RESUMO
Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias de Cabeça e Pescoço/terapia , Nitroimidazóis/uso terapêutico , Mostardas de Fosforamida/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Adulto , Idoso , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Quimiorradioterapia/métodos , Resistencia a Medicamentos Antineoplásicos , Feminino , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Concentração Inibidora 50 , Pessoa de Meia-Idade , Nitroimidazóis/farmacologia , Papillomaviridae/isolamento & purificação , Mostardas de Fosforamida/farmacologia , Pró-Fármacos/administração & dosagem , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Sequenciamento do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
Defective fetoplacental vascular maturation causes intrauterine growth restriction (IUGR). A transcriptional switch initiates placental maturation, during which blood vessels elongate. However, the cellular mechanisms and regulatory pathways involved are unknown. We show that the histone methyltransferase G9a, also known as Ehmt2, activates the Notch pathway to promote placental vascular maturation. Placental vasculature from embryos with G9a-deficient endothelial progenitor cells failed to expand owing to decreased endothelial cell proliferation and increased trophoblast proliferation. Moreover, G9a deficiency altered the transcriptional switch initiating placental maturation and caused downregulation of Notch pathway effectors including Rbpj Importantly, Notch pathway activation in G9a-deficient endothelial progenitors extended embryonic life and rescued placental vascular expansion. Thus, G9a activates the Notch pathway to balance endothelial cell and trophoblast proliferation and coordinates the transcriptional switch controlling placental vascular maturation. Accordingly, G9A and RBPJ were downregulated in human placentae from IUGR-affected pregnancies, suggesting that G9a is an important regulator in placental diseases caused by defective vascular maturation.
