RESUMO
Death Receptor 5 (DR5) agonists demonstrate anti-tumor activity in preclinical models but have yet to demonstrate robust clinical responses. A key limitation may be the lack of patient selection strategies to identify those most likely to respond to treatment. To overcome this limitation, we screened a DR5 agonist Nanobody across >600 cell lines representing 21 tumor lineages and assessed molecular features associated with response. High expression of DR5 and Casp8 were significantly associated with sensitivity, but their expression thresholds were difficult to translate due to low dynamic ranges. To address the translational challenge of establishing thresholds of gene expression, we developed a classifier based on ratios of genes that predicted response across lineages. The ratio classifier outperformed the DR5+Casp8 classifier, as well as standard approaches for feature selection and classification using genes, instead of ratios. This classifier was independently validated using 11 primary patient-derived pancreatic xenograft models showing perfect predictions as well as a striking linearity between prediction probability and anti-tumor response. A network analysis of the genes in the ratio classifier captured important biological relationships mediating drug response, specifically identifying key positive and negative regulators of DR5 mediated apoptosis, including DR5, CASP8, BID, cFLIP, XIAP and PEA15. Importantly, the ratio classifier shows translatability across gene expression platforms (from Affymetrix microarrays to RNA-seq) and across model systems (in vitro to in vivo). Our approach of using gene expression ratios presents a robust and novel method for constructing translatable biomarkers of compound response, which can also probe the underlying biology of treatment response.
Assuntos
Linhagem da Célula/genética , Regulação Neoplásica da Expressão Gênica/genética , Expressão Gênica/genética , Neoplasias Pancreáticas/genética , Biossíntese de Proteínas/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Animais , Apoptose/genética , Caspase 8/genética , Linhagem Celular Tumoral , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Adjuvants are components that when added to subunit antigen (Ag) vaccines boost their immunogenicity and thus immune efficacy. However, there are few adjuvants that are approved for clinical use resulting in a critical need for the development of safe and effective adjuvants for use in both prophylactic and therapeutic vaccines. The paucity of appropriate adjuvants is more chronic for the development of therapeutic vaccines for cancer and chronic infectious disease, which need to induce cytotoxic T-cell responses via cross-presentation of the vaccine Ag by dendritic cells. The ISCOMATRIX adjuvant represents a unique adjuvant system that facilitates Ag delivery and presentation as well as immunomodulation to provide enhanced and accelerated immune responses. The immune responses generated are of broad specificity to the vaccine Ag, and include robust antibody responses of multiple subclasses as well as both CD4(+) and CD8(+) T-cell responses. Here we discuss our understanding of the mechanisms of action by which ISCOMATRIX adjuvant may facilitate these integrated immune responses and touch on insights gained through its clinical experience.