ABSTRACT
Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E. We found that AXL-107-MMAE, as a single agent, displayed potent in vivo anti-tumor activity in patient-derived xenografts, including melanoma, lung, pancreas and cervical cancer. By eliminating distinct populations in heterogeneous melanoma cell pools, AXL-107-MMAE and MAPK pathway inhibitors cooperatively inhibited tumor growth. Furthermore, by inducing AXL transcription, BRAF/MEK inhibitors potentiated the efficacy of AXL-107-MMAE. These findings provide proof of concept for the premise that rationalized combinatorial targeting of distinct populations in heterogeneous tumors may improve therapeutic effect, and merit clinical validation of AXL-107-MMAE in both treatment-naive and drug-resistant cancers in mono- or combination therapy.
Subject(s)
Immunoconjugates/pharmacology , Melanoma/drug therapy , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins/immunology , Receptor Protein-Tyrosine Kinases/immunology , Animals , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/immunology , Genetic Heterogeneity/drug effects , Humans , Immunoconjugates/immunology , Melanoma/genetics , Melanoma/immunology , Melanoma/pathology , Mice , Oligopeptides/chemistry , Oligopeptides/immunology , Oligopeptides/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/immunology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/chemistry , Proto-Oncogene Proteins/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/immunology , Receptor Protein-Tyrosine Kinases/chemistry , Receptor Protein-Tyrosine Kinases/pharmacology , Xenograft Model Antitumor Assays , Axl Receptor Tyrosine KinaseABSTRACT
Over the past 3 decades minipigs have moved from being an obscure alternative to dogs and nonhuman primates to being a standard animal model in regulatory toxicity studies. This article covers the use of minipigs as a model in the context of nonclinical drug safety and provides an overview of the minipig's developmental history and relates minipigs to other animal species commonly used in toxicology; and the minipig's translational power is supported by 43 case studies of marketed drug products covered. Special focus is given to criteria for selecting minipigs in nonclinical programs supporting the development of new medicines; the use of swine in the assessment of food additives, agrochemicals, and pesticides; as well as a regulatory perspective on the use of minipigs in Food and Drug Administration (FDA)-regulated products. This article presents the main points conveyed at a symposium held at the 2010 American College of Toxicology meeting in Baltimore, Maryland.
