RESUMO
BACKGROUND: Biomarkers are key tools in cancer management. In neuroendocrine tumors (NETs), Chromogranin A (CgA) was considered acceptable as a biomarker. We compared the clinical efficacy of a multigenomic blood biomarker (NETest) to CgA over a 5-year period. PATIENTS AND METHODS: An observational, prospective, cross-sectional, multicenter, multinational, comparative cohort assessment. Cohort 1: NETest evaluation in NETs (n = 1684) and cancers, benign diseases, controls (n = 731). Cohort 2: (n = 1270): matched analysis of NETest/CgA in a sub-cohort of NETs (n = 922) versus other diseases and controls (n = 348). Disease status was assessed by response evaluation criteria in solid tumors (RECIST). NETest measurement: qPCR [upper limit of normal (ULN: 20)], CgA (EuroDiagnostica, ULN: 108 ng/ml). STATISTICS: Mann-Whitney U-test, AUROC, chi-square and McNemar' test. RESULTS: Cohort 1: NETest diagnostic accuracy was 91% (P < 0.0001) and identified pheochromocytomas (98%), small intestine (94%), pancreas (91%), lung (88%), gastric (80%) and appendix (79%). NETest reflected grading: G1: 40 ± 1, G2 (50 ± 1) and G3 (52 ± 1). Locoregional disease levels were lower (38 ± 1) than metastatic (52 ± 1, P < 0.0001). NETest accurately stratified RECIST-assessed disease extent: no disease (21 ± 1), stable (43 ± 2), progressive (62 ± 2) (P < 0.0001). NETest concordance with imaging (CT/MRI/68Ga-SSA-PET) 91%. Presurgery, all NETs (n = 153) were positive (100%). After palliative R1/R2 surgery (n = 51) all (100%) remained elevated. After curative R0-surgery (n = 102), NETest levels were normal in 81 (70%) with no recurrence at 2 years. In the 31 (30%) with elevated levels, 25 (81%) recurred within 2 years. Cohort #2: NETest diagnostic accuracy was 87% and CgA 54% (P < 0.0001). NETest was more accurate than CgA for grading (chi-square = 7.7, OR = 18.5) and metastatic identification (chi-square = 180, OR = 8.4). NETest identified progressive disease (95%) versus CgA (57%, P < 0.0001). Imaging concordance for NETest was 91% versus CgA (46%) (P < 0.0001). Recurrence prediction after surgery was NETest-positive in >94% versus CgA 11%. CONCLUSION: NETest accurately diagnoses NETs and is an effective surrogate marker for imaging, grade, metastases and disease status compared to CgA. A multigenomic liquid biopsy is an accurate biomarker of NET disease.
Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Biomarcadores Tumorais/genética , Cromogranina A , Estudos Transversais , Humanos , Biópsia Líquida , Recidiva Local de Neoplasia , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Estudos ProspectivosAssuntos
Neoplasias Gastrointestinais , Neoplasias Intestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Seguimentos , Humanos , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/epidemiologia , Neoplasias Intestinais/terapia , Antígeno Ki-67 , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/terapia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/terapiaRESUMO
BACKGROUND: The lack of an accurate blood biomarker in neuroendocrine tumor (NET) disease has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy-liquid biopsy-to facilitate real-time management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD). PATIENTS AND METHODS: A systematic review of the literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was undertaken. The methodological quality was evaluated using the QUADAS-2 tool. We identified ten original scientific papers that met the inclusion criteria. These were assessed by qualitative analysis and thereafter meta-analysis. Data were pooled and a median [95% confidence interval (CI)] diagnostic odds ratio (DOR), positive likelihood ratio (+LR), and negative likelihood ratio (-LR) were calculated. For the meta-analysis, a generic inverse variance method was undertaken using the accuracy and area under the curve (AUC) data. RESULTS: The ten studies exhibited moderate to high methodological quality. They evaluated NETest usage both as a diagnostic and as a monitoring tool. The meta-analysis identified the diagnostic accuracy of the NETest to be 95%-96% with a mean DOR of 5 853, +LR of 195, and -LR of 0.06. The NETest was 84.5%-85.5% accurate in differentiating stable disease from progressive disease. As a marker of natural history, the accuracy was 91.5%-97.8%. As an interventional/response biomarker, the accuracy was 93.7%-97.4%. The pooled AUC for the NETest was 0.954 ± 0.005, with a z-statistic of 175.06 (P < 0.001). CONCLUSIONS: The NETest is an accurate biomarker suitable for clinical use in NET disease management. The meta-analysis supports the utility of the NETest as an IVD to establish a diagnosis and monitor therapeutic efficacy. The use of this as a biomarker provides information relevant to NET management consistent with observations regarding utility of liquid biopsies in other oncological disciplines.
Assuntos
Biomarcadores Tumorais , Tumores Neuroendócrinos , Biomarcadores Tumorais/genética , Genômica , Humanos , Biópsia Líquida , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/genética , RNA MensageiroRESUMO
Objective: Intra-articular glucocorticoid (IAGC) injection treatment is an easy and effective way to treat the signs and symptoms of arthritis, but there is limited knowledge on the adequate dosing for different joints. The aim of this study was to compare the outcome between two common doses of intra-articular triamcinolone hexacetonide (THA) for knee synovitis using the relapse rate during 6 months. Methods: A total of 159 adult patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) and active knee synovitis were randomized to IAGC injection with 20 mg or 40 mg THA. Participants were blinded to the treatment dose. The primary endpoint was relapse of arthritis. When symptoms from the treated joint recurred and signs of arthritis could be confirmed on a subsequent clinical examination, a relapse was recorded and the duration of response survival was calculated. At the end of the observation period, patients without relapse were telephoned to verify the persistence of the good treatment response. Results: The proportion of relapse after 6 months was equal in the 20 mg and 40 mg THA treatment arms (30% vs 32%, respectively, p = 0.822), and no significant differences were found in the subgroups with RA and PsA patients. Conclusion: As no difference in outcome was found between the compared doses, the lower 20 mg THA dose should be preferred in IAGC treatment for knee synovitis in chronic polyarthritis. This may also reduce pharmaceutical costs and metabolic side effects. EudraCT number: 2014-000993-20, Clinical Trials.gov identifier: NCT02437461.
Assuntos
Artrite Psoriásica/complicações , Artrite Reumatoide/complicações , Glucocorticoides , Articulação do Joelho , Sinovite/tratamento farmacológico , Triancinolona Acetonida/análogos & derivados , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos/métodos , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Injeções Intra-Articulares/métodos , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/patologia , Masculino , Pessoa de Meia-Idade , Prevenção Secundária/métodos , Sinovite/diagnóstico , Sinovite/etiologia , Resultado do Tratamento , Triancinolona Acetonida/administração & dosagem , Triancinolona Acetonida/efeitos adversosRESUMO
Background: In the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2. Patients and methods: The RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated. Results: A total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm. Conclusion: No significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates. Clinical Trial Number: NCT00412061, www.clinicaltrials.gov.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Everolimo/administração & dosagem , Síndrome do Carcinoide Maligno/tratamento farmacológico , Octreotida/administração & dosagem , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Progressão da Doença , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Everolimo/efeitos adversos , Humanos , Injeções Intramusculares , Estimativa de Kaplan-Meier , Síndrome do Carcinoide Maligno/mortalidade , Síndrome do Carcinoide Maligno/patologia , Octreotida/efeitos adversos , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoAssuntos
Neoplasias Brônquicas/terapia , Neoplasias Intestinais/terapia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/terapia , Neoplasias Brônquicas/secundário , Europa (Continente) , Humanos , Neoplasias Intestinais/secundário , Tumores Neuroendócrinos/secundário , Neoplasias Pancreáticas/secundárioAssuntos
Neoplasias do Apêndice/terapia , Tumores Neuroendócrinos/terapia , Neoplasias do Apêndice/diagnóstico , Neoplasias do Apêndice/epidemiologia , Neoplasias do Apêndice/patologia , Europa (Continente) , Humanos , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/patologiaAssuntos
Neoplasias do Íleo/terapia , Neoplasias do Jejuno/terapia , Tumores Neuroendócrinos/terapia , Consenso , Europa (Continente) , Humanos , Neoplasias do Íleo/diagnóstico , Neoplasias do Íleo/epidemiologia , Neoplasias do Íleo/patologia , Neoplasias do Jejuno/diagnóstico , Neoplasias do Jejuno/epidemiologia , Neoplasias do Jejuno/patologia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/patologiaRESUMO
BACKGROUND: Pulmonary carcinoids (PCs) are rare tumors. As there is a paucity of randomized studies, this expert consensus document represents an initiative by the European Neuroendocrine Tumor Society to provide guidance on their management. PATIENTS AND METHODS: Bibliographical searches were carried out in PubMed for the terms 'pulmonary neuroendocrine tumors', 'bronchial neuroendocrine tumors', 'bronchial carcinoid tumors', 'pulmonary carcinoid', 'pulmonary typical/atypical carcinoid', and 'pulmonary carcinoid and diagnosis/treatment/epidemiology/prognosis'. A systematic review of the relevant literature was carried out, followed by expert review. RESULTS: PCs are well-differentiated neuroendocrine tumors and include low- and intermediate-grade malignant tumors, i.e. typical (TC) and atypical carcinoid (AC), respectively. Contrast CT scan is the diagnostic gold standard for PCs, but pathology examination is mandatory for their correct classification. Somatostatin receptor imaging may visualize nearly 80% of the primary tumors and is most sensitive for metastatic disease. Plasma chromogranin A can be increased in PCs. Surgery is the treatment of choice for PCs with the aim of removing the tumor and preserving as much lung tissue as possible. Resection of metastases should be considered whenever possible with curative intent. Somatostatin analogs are the first-line treatment of carcinoid syndrome and may be considered as first-line systemic antiproliferative treatment in unresectable PCs, particularly of low-grade TC and AC. Locoregional or radiotargeted therapies should be considered for metastatic disease. Systemic chemotherapy is used for progressive PCs, although cytotoxic regimens have demonstrated limited effects with etoposide and platinum combination the most commonly used, however, temozolomide has shown most clinical benefit. CONCLUSIONS: PCs are complex tumors which require a multidisciplinary approach and long-term follow-up.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Tumor Carcinoide/terapia , Neoplasias Pulmonares/terapia , Broncoscopia , Carboplatina/administração & dosagem , Doença Cardíaca Carcinoide/diagnóstico por imagem , Tumor Carcinoide/diagnóstico , Cisplatino/administração & dosagem , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Etoposídeo/administração & dosagem , Europa (Continente) , Humanos , Neoplasias Pulmonares/diagnóstico , Pneumonectomia , Tomografia por Emissão de Pósitrons , Receptores de Somatostatina/metabolismo , Sociedades Médicas , Temozolomida , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
This paper summarizes the current understanding of the biology of somatostatin receptor (sst), role of immunotherapy in neuroendocrine tumor (NET), new agents for PPRT, and methods to assess response and clinical benefit in NET. One of the most interesting aspects of sst biology is the recent discovery of truncated variants of the sst5 receptor subtype with unique tissue distribution and response to somatostatin (SST). These truncated receptors are associated with bad patient prognosis, decreased response to SST analogs, and may be new targets for diagnoses and treatment. IFN remains a cost-effective agent, particularly in classic mid gut carcinoids, and there is interest to continue examining immunotherapy's in this disease. PRRT remains a key strategy for treatment and imaging. In addition to the classic agents, there are a series of new agents targeting other receptors such as the incretin receptors (GLP-1R; GIPR) and other G-protein coupled receptors with great potential. With regards to therapy monitoring, the most commonly used criteria are Response Criteria Evaluation in Solid Tumors (RECIST). However, for different reasons, these criteria are not very useful in NET. Incorporation of other criteria such as Choi as well as functional imaging assessment with PET would be of great interest in this area.
Assuntos
Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/terapia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/terapia , Diagnóstico por Imagem/métodos , Neoplasias Gastrointestinais/metabolismo , Humanos , Imunoterapia/métodos , Tumores Neuroendócrinos/metabolismo , Receptores de Somatostatina/metabolismo , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Resultado do TratamentoAssuntos
Neoplasias Brônquicas/diagnóstico , Tumores Neuroendócrinos/diagnóstico , Neoplasias do Timo/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Brônquicas/patologia , Neoplasias Brônquicas/terapia , Humanos , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Medição de Risco , Neoplasias do Timo/patologia , Neoplasias do Timo/terapiaAssuntos
Neoplasias Intestinais/diagnóstico , Neoplasias Hormônio-Dependentes/diagnóstico , Tumores Neuroendócrinos/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Gástricas/diagnóstico , Antineoplásicos Hormonais/uso terapêutico , Terapia Combinada , Humanos , Neoplasias Intestinais/patologia , Neoplasias Intestinais/terapia , Estadiamento de Neoplasias , Neoplasias Hormônio-Dependentes/patologia , Neoplasias Hormônio-Dependentes/terapia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Resultado do TratamentoRESUMO
CONTEXT: Hypersecretion of PTHrP is a relatively common cause of malignancy-related hypercalcemia but has only been described in a few cases of neuroendocrine tumors (NET). OBJECTIVE: The aim of this case report is to describe the clinical syndrome, complex therapeutic interventions, and unusual complications caused by persistent PTHrP hypersecretion in a patient with a pancreatic NET. CASE ILLUSTRATION: A 58-yr-old male patient presented with nonspecific abdominal pain and was found to have severe hypercalcemia secondary to a well-differentiated NET of the pancreas associated with extensive liver metastases. Elevated ionized calcium levels accompanied by low serum PTH and remarkably elevated PTHrP concentrations were consistent with PTHrP-related hypercalcemia that proved to be resistant to various chemotherapeutic regimens and supportive therapy. Partial control of the humoral syndrome was obtained only after the application of cytoreductive interventions and the introduction of various molecular targeted therapies. Due to persistent PTHrP action, bone disease emerged in the form of brown tumors. DISCUSSION: The manifestation of paraneoplastic syndrome due to PTHrP hypersecretion, despite its rareness in NET, should be considered in the differential diagnosis of hypercalcemia in such tumors. Moreover, the appearance of bone lesions in this setting may be in the context of metabolic bone disease and could be misdiagnosed as bone metastases.
Assuntos
Hipercalcemia/etiologia , Tumores Neuroendócrinos/fisiopatologia , Neoplasias Pancreáticas/fisiopatologia , Dor Abdominal/etiologia , Humanos , Hipercalcemia/fisiopatologia , Hipercalcemia/terapia , Hiperparatireoidismo/etiologia , Hiperparatireoidismo/fisiopatologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/secundário , Tumores Neuroendócrinos/terapia , Osteíte Fibrosa Cística/etiologia , Osteíte Fibrosa Cística/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/terapia , Proteína Relacionada ao Hormônio Paratireóideo/sangue , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Neuroendocrine tumours (NETs) are a genetically diverse group of malignancies that sometimes produce peptides causing characteristic hormonal syndromes. NETs can be clinically symptomatic (functioning) or silent (non-functioning); both types frequently synthesise more than one peptide, although often these are not associated with specific syndromes. Based on data from various sources, the incidence and prevalence of NETs is increasing. The primary treatment goal for patients with NETs is curative, with symptom control and the limitation of tumour progression as secondary goals. Surgery is the only possible curative approach and so represents the traditional first-line therapy. However, as most patients with NETs are diagnosed once metastases have occurred, curative surgery is generally not possible. Patients therefore require chronic postoperative medical management with the aim of relieving symptoms and, in recent years, suppressing tumour growth and spread. Somatostatin analogues, such as octreotide long-acting repeatable (LAR), can improve the symptoms of carcinoid syndrome and stabilise tumour growth in many patients. Results from the PROMID study show that octreotide LAR 30mg is an effective antiproliferative treatment in patients with newly diagnosed, functionally active or inactive, well-differentiated metastatic midgut NETs. An antiproliferative effect can also be achieved with everolimus, and combination therapy with octreotide LAR has shown synergistic antiproliferative activity. In the future, pasireotide, the multi-receptor targeted somatostatin analogue, has the potential to be an effective therapy for de novo or octreotide-refractory carcinoid syndrome and for inhibiting tumour cell proliferation. Peptide receptor radiotherapy with [90]yttrium-DOTATOC or [177]lutetium-DOTATE is also a new interesting treatment option for NETs.
Assuntos
Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/terapia , HumanosRESUMO
Neuroendocrine gastrointestinal and pancreatic tumors (GEP-NETs) are a heterogenous group of cancers with various clinical expressions. All tumors produce and secret various amines and peptides, which can be used as tissue and circulating markers. Chromogranin A (CgA) is a general tumor marker stored in secretory granules within the tumor cell and released upon stimulation. CgA is the best general tumor marker at the moment, expressed in 80-90% in all patients with GEP-NETs. CgA and NSE are used as tissue markers for the delineation of the neuroendocrine features of the tumors, but recently also the proliferation marker Ki-67 has been included in the standard procedure for evaluation of the proliferation. GEP-NETs are classified into well differentiated neuroendocrine tumors (Ki-67<2%), well-differentiated neuroendocrine carcinoma (Ki-67 2-20%), poorly differentiated neuroendocrine carcinoma (Ki-67>20%). The molecular imaging of NETs is based on the ability of these tumor cells to express somatostatin receptors as well as the APUD features. Octreoscan has been applied for imaging and staging of the disease for more than 2 decades and will nowadays be replaced by 68Ga-DOTA-Octreotate, with higher specificity and sensitivity. 18Fluoro-DOPA and 11C-5HTP are specific tracers for NETs with high specificity and selectivity. A new potential biomarker is auto-antibodies to paraneoplastic antigen MA2, which might indicate early recurrence of carcinoids after surgery with a curative intent. Circulating tumor cells (CTC) have been applied in GEP-NETs quite recently. There is still an unmet need for new markers.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Gastrointestinais/metabolismo , Imagem Molecular/métodos , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Biomarcadores Tumorais/sangue , Neoplasias Gastrointestinais/sangue , Humanos , Tumores Neuroendócrinos/sangue , Neoplasias Pancreáticas/sangueRESUMO
Oncolytic viruses are emerging as anticancer agents, and they have also shown great promise for use against neuroendocrine tumors. Many viruses have a natural tropism for replication in tumor cells. Others can be genetically engineered to selectively kill tumor cells. Viruses have some advantages as therapeutic agents over current cytotoxic drugs and small molecules. They replicate in tumor cells and thereby increase in number over time leading to increased dosage. They are immunogenic and can alter the immunosuppressive tumor microenvironment and activate immune effector cells. They have also been shown to be able to kill drug-resistant cancer stem cells. This article reviews the recent literature on oncolytic viruses used so far for neuroendocrine tumors and indicates important issues to focus on in the future.
Assuntos
Tumores Neuroendócrinos/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/fisiologia , Antineoplásicos/uso terapêutico , Terapia Combinada , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/imunologia , Tumores Neuroendócrinos/patologia , Sistemas Neurossecretores/patologiaRESUMO
We have previously described the oncolytic adenovirus, Ad(CgA-E1A-miR122), herein denoted Ad5(CgA-E1A-miR122) that selectively replicates in and kills neuroendocrine cells, including freshly isolated midgut carcinoid cells from liver metastases. Ad5(CgA-E1A-miR122) is based on human adenovirus serotype 5 (Ad5) and infects target cells by binding to the coxsackie-adenovirus receptor (CAR) and integrins on the cell surface. Some neuroendocrine tumor (NET) and neuroblastoma cells express low levels of CAR and are therefore poorly transduced by Ad5. However, they often express high levels of somatostatin receptors (SSTRs). Therefore, we introduced cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site for SSTRs in the virus fiber knob. We show that FWKT-modified Ad5 binds to SSTR2 on NET cells and transduces midgut carcinoid cells from liver metastases about 3-4 times better than non-modified Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to greater extent than Ad5, indicating that fiber knob modification may prolong the systemic circulation time. We conclude that modification of adenovirus with the FWKT motif may be beneficial for NET therapy.
Assuntos
Adenovírus Humanos/genética , Tumores Neuroendócrinos/terapia , Vírus Oncolíticos/genética , Receptores de Somatostatina/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Humanos , Neoplasias Intestinais/terapia , Tumores Neuroendócrinos/genética , Terapia Viral Oncolítica , Transdução GenéticaRESUMO
Gastrointestinal neuroendocrine tumors (GI-NETs) are a genetically diverse group of malignancies that sometimes produce peptides causing characteristic hormonal syndromes. NETs can be clinically symptomatic (functioning) or silent (non-functioning); both types frequently synthesize more than one peptide, although often these are not associated with specific syndromes. Based on data from various sources the incidence and prevalence of GI-NETs is increasing. Surgery is the only possible curative approach and so represents the traditional first-line therapy. However, as most patients with NETs are diagnosed once metastases have occurred, curative surgery is generally not possible. Patients therefore require medical management with the aim of relieving symptoms and suppressing tumor growth and spread. Somatostatin analogues can improve the symptoms of carcinoid syndrome and stabilize tumor growth (PROMID study) in many patients. An antiproliferative effect can also be achieved with the m-TOR inhibitor everolimus, alone or in combination with octreotide LAR. The vascular endothelial growth factor inhibitor sunitinib has demonstrated antitumor effects in pancreatic NETs. Pasireotide, the multi-receptor targeted somatostatin analogue, has the potential to be an effective therapy for de novo or octreotide-refractory carcinoid syndrome. Peptide receptor radiotherapy with yttrium 90-DOTATOC or lutetium 177-DOTATE are also new interesting treatment options for NETs.