 inhibitor (MMP9I) AG-L-66085, diminished the Y79 angiogenic response. In Weri-1 cells, VEGF was significantly reduced and cell viability was decreased by both MMP-2 and MMP-9 inhibitors. Furthermore, inhibition of MMP-2 significantly reduced secretion of TGF-ß1 in both Rb models. CONCLUSIONS: Collectively, our data indicates MMP-2 and MMP-9 drive metastatic pathways, including migration, viability and secretion of angiogenic factors in Rb cells. These two subtypes of matrix metalloproteinases represent new potential candidates for targeted anti-metastatic therapy for Rb.


Assuntos
Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Neovascularização Patológica/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Retinoblastoma/genética , Retinoblastoma/patologia , Fator A de Crescimento do Endotélio Vascular/genética
5.
Cancer Lett ; 586: 216681, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38311054

RESUMO

Triple-negative breast cancer (TNBC) is a heterogeneous and challenging-to-treat breast cancer subtype. The clinical introduction of immune checkpoint inhibitors (ICI) for TNBC has had mixed results, and very few patients achieved a durable response. The PI3K/AKT pathway is frequently mutated in breast cancer. Given the important roles of the PI3K pathway in immune and tumor cell signaling, there is an interest in using inhibitors of this pathway to increase the response to ICI. This study sought to determine if AKT inhibition could enhance the response to ICI in murine TNBC models. We further sought to understand underlying mechanisms of response or non-response to AKT inhibition in combination with ICI. Using four murine TNBC-like cell lines and corresponding orthotopic mouse tumor models, we found that hyperactivity of the PI3K pathway, as evidenced by levels of phospho-AKT rather than PI3K pathway mutational status, was associated with response to AKT inhibition alone and in combination with ICI. Additional mutations in other growth regulatory pathways could override the response of PI3K pathway mutant tumors to AKT inhibition. Furthermore, we observed that AKT inhibition enhanced the response to ICI in an already sensitive model. However, AKT inhibition failed to convert ICI-resistant tumors, to responsive tumors. These findings suggest that analysis of both the mutational status and phospho-AKT protein levels may be beneficial in predicting which TNBC tumors will respond to AKT inhibition in combination with ICI.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Modelos Animais de Doenças , Linhagem Celular Tumoral
6.
Tetrahedron Lett ; 54(9): 1141-1144, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24926109

RESUMO

Microwave irradiated palladium-catalyzed cross-coupling reaction of potassium styryltrifluoroborates and sodium nitrite gives the corresponding styryl nitrites in high yields. Potassium aryltrifluoroborates also furnish aryl nitrites under same reaction condition. This unprecedented cross-coupling is an interesting development and has the potential to lead to new nitration protocols.

7.
SAGE Open Med ; 11: 20503121231199857, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37808510

RESUMO

Objective: Lebanon has historically maintained high immunization coverage rates for most routine vaccines. However, an increase in poverty rates coupled with an influx of over a million refugees posed significant challenges to the national immunization program. In response, an accelerated immunization activities (AIA) program, encompassing community-based outreach and referral activities, was launched to increase the demand for childhood vaccination through the public healthcare system. Despite this effort, uptake among refugee and host community households remained low, resulting in pockets of low immunization coverage rates. This study investigates the barriers that prevent households in low coverage areas from vaccinating their children, and evaluates a behavior change intervention designed to overcome the identified social, perceptual, and cognitive barriers. Methods: Households with un- or under-vaccinated children were recruited from seven cadastres with low immunization coverage rates. A mixed methods approach, including stakeholder interviews and field observations, was employed to identify the main barriers to vaccination. Thereafter, a cluster randomized trial was conducted to evaluate the impact of a visual planning aid comprising five behavior change techniques (nudges) on vaccine uptake. Results: A total of 12,332 un- or under-vaccinated children from 6160 households (3045 (49.4%) control households; 3115 (50.6%) treated households) were reached during the trial. The observed vaccination rates were 13.5% and 20.2% for control and treated households, respectively. This represents a 6.7 percentage points increase in the likelihood of a treated household to vaccinate at least one child, compared to the control group. At least 390 additional children benefited from life-saving vaccines due to the behavioral intervention. Conclusions: This study highlights the importance of integrating behavioral insights into vaccination campaigns and programs, especially in low resource settings, to ensure that more children can benefit from life-saving vaccines.

8.
J Ethnopharmacol ; 308: 116254, 2023 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-36781058

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Depression is a public health problem. Despite the availability of treatment options, its prevalence is increasing. A high rate of treatment failure is often reported, along with considerable side effects associated with synthetic antidepressants. Therefore, developing effective and safe antidepressants from traditional herbs or natural products as an alternative strategy is warranted to avoid side effects and increase drug efficacy. In traditional medicine, cardamom has traditionally been used to treat conditions like asthma, tooth and gum infections, cataracts, nausea, diarrhea, and even depression and anxiety as well as some problems with the heart, kidneys, and digestive system. AIM OF THE STUDY: The current study aimed to evaluate the antidepressant activity of cardamom oil in a rat model of depression induced by reserpine and compare it with the activity of the antidepressant drug fluoxetine. MATERIALS AND METHODS: Depression-like symptoms were induced in male rats by daily i. p. injection of reserpine (0.2 mg/kg/d for 15 d followed by 0.1 mg/kg/d for 21 d to maintain the depressive state), and the rats were treated with cardamom oil (oral dose = 200 mg/kg/d) for 21 d along with the maintenance dose of reserpine. We performed behavioral tests (forced swimming test and open-field test) and evaluated biochemical markers of depression. RESULTS: Our findings revealed that cardamom oil attenuated depression-like symptoms in reserpine-injected rats by improving the behavioral changes measured by the forced swimming test and the locomotor activities measured by the open-field test. In reserpine-injected rats, cardamom oil exerted antidepressant-like effects by modulating lower levels of brain monoamine neurotransmitters (serotonin, norepinephrine, and dopamine), GSH, and higher oxido-nitrosative stress parameters (malondialdehyde and nitric oxide). Moreover, cardamom oil alleviated depression-like behaviors by lowering monoamine oxidase activity and raising the activities of Na+/K+-ATPase and acetylcholinesterase and levels of a brain-derived neurotrophic factor in the cortex and hippocampus. CONCLUSION: We recommend the use of cardamom oil as a safe and reliable treatment or an adjuvant for preventing depression-like symptoms in patients suffering from depression.


Assuntos
Elettaria , Reserpina , Ratos , Masculino , Animais , Reserpina/farmacologia , Depressão/tratamento farmacológico , Acetilcolinesterase , Antidepressivos/farmacologia , Comportamento Animal , Modelos Animais de Doenças
9.
Cancers (Basel) ; 15(14)2023 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-37509357

RESUMO

Current methodologies for developing PDX in humanized mice in preclinical trials with immune-based therapies are limited by GVHD. Here, we compared two approaches for establishing PDX tumors in humanized mice: (1) PDX are first established in immune-deficient mice; or (2) PDX are initially established in humanized mice; then established PDX are transplanted to a larger cohort of humanized mice for preclinical trials. With the first approach, there was rapid wasting of PDX-bearing humanized mice with high levels of activated T cells in the circulation and organs, indicating immune-mediated toxicity. In contrast, with the second approach, toxicity was less of an issue and long-term human melanoma tumor growth and maintenance of human chimerism was achieved. Preclinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with PDX tumors established from tumors with limited CD8+ T cell content. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in humanized mice before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response.

10.
Artigo em Inglês | MEDLINE | ID: mdl-37297644

RESUMO

The COVID-19 pandemic led many countries to apply lockdown measures that could prevent children from achieving the physical activity, sedentary behavior, and sleep levels suggested for their psychophysical health. The current study tested changes in physical activity, sedentary behavior, and sleep length of children and the incidence of achieving the 24 h movement standards through the limitations of COVID-19. A total of 490 Arab Israeli parents were surveyed. An electronic cross-sectional survey was performed, including questions addressing engagement in physical activities, use of screens, and sleep duration. Throughout the COVID-19 outbreak, time spent participating in physical activity was reduced, sedentary behavior and sleep duration were increased, and the percentage of the sample who met the physical activity and sedentary behavior suggestions lessened. The percentage of participants who attained the overall 24 h movement recommendations was very low during the pandemic; school children met the guideline recommendations for physical activity and sleep duration more than preschool children, and girls spent more time in physical activity. These findings highlight the need for strategies to enhance physical activity and decrease sedentary behavior in children to prevent long-term effects of limitations imposed by COVID-19. Efforts to perceive and encourage healthy routines in Arab Israeli children in the case of pandemic limitations are expected to serve as a precedence.


Assuntos
COVID-19 , Exercício Físico , Comportamento Sedentário , Duração do Sono , Criança , Pré-Escolar , Feminino , Humanos , Árabes , Controle de Doenças Transmissíveis , COVID-19/epidemiologia , Estudos Transversais , Israel/epidemiologia , Pandemias , Sono , Masculino
11.
J Immunother Cancer ; 11(5)2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37230537

RESUMO

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are a mainstay treatment for hormone receptor-positive breast cancer. While their principal mechanism is inhibition of cancer cell proliferation, preclinical and clinical evidence suggests that CDK4/6i can also promote antitumor T-cell responses. However, this pro-immunogenic property is yet to be successfully harnessed in the clinic, as combining CDK4/6i with immune checkpoint blockade (ICB) has not shown a definitive benefit in patients. METHOD: We performed an in-depth analysis of the changes in the tumor immune microenvironment and systemic immune modulation associated with CDK4/6i treatment in muring breast cancer models and in patients with breast cancer using high dimensional flow cytometry and RNA sequencing. Gain and loss of function in vivo experiments employing cell transfer and depletion antibody were performed to uncover immune cell populations critical for CDK4/6i-mediated stimulation of antitumor immunity. RESULTS: We found that loss of dendritic cells (DCs) within the tumor microenvironment resulting from CDK4/6 inhibition in bone marrow progenitors is a major factor limiting antitumor immunity after CDK4/6i and ICB. Consequently, restoration of DC compartment by adoptively transferring ex vivo differentiated DCs to mice treated with CDK4/6i and ICB therapy enabled robust tumor inhibition. Mechanistically, the addition of DCs promoted the induction of tumor-localized and systemic CD4 T-cell responses in mice receiving CDK4/6i-ICB-DC combination therapy, as characterized by enrichment of programmed cell death protein-1-negative T helper (Th)1 and Th2 cells with an activated phenotype. CD4 T-cell depletion abrogated the antitumor benefit of CDK4/6i-ICB-DC combination, with outgrowing tumors displaying an increased proportion of terminally exhausted CD8 T cells. CONCLUSIONS: Our findings suggest that CDK4/6i-mediated DC suppression limits CD4 T-cell responses essential for the sustained activity of CD8 T cells and tumor inhibition. Furthermore, they imply that restoring DC-CD4 T-cell crosstalk via DC transfer enables effective breast cancer immunity in response to CDK4/6i and ICB treatment.


Assuntos
Linfócitos T CD4-Positivos , Inibidores de Checkpoint Imunológico , Camundongos , Animais , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linhagem Celular Tumoral , Linfócitos T Auxiliares-Indutores , Células Dendríticas
12.
Cell Rep ; 35(1): 108944, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33826903

RESUMO

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Here, we show that CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models. This effect is driven by the induction of chemokines CCL5, CXCL9, and CXCL10 in CDK4/6i-treated tumor cells facilitating recruitment of activated CD8+ T cells, but not Tregs, into the tumor. Mechanistically, chemokine induction is associated with metabolic stress that CDK4/6i treatment induces in breast cancer cells. Despite the cell cycle arrest, CDK4/6i-treated cells retain high metabolic activity driven by deregulated PI3K/mTOR pathway. This causes cell hypertrophy and increases mitochondrial content/activity associated with oxidative stress and inflammatory stress response. Our findings uncover a link between tumor metabolic vulnerabilities and anti-tumor immunity and support further development of CDK4/6i and immunotherapy combinations.


Assuntos
Quimiocinas/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias Mamárias Animais/imunologia , Inibidores de Proteínas Quinases/farmacologia , Linfócitos T/imunologia , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Humanos , Hipertrofia , Imunoterapia , Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Animais/terapia , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Receptores de Quimiocinas/metabolismo , Linfócitos T/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
13.
Sci Transl Med ; 11(505)2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413145

RESUMO

Intrinsic resistance of unknown mechanism impedes the clinical utility of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) in malignancies other than breast cancer. Here, we used melanoma patient-derived xenografts (PDXs) to study the mechanisms for CDK4/6i resistance in preclinical settings. We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner. We showed that a target of p21, CDK2, was necessary for proliferation in CDK4/6i-treated cells. Upon treatment with CDK4/6i, melanoma cells up-regulated cyclin D1, which sequestered p21 and another CDK inhibitor, p27, leaving a shortage of p21 and p27 available to bind and inhibit CDK2. Therefore, we tested whether induction of p21 in resistant melanoma cells would render them responsive to CDK4/6i. Because p21 is transcriptionally driven by p53, we coadministered CDK4/6i with a murine double minute (MDM2) antagonist to stabilize p53, allowing p21 accumulation. This resulted in improved antitumor activity in PDXs and in murine melanoma. Furthermore, coadministration of CDK4/6 and MDM2 antagonists with standard of care therapy caused tumor regression. Notably, the molecular features associated with response to CDK4/6 and MDM2 inhibitors in PDXs were recapitulated by an ex vivo organotypic slice culture assay, which could potentially be adopted in the clinic for patient stratification. Our findings provide a rationale for cotargeting CDK4/6 and MDM2 in melanoma.


Assuntos
Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Análise de Variância , Animais , Western Blotting , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Replicação do DNA/efeitos dos fármacos , Replicação do DNA/genética , Dimetil Sulfóxido/farmacologia , Humanos , Imunoprecipitação , Células MCF-7 , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteômica , Ensaio de Radioimunoprecipitação
14.
EBioMedicine ; 24: 43-55, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29030058

RESUMO

Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations.


Assuntos
Azepinas/administração & dosagem , Dano ao DNA/efeitos dos fármacos , Imidazóis/administração & dosagem , Melanoma/tratamento farmacológico , Piperazinas/administração & dosagem , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirimidinas/administração & dosagem , Pirrolidinas/administração & dosagem , para-Aminobenzoatos/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Azepinas/farmacologia , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Replicação do DNA/efeitos dos fármacos , Células HCT116 , Humanos , Imidazóis/farmacologia , Melanoma/genética , Camundongos , Piperazinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , para-Aminobenzoatos/farmacologia
16.
J Neurosurg ; 123(3): 547-60, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26115470

RESUMO

OBJECT: Various bibliometric indices based on the citations accumulated by scholarly articles, including the h-index, g-index, e-index, and Google's i10-index, may be used to evaluate academic productivity in neurological surgery. The present article provides a comprehensive assessment of recent academic publishing output from 103 US neurosurgical residency programs and investigates intradepartmental publishing equality among faculty members. METHODS: Each institution was considered a single entity, with the 5-year academic yield of every neurosurgical faculty member compiled to compute the following indices: ih(5), cumulative h, ig(5), ie(5), and i10(5) (based on publications and citations from 2009 through 2013). Intradepartmental comparison of productivity among faculty members yielded Gini coefficients for publications and citations. National and regional comparisons, institutional rankings, and intradepartmental publishing equality measures are presented. RESULTS: The median numbers of departmental faculty, total publications and citations, ih(5), summed h, ig(5), ie(5), i10(5), and Gini coefficients for publications and citations were 13, 82, 716, 12, 144, 23, 16, 17, 0.57, and 0.71, respectively. The top 5 most academically productive neurosurgical programs based on ih(5)-index were University of California, San Francisco, University of California, Los Angeles, University of Pittsburgh, Brigham & Women's Hospital, and Johns Hopkins University. The Western US region was most academically productive and displayed greater intradepartmental publishing equality (median ih[5]-index = 18, median Ginipub = 0.56). In all regions, large departments with relative intradepartmental publishing equality tend to be the most academically productive. Multivariable logistic regression analysis identified the ih(5)-index as the only independent predictor of intradepartmental publishing equality (Ginipub ≤ 0.5 [OR 1.20, 95% CI 1.20-1.40, p = 0.03]). CONCLUSIONS: The ih(5)-index is a novel, simple, and intuitive metric capable of accurately comparing the recent scholarly efforts of neurosurgical programs and accurately predicting intradepartmental publication equality. The ih(5)-index is relatively insensitive to factors such as isolated highly productive and/or no longer academically active senior faculty, which tend to distort other bibliometric indices and mask the accurate identification of currently productive academic environments. Institutional ranking by ih(5)-index may provide information of use to faculty and trainee applicants, research funding institutions, program leaders, and other stakeholders.


Assuntos
Bibliometria , Internato e Residência/estatística & dados numéricos , Neurocirurgia/educação , Publicações/estatística & dados numéricos , Editoração/estatística & dados numéricos , Eficiência , Humanos , Estados Unidos
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