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1.
Future Oncol ; : 1-14, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38501262

RESUMO

What is this summary about? This PLSP provides a short summary of an original scientific article that presented results from the PRIMA study after 3.5 years of follow-up time. The original article was published in the European Journal of Cancer in 2023.The PRIMA study included adult patients with newly diagnosed advanced high-risk ovarian cancer whose tumors shrunk or became undetectable after treatment with chemotherapy with or without surgery. The PRIMA study evaluated how well the drug niraparib, also known as Zejula, worked at delaying or preventing ovarian cancer from coming back (recurring) or getting worse (progressing) compared with placebo (a substance with no effects that a doctor gives to a patient instead of a drug). The first results from the PRIMA study were published in 2019, when patients had participated in the PRIMA study for about 1.2 years.The article this PLSP is based on reports longer-term data from the PRIMA study, when patients had participated in the PRIMA study for about 3.5 years. Patients were monitored (or followed) for a longer time to understand how well niraparib continued to work and to evaluate whether the safety of niraparib changed with additional time being monitored.What were the results? Patients who took niraparib had more time before their cancer came back or got worse than patients who took placebo. In terms of safety, no new types of side effects with niraparib treatment were observed with additional time being monitored as part of the PRIMA study.What do the results mean? These results support that niraparib remains an important treatment option to help delay the cancer from coming back or getting worse in patients with newly diagnosed advanced ovarian cancer that responded to initial treatment.Clinical Trial Registration: NCT02655016 (PRIMA study) (ClinicalTrials.gov).

2.
Clin Ther ; 46(3): 228-238, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38423866

RESUMO

PURPOSE: The poly (ADP-ribose) polymerase inhibitor niraparib is indicated as maintenance treatment in patients with certain subtypes of advanced ovarian cancer, and is being investigated in patients with other solid tumors. Niraparib is available in 100-mg capsules with a starting dosage of 200 or 300 mg/d. This study assessed the relative bioavailability (BA) and bioequivalence (BE) between a 1 × 300-mg tablet relative to 3 × 100-mg niraparib capsules. In addition, the food effect (FE) of a high-fat meal on the pharmacokinetic (PK) properties of tablet-formulated niraparib was investigated. METHODS: This was a US-based, 3-stage, open-label, multicenter, single-crossover, randomized-sequence study. Enrolled patients were 18 years and older, with histologically or cytologically confirmed advanced solid tumors (metastatic or local) and disease progression despite standard therapy. Patients were randomly assigned 1:1 to receive niraparib 1 × 300-mg tablet or 3 × 100-mg capsules in the BA and BE stages or 1 × 300-mg tablet in a fasted or fed (high-fat meal) state in the FE stage. Across all study stages, PK parameters were assessed for 7 days after each dose (tablet or capsule) or prandial state (fasted or fed). In the BA stage, patients crossed over to the other treatment after a 7-day washout period, which was extended to 14 days in the BE and FE stages. Tolerability was assessed for patients who received any amount of niraparib. FINDINGS: The BA-, BE-, and FE-evaluable populations comprised 23, 108, and 19 patients, respectively, who completed both treatment periods in each study stage, had sufficient concentration data to accurately estimate PK parameters without niraparib carryover, and did not experience disqualifying events. PK parameters were similar after dosing with tablet or capsule formulations; the 90% CIs of the geometric least square means for Cmax, AUC0-t, and AUC0-∞ were within the 0.80 to 1.25 BE limits. In the FE stage, Cmax, AUC0-t, and AUC0-∞ were 11%, 32%, and 28% higher, respectively, in the fed versus fasted state. The safety population included 29, 168, and 28 patients in the BA, BE, and FE stages, respectively, who received niraparib. No new safety signals were identified. IMPLICATIONS: Niraparib tablets were found to be bioequivalent to capsules. A modest (≤32%) FE was observed with a high-fat meal, but was not considered to be clinically meaningful, given niraparib's PK variability. CLINICALTRIALS: gov identifier: NCT03329001. (Clin Ther. 2024;46:XXX-XXX) © 2024 Elsevier HS Journals, Inc.


Assuntos
Antineoplásicos , Indazóis , Neoplasias , Piperidinas , Humanos , Antineoplásicos/farmacologia , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Jejum , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Comprimidos/farmacocinética , Equivalência Terapêutica
3.
Int J Gynecol Cancer ; 33(11): 1733-1742, 2023 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-37931976

RESUMO

OBJECTIVE: Progression-free survival is an established clinically meaningful endpoint in ovarian cancer trials, but it may be susceptible to bias; therefore, blinded independent centralized radiological review is often included in trial designs. We compared blinded independent centralized review and investigator-assessed progressive disease performance in the PRIMA/ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy. METHODS: PRIMA/ENGOT-ov26/GOG-3012 was a randomized, double-blind phase 3 trial; patients with newly diagnosed stage III/IV ovarian cancer received niraparib or placebo. The primary endpoint was progression-free survival (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), determined by two independent radiologists, an arbiter if required, and by blinded central clinician review. Discordance rates between blinded independent centralized review and investigator assessment of progressive disease and non-progressive disease were routinely assessed. To optimize disease assessment, a training intervention was developed for blinded independent centralized radiological reviewers, and RECIST refresher training was provided for investigators. Discordance rates were determined post-intervention. RESULTS: There was a 39% discordance rate between blinded independent centralized review and investigator-assessed progressive disease/non-progressive disease in an initial patient subset (n=80); peritoneal carcinomatosis was the most common source of discordance. All reviewers underwent training, and as a result, changes were implemented, including removal of two original reviewers and identification of 10 best practices for reading imaging data. Post-hoc analysis indicated final discordance rates between blinded independent centralized review and investigator improved to 12% in the overall population. Median progression-free survival and hazard ratios were similar between blinded independent centralized review and investigators in the overall population and across subgroups. CONCLUSION: PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize blinded independent centralized review and investigator concordance using early, specialized, ovarian-cancer-specific radiology training to maximize validity of outcome data.


Assuntos
Neoplasias Ovarianas , Neoplasias Peritoneais , Feminino , Humanos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Progressão da Doença , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase III como Assunto
4.
Eur J Cancer ; 189: 112908, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37263896

RESUMO

PURPOSE: To report updated long-term efficacy and safety from the double-blind, placebo-controlled, phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). METHODS: Patients with newly diagnosed advanced ovarian cancer with complete or partial response (CR or PR) to first-line platinum-based chemotherapy received niraparib or placebo once daily (2:1 ratio). Stratification factors were best response to first-line chemotherapy regimen (CR/PR), receipt of neoadjuvant chemotherapy (yes/no), and homologous recombination deficiency (HRD) status (deficient [HRd]/proficient [HRp] or not determined). Updated (ad hoc) progression-free survival (PFS) data (as of November 17, 2021) by investigator assessment (INV) are reported. RESULTS: In 733 randomised patients (niraparib, 487; placebo, 246), median PFS follow-up was 3.5years. Median INV-PFS was 24.5 versus 11.2months (hazard ratio, 0.52; 95% confidence interval [CI], 0.40-0.68) in the HRd population and 13.8 versus 8.2months (hazard ratio, 0.66; 95% CI, 0.56-0.79) in the overall population for niraparib and placebo, respectively. In the HRp population, median INV-PFS was 8.4 versus 5.4months (hazard ratio, 0.65; 95% CI, 0.49-0.87), respectively. Results were concordant with the primary analysis. Niraparib-treated patients were more likely to be free of progression or death at 4years than placebo-treated patients (HRd, 38% versus 17%; overall, 24% versus 14%). The most common grade ≥ 3 treatment-emergent adverse events in niraparib patients were thrombocytopenia (39.7%), anaemia (31.6%), and neutropenia (21.3%). Myelodysplastic syndromes/acute myeloid leukaemia incidence rate (1.2%) was the same for niraparib- and placebo-treated patients. Overall survival remained immature. CONCLUSIONS: Niraparib maintained clinically significant improvements in PFS with 3.5years of follow-up in patients with newly diagnosed advanced ovarian cancer at high risk of progression irrespective of HRD status. No new safety signals were identified.


Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Intervalo Livre de Progressão , Neoplasias Ovarianas/tratamento farmacológico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Indazóis/efeitos adversos , Quimioterapia de Manutenção/métodos
5.
Cancer ; 129(12): 1846-1855, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37060236

RESUMO

BACKGROUND: The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer. METHODS: In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg once daily. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg once daily in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/µL, and 300 mg once daily in all other patients. Efficacy and safety outcomes were assessed by starting dose. RESULTS: Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46-0.76] vs. ISD HR, 0.69 [95% CI, 0.48-0.98]) and the homologous recombination-deficient (FSD HR, 0.44 [95% CI, 0.30-0.64] vs. ISD HR, 0.39 [95% CI, 0.22-0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD. CONCLUSIONS: In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.


Assuntos
Neoplasias Ovarianas , Feminino , Humanos , Peso Corporal , Carcinoma Epitelial do Ovário/tratamento farmacológico , Indazóis , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Estudos Prospectivos
6.
Future Oncol ; 18(30): 3435-3447, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36102225

RESUMO

Aim: To review safety and efficacy outcomes in studies of first-line maintenance therapies for advanced ovarian cancer. Methods: A systematic literature review was performed (27 February 2020) to identify clinical outcomes including progression-free survival (PFS), overall survival (OS) and Grade ≥3 adverse events. Results: Overall 50 references met prespecified criteria; 18 studies evaluated 10 different agents, including PARP inhibitors. PFS was an end point in 16 trials and OS in 12 trials. PARP inhibitors reported better PFS hazard ratios (HRs: 0.59-0.68) compared with other classes; no mature OS data were identified. Safety reporting was inconsistent. Conclusion: Reported PFS HRs were better for PARP inhibitors than for other ovarian cancer maintenance therapies; overall survival data remain immature.


This article reports the results from a systematic literature review (SLR), enabling a critical and unbiased comparison of clinical studies, of responses and side effects of first-line maintenance therapies used for advanced ovarian cancer. Overall, this SLR supports the use of PARP inhibitors as maintenance therapy for patients with advanced ovarian cancer as they demonstrated a greater effect on delaying further disease progression than other drug types assessed. However, due to large differences between the clinical studies included (e.g. design of the trial), direct comparisons between first-line maintenance therapies must be made with caution. Healthcare professionals must factor individual patient circumstances when choosing the most appropriate therapy.


Assuntos
Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Intervalo Livre de Progressão
7.
Gynecol Oncol ; 166(1): 36-43, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35550709

RESUMO

OBJECTIVE: To evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer at high risk of recurrence. METHODS: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible residual disease [VRD]) in the intent-to-treat population. RESULTS: In PRIMA (N = 733), 236 (32.2%) patients underwent PDS, and 481 (65.6%) received NACT/IDS before enrollment. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) for progression were similar in PDS (13.7 vs 8.2 months; HR, 0.67 [0.47-0.96]) and NACT/IDS (14.2 vs 8.2 months; HR, 0.57 [0.44-0.73]) subgroups. In patients who received NACT/IDS and had NVRD (n = 304), the hazard ratio (95% CI) for progression was 0.65 (0.46-0.91). In patients with VRD following PDS (n = 183) or NACT/IDS (n = 149), the hazard ratios (95% CI) for progression were 0.58 (0.39-0.86) and 0.41 (0.27-0.62), respectively. PFS was not evaluable for patients with PDS and NVRD because of sample size (n = 37). CONCLUSIONS: In this post hoc analysis, niraparib efficacy was similar across PDS and NACT/IDS subgroups. Patients who had NACT/IDS and VRD had the highest reduction in the risk of progression with niraparib maintenance.


Assuntos
Neoplasias Ovarianas , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/cirurgia , Quimioterapia Adjuvante , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Indazóis/uso terapêutico , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasia Residual , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Piperidinas
8.
PLoS One ; 16(4): e0248380, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33891611

RESUMO

Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored. Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay.


Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Benzoxazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Mutação/efeitos dos fármacos , Naftiridinas/farmacologia , Neoplasias/genética , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Esclerose Tuberosa/genética , Esclerose Tuberosa/metabolismo , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
N Engl J Med ; 381(25): 2391-2402, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31562799

RESUMO

BACKGROUND: Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence of BRCA mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival. RESULTS: Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred. CONCLUSIONS: Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).


Assuntos
Indazóis/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Indazóis/efeitos adversos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/cirurgia , Piperidinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Qualidade de Vida , Análise de Sobrevida
11.
Cancer Res ; 77(12): 3255-3267, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28512249

RESUMO

p62/sequestosome-1 (SQSTM1) is a multifunctional adaptor protein and autophagic substrate that accumulates in cells with hyperactive mTORC1, such as kidney cells with mutations in the tumor suppressor genes tuberous sclerosis complex (TSC)1 or TSC2. Here we report that p62 is a critical mediator of TSC2-driven tumorigenesis, as Tsc2+/- and Tsc2f/f Ksp-CreERT2+ mice crossed to p62-/- mice were protected from renal tumor development. Metabolic profiling revealed that depletion of p62 in Tsc2-null cells decreased intracellular glutamine, glutamate, and glutathione (GSH). p62 positively regulated the glutamine transporter Slc1a5 and increased glutamine uptake in Tsc2-null cells. We also observed p62-dependent changes in Gcl, Gsr, Nqo1, and Srxn1, which were decreased by p62 attenuation and implicated in GSH production and utilization. p62 attenuation altered mitochondrial morphology, reduced mitochondrial membrane polarization and maximal respiration, and increased mitochondrial reactive oxygen species and mitophagy marker PINK1. These mitochondrial phenotypes were rescued by addition of exogenous GSH and overexpression of Sod2, which suppressed indices of mitochondrial damage and promoted growth of Tsc2-null cells. Finally, p62 depletion sensitized Tsc2-null cells to both oxidative stress and direct inhibition of GSH biosynthesis by buthionine sulfoximine. Our findings show how p62 helps maintain intracellular pools of GSH needed to limit mitochondrial dysfunction in tumor cells with elevated mTORC1, highlighting p62 and redox homeostasis as nodal vulnerabilities for therapeutic targeting in these tumors. Cancer Res; 77(12); 3255-67. ©2017 AACR.


Assuntos
Carcinogênese/metabolismo , Mitocôndrias/patologia , Complexos Multiproteicos/metabolismo , Proteína Sequestossoma-1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Esclerose Tuberosa/metabolismo , Animais , Carcinogênese/patologia , Modelos Animais de Doenças , Imunofluorescência , Glutationa/biossíntese , Imuno-Histoquímica , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Knockout , Esclerose Tuberosa/patologia , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/metabolismo
12.
PLoS Genet ; 12(8): e1006242, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27494029

RESUMO

Renal angiomyolipoma is a kidney tumor in the perivascular epithelioid (PEComa) family that is common in patients with Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) but occurs rarely sporadically. Though histologically benign, renal angiomyolipoma can cause life-threatening hemorrhage and kidney failure. Both angiomyolipoma and LAM have mutations in TSC2 or TSC1. However, the frequency and contribution of other somatic events in tumor development is unknown. We performed whole exome sequencing in 32 resected tumor samples (n = 30 angiomyolipoma, n = 2 LAM) from 15 subjects, including three with TSC. Two germline and 22 somatic inactivating mutations in TSC2 were identified, and one germline TSC1 mutation. Twenty of 32 (62%) samples showed copy neutral LOH (CN-LOH) in TSC2 or TSC1 with at least 8 different LOH regions, and 30 of 32 (94%) had biallelic loss of either TSC2 or TSC1. Whole exome sequencing identified a median of 4 somatic non-synonymous coding region mutations (other than in TSC2/TSC1), a mutation rate lower than nearly all other cancer types. Three genes with mutations were known cancer associated genes (BAP1, ARHGAP35 and SPEN), but they were mutated in a single sample each, and were missense variants with uncertain functional effects. Analysis of sixteen angiomyolipomas from a TSC subject showed both second hit point mutations and CN-LOH in TSC2, many of which were distinct, indicating that they were of independent clonal origin. However, three tumors had two shared mutations in addition to private somatic mutations, suggesting a branching evolutionary pattern of tumor development following initiating loss of TSC2. Our results indicate that TSC2 and less commonly TSC1 alterations are the primary essential driver event in angiomyolipoma/LAM, whereas other somatic mutations are rare and likely do not contribute to tumor development.


Assuntos
Angiomiolipoma/genética , Neoplasias Renais/genética , Linfangioleiomiomatose/genética , Proteínas Supressoras de Tumor/genética , Adulto , Angiomiolipoma/patologia , Carcinogênese/genética , Exoma/genética , Feminino , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Renais/patologia , Perda de Heterozigosidade/genética , Linfangioleiomiomatose/patologia , Masculino , Mutação , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa
13.
Hum Mol Genet ; 24(7): 1836-42, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25432535

RESUMO

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by seizures and tumor formation in multiple organs, mainly in the brain, skin, kidney, lung and heart. Renal cell carcinoma (RCC) occurs in ∼3% of TSC patients, and typically develops at age <50. Here we describe genetic findings in two TSC patients with multiple renal tumors, each of whom had the germline mutation TSC2 p.R905Q. The first (female) TSC patient had a left followed by a right nephrectomy at ages 24 and 27. Both kidneys showed multifocal TSC-associated papillary RCC (PRCC). Targeted, next-generation sequencing (NGS) analysis of TSC2 in five tumors (four from the left kidney, one from the right) showed loss of heterozygosity in one tumor, and four different TSC2 point mutations (p.E1351*, p.R1032*, p.R1713H, c.4178_4179delCT) in the other four samples. Only one of the 11 other tumors available from this patient had one of the TSC2 second hit mutations identified. Whole-exome analysis of the five tumors identified a very small number of additional mutated genes, with an average of 3.4 nonsilent coding, somatic mutations per tumor, none of which were seen in >1 tumor. The second (male) TSC patient had bilateral partial nephrectomies (both at age 36), with similar findings of multifocal PRCC. NGS analysis of TSC2 in two of these tumors identified a second hit mutation c.2355+1G>T in one sample that was not seen in other tumors. In conclusion, we report the first detailed genetic analysis of RCCs in TSC patients. Molecular studies indicate that tumors developed independently due to various second hit events, suggesting that these patients experienced a 'shower' of second hit mutations in TSC2 during kidney development leading to this severe phenotype.


Assuntos
Carcinoma de Células Renais/genética , Mutação , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Criança , Pré-Escolar , Feminino , Humanos , Rim/crescimento & desenvolvimento , Rim/metabolismo , Rim/patologia , Perda de Heterozigosidade , Masculino , Esclerose Tuberosa/metabolismo , Esclerose Tuberosa/patologia , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/metabolismo , Adulto Jovem
14.
Am J Respir Cell Mol Biol ; 51(6): 738-49, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24874429

RESUMO

Lymphangioleiomyomatosis (LAM) is a female-predominant cystic lung disease that can lead to respiratory failure. LAM cells typically have inactivating tuberous sclerosis complex 2 (TSC2) mutations and mammalian target of rapamycin (mTOR) complex (mTORC) 1 activation. Clinical response to the mTORC1 inhibitors has been limited, prompting a search for additional therapy for LAM. In this study, we investigated the impact of TSC2 on the expression of poly (ADP-ribose) polymerase (PARP)-1 that initiates the DNA repair pathway, and tested the efficacy of PARP1 inhibitors in the survival of TSC2-deficient (TSC2(-)) cells. We analyzed publicly available expression arrays of TSC2(-) cells and validated the findings using real-time RT-PCR, immunoblotting, and immunohistochemistry. We examined the impact of rapamycin and Torin 1 on PARP1 expression. We also tested the effect of PARP1 inhibitors, 8-hydroxy-2-methylquinazoline-4-one and 3,4-dihydro-5[4-(1-piperindinyl)butoxy]-1(2H)-isoquinoline, on the survival of TSC2(-) cells. We identified the up-regulation of PARP1 in TSC2(-) cells relative to cells in which wild-type TSC2 has been reintroduced (TSC2-addback [TSC2(+)] cells). The transcript levels of PARP1 in TSC2(-) cells were not affected by rapamycin. PARP1 levels were increased in TSC2(-) cells, xenograft tumors of rat-derived TSC2(-) cells, renal cystadenomas from Tsc2(+/-) mice, and human LAM nodules. RNA interference of mTOR failed to reduce PARP1 levels. Proliferation and survival of TSC2(-) cells was reduced in response to PARP1 inhibitor treatment, more so than TSC2(+) cells. TSC2(-) cells exhibit higher levels of PARP1 relative to TSC2(+) cells in an mTOR-insensitive manner. PARP1 inhibitors selectively suppress the growth and induce apoptosis of TSC2(-) cells from patients with LAM. Targeting PARP1 may be beneficial in the treatment of LAM and other neoplasm with mTORC1 activation.


Assuntos
Neoplasias Pulmonares/enzimologia , Linfangioleiomiomatose/enzimologia , Poli(ADP-Ribose) Polimerases/metabolismo , Quinazolinas/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular , Reparo do DNA , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Isoquinolinas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Linfangioleiomiomatose/tratamento farmacológico , Camundongos Endogâmicos C57BL , Camundongos SCID , Terapia de Alvo Molecular , Ftalazinas/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/genética , Ratos , Sirolimo/farmacologia , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Mol Cancer Res ; 12(1): 48-57, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24296756

RESUMO

UNLABELLED: The mammalian target of rapamycin complex 1 (mTORC1) is hyperactive in many human cancers and in tuberous sclerosis complex (TSC). Autophagy, a key mTORC1-targeted process, is a critical determinant of metabolic homeostasis. Metabolomic profiling was performed to elucidate the cellular consequences of autophagy dysregulation under conditions of hyperactive mTORC1. It was discovered that TSC2-null cells have distinctive autophagy-dependent pentose phosphate pathway (PPP) alterations. This was accompanied by enhanced glucose uptake and utilization, decreased mitochondrial oxygen consumption, and increased mitochondrial reactive oxygen species (ROS) production. Importantly, these findings revealed that the PPP is a key autophagy-dependent compensatory metabolic mechanism. Furthermore, PPP inhibition with 6-aminonicotinamide (6-AN) in combination with autophagy inhibition suppressed proliferation and prompted the activation of NF-κB and CASP1 in TSC2-deficient, but not TSC2-proficient cells. These data demonstrate that TSC2-deficient cells can be therapeutically targeted, without mTORC1 inhibitors, by focusing on their metabolic vulnerabilities. IMPLICATIONS: This study provides proof-of-concept that therapeutic targeting of diseases with hyperactive mTORC1 can be achieved without the application of mTORC1 inhibitors.


Assuntos
6-Aminonicotinamida/farmacologia , Autofagia/efeitos dos fármacos , Complexos Multiproteicos/metabolismo , Via de Pentose Fosfato/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/genética , Animais , Proteínas Reguladoras de Apoptose/genética , Proteína 5 Relacionada à Autofagia , Proteína Beclina-1 , Caspase 1/biossíntese , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Reprogramação Celular , Cloroquina/farmacologia , Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Hidroxicloroquina/farmacologia , Proteína 2 de Membrana Associada ao Lisossomo/genética , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos A , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/genética , Mitocôndrias/metabolismo , Complexos Multiproteicos/biossíntese , NF-kappa B/biossíntese , Consumo de Oxigênio/genética , Via de Pentose Fosfato/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/biossíntese , Teratogênicos/farmacologia , Proteína 2 do Complexo Esclerose Tuberosa
16.
PLoS One ; 8(2): e56199, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23437092

RESUMO

CONTEXT: We have previously shown that serum VEGF-D is elevated at baseline, correlates with kidney angiomyolipoma size at baseline and 12 months, and decreases with sirolimus treatment in adults with tuberous sclerosis complex (TSC). To further investigate the utility of serum VEGF-D for longer term monitoring of TSC kidney disease, we present VEGF-D level results with 24 month follow-up. OBJECTIVE: To compare 24 month VEGF-D levels in two subgroups of sirolimus treated patients (OFF SIROLIMUS AFTER 12 MONTHS or ON SIROLIMUS AFTER 12 MONTHS). DESIGN AND INTERVENTION(S): Serum VEGF-D was measured in samples collected from subjects enrolled in a phase 2 multicenter trial evaluating sirolimus for the treatment of kidney angiomyolipomas associated with TSC or TSC/LAM. All participants were treated with sirolimus from 0-12 months. During months 12-24, sirolimus was discontinued in one subgroup. The other subgroup was treated with additional sirolimus. SETTING: Adult TSC participants were recruited from six clinical sites in the United States (comprehensive TSC clinics, 5; urology clinic, 1). PATIENTS: There were 28 TSC patients who completed all 24 months of the study and serum samples were available at 24 months from 18/28 patients. MAIN OUTCOME MEASURE(S): We compared the percent change in VEGF-D levels (baseline to 24 months) in patients from the two treatment subgroups. RESULTS: At 24 months, VEGF-D levels decreased by 67% compared with baseline (to 787 ± 426 pg/ml) in the ON SIROLIMUS AFTER 12 MONTHS group versus a 13% decrease (to 2971 ± 4014 pg/ml) in the OFF SIROLIMUS AFTER 12 MONTHS group (p=0.013, Mann-Whitney test). A similar trend was observed in kidney angiomyolipoma size but not in pulmonary function tests. Conclusions Serum VEGF-D may be useful for monitoring response to treatment with sirolimus and kidney angiomyolipoma size in patients with TSC, but confirmation is needed. TRIAL REGISTRATION: Clinical trials.gov NCT00126672.


Assuntos
Angiomiolipoma/sangue , Angiomiolipoma/tratamento farmacológico , Rim/patologia , Sirolimo/uso terapêutico , Esclerose Tuberosa/sangue , Esclerose Tuberosa/tratamento farmacológico , Fator D de Crescimento do Endotélio Vascular/sangue , Adulto , Angiomiolipoma/patologia , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Masculino , Sirolimo/farmacologia , Fatores de Tempo , Esclerose Tuberosa/patologia
17.
Int J Cancer ; 132(7): 1711-7, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22927055

RESUMO

Perivascular epithelioid cell tumors (PEComas) are a group of rare mesenchymal tumors that typically show both melanocytic and smooth muscle cell features. Some types of PEComa are seen at high frequency in tuberous sclerosis complex (TSC). The TSC1 and TSC2 genes are commonly mutated in both TSC-associated and sporadic PEComas, and mTOR signaling pathway activation is also common in these tumors. Preliminary reports have indicated that the mTOR inhibitors sirolimus and related drugs have activity in some patients with non-TSC-associated PEComa. Here, we report on the use of these medications in the treatment of five consecutive patients with extrarenal nonpulmonary PEComas seen at one institution. Three complete responses, one partial response and one case of progression were seen. Molecular studies identified TSC2 aberrations in four of these patients, and TFE3 translocation was excluded in the resistant case. A review of all published cases as well as those reported here indicates that partial or complete response was seen in 6 of 11 PEComas, with 5 of 6 having a complete response. These findings highlight the consistent though incomplete activity of mTOR inhibitors in the treatment of PEComas.


Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias de Células Epitelioides Perivasculares/tratamento farmacológico , Neoplasias Retroperitoneais/tratamento farmacológico , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Antibióticos Antineoplásicos/uso terapêutico , Everolimo , Feminino , Humanos , Técnicas Imunoenzimáticas , Imunossupressores/uso terapêutico , Hibridização in Situ Fluorescente , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Mutação/genética , Neoplasias de Células Epitelioides Perivasculares/genética , Neoplasias de Células Epitelioides Perivasculares/patologia , Prognóstico , Indução de Remissão , Neoplasias Retroperitoneais/genética , Neoplasias Retroperitoneais/patologia , Literatura de Revisão como Assunto , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética
18.
Hum Mol Genet ; 21(19): 4286-300, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22752306

RESUMO

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with prominent brain manifestations due to mutations in either TSC1 or TSC2. Here, we describe novel mouse brain models of TSC generated using conditional hypomorphic and null alleles of Tsc2 combined with the neuron-specific synapsin I cre (SynIcre) allele. This allelic series of homozygous conditional hypomorphic alleles (Tsc2(c-del3/c-del3)SynICre(+)) and heterozygote null/conditional hypomorphic alleles (Tsc2(k/c-del3)SynICre(+)) achieves a graded reduction in expression of Tsc2 in neurons in vivo. The mice demonstrate a progressive neurologic phenotype including hunchback, hind limb clasp, reduced survival and brain and cortical neuron enlargement that correlates with a graded reduction in expression of Tsc2 in the two sets of mice. Both models also showed behavioral abnormalities in anxiety, social interaction and learning assays, which correlated with Tsc2 protein levels as well. The observations demonstrate that there are graded biochemical, cellular and clinical/behavioral effects that are proportional to the extent of reduction in Tsc2 expression in neurons. Further, they suggest that some patients with milder manifestations of TSC may be due to persistent low-level expression of functional protein from their mutant allele. In addition, they point to the potential clinical benefit of strategies to raise TSC2 protein expression from the wild-type allele by even modest amounts.


Assuntos
Encéfalo/metabolismo , Esclerose Tuberosa/mortalidade , Esclerose Tuberosa/psicologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Alelos , Animais , Comportamento , Modelos Animais de Doenças , Feminino , Histologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Sobrevida , Sinapsinas/genética , Sinapsinas/metabolismo , Esclerose Tuberosa/genética , Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa
20.
Proc Natl Acad Sci U S A ; 108(45): E1070-9, 2011 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-22025691

RESUMO

Tuberous sclerosis complex (TSC) is a multiorgan genetic disease in which brain involvement causes epilepsy, intellectual disability, and autism. The hallmark pathological finding in TSC is the cerebral cortical tuber and its unique constituent, giant cells. However, an animal model that replicates giant cells has not yet been described. Here, we report that mosaic induction of Tsc1 loss in neural progenitor cells in Tsc1(cc) Nestin-rtTA(+) TetOp-cre(+) embryos by doxycycline leads to multiple neurological symptoms, including severe epilepsy and premature death. Strikingly, Tsc1-null neural progenitor cells develop into highly enlarged giant cells with enlarged vacuoles. We found that the vacuolated giant cells had multiple signs of organelle dysfunction, including markedly increased mitochondria, aberrant lysosomes, and elevated cellular stress. We found similar vacuolated giant cells in human tuber specimens. Postnatal rapamycin treatment completely reversed these phenotypes and rescued the mutants from epilepsy and premature death, despite prenatal onset of Tsc1 loss and mTOR complex 1 activation in the developing brain. This TSC brain model provides insights into the pathogenesis and organelle dysfunction of giant cells, as well as epilepsy control in patients with TSC.


Assuntos
Modelos Animais de Doenças , Neurônios/metabolismo , Células-Tronco/metabolismo , Esclerose Tuberosa/patologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Humanos , Camundongos , Microscopia Eletrônica , Microscopia de Fluorescência , Reação em Cadeia da Polimerase , Sirolimo/farmacologia , Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
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