RESUMO
CIGB-552 is a synthetic peptide that interacts with COMMD1 and upregulates its protein levels. The objectives of this phase I study were safety, pharmacokinetic profile, evaluation of the lymphocytes CD4+ and CD8+ and preliminary activity in patients with advanced tumors. A 3 + 3 dose-escalation design with seven dose levels was implemented. Patients were included until a grade 3 related adverse event occurred and the maximum tolerated dose was reached. The patients received subcutaneous administration of CIGB-552 three times per week for 2 weeks. Single-dose plasma pharmacokinetics was characterized at two dose levels, and tumor responses were classified by RECIST 1.1. Twenty-four patients received CIGB-552. Dose-limiting toxicity was associated with a transient grade 3 pruritic maculopapular rash at a dose of 7.0 mg. The maximum tolerated dose was defined as 4.7 mg. Ten patients were assessable for immunological status. Seven patients had significant changes in the ratio CD4/CD8 in response to CIGB-552 treatment; three patients did not modify the immunological status. Stable disease was observed in five patients, including two metastatic soft sarcomas. We conclude that CIGB-552 at dose 4.7 mg was well tolerated with no significant adverse events and appeared to provide some clinical benefits.
Assuntos
Antineoplásicos/administração & dosagem , Peptídeos Penetradores de Células/administração & dosagem , NF-kappa B/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Peptídeos Penetradores de Células/efeitos adversos , Peptídeos Penetradores de Células/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/metabolismo , Neoplasias/patologia , Projetos de Pesquisa , Resultado do TratamentoRESUMO
CIGB-552 is a cell-penetrating peptide that exerts in vitro and in vivo antitumor effect on cancer cells. In the present work, the mechanism involved in such anticancer activity was studied using chemical proteomics and expression-based proteomics in culture cancer cell lines. CIGB-552 interacts with at least 55 proteins, as determined by chemical proteomics. A temporal differential proteomics based on iTRAQ quantification method was performed to identify CIGB-552 modulated proteins. The proteomic profile includes 72 differentially expressed proteins in response to CIGB-552 treatment. Proteins related to cell proliferation and apoptosis were identified by both approaches. In line with previous findings, proteomic data revealed that CIGB-552 triggers the inhibition of NF-κB signaling pathway. Furthermore, proteins related to cell invasion were differentially modulated by CIGB-552 treatment suggesting new potentialities of CIGB-552 as anticancer agent. Overall, the current study contributes to a better understanding of the antitumor action mechanism of CIGB-552.
Assuntos
Peptídeos Penetradores de Células/administração & dosagem , Peptídeos Penetradores de Células/química , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular Tumoral , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Dados de Sequência Molecular , Neoplasias Experimentais/genética , Ligação Proteica , Mapeamento de Interação de Proteínas/métodos , Proteoma/química , Proteoma/metabolismo , Proteômica/métodos , Análise de Sequência de Proteína/métodos , Resultado do TratamentoRESUMO
Accumulation of the COMMD1 protein as a druggable pharmacology event to target cancer cells has not been evaluated so far in cancer animal models. We have previously demonstrated that a second-generation peptide, with cell-penetrating capacity, termed CIGB-552, was able to induce apoptosis mediated by stabilization of COMMD1. Here, we explore the antitumor effect by subcutaneous administration of CIGB-552 in a therapeutic schedule. Outstandingly, a significant delay of tumor growth was observed at 0.2 and 0.7 mg/kg (p < 0.01) or 1.4 mg/kg (p < 0.001) after CIGB-552 administration in both syngeneic murine tumors and patient-derived xenograft models. Furthermore, we evidenced that (131)I-CIGB-552 peptide was actually accumulated in the tumors after administration by subcutaneous route. A typical serine-proteases degradation pattern for CIGB-552 in BALB/c mice serum was identified. Further, biological characterization of the main metabolites of the peptide CIGB-552 suggests that the cell-penetrating capacity plays an important role in the cytotoxic activity. This report is the first in describing the antitumor effect induced by systemic administration of a peptide that targets COMMD1 for stabilization. Moreover, our data reinforce the perspectives of CIGB-552 for cancer targeted therapy.