ABSTRACT
The objective of tailoring medicines for cancer patients according to the molecular profile of their disease holds great promise for the improvement of cancer therapy. Nevertheless, this approach has been limited, in part, due to the lack of predictive and informative preclinical studies. Herein, we describe an assessment of the therapeutic potential of targeting PI3K/mTOR and MAPK signaling in genetically defined mouse models of colorectal cancer mirroring disease subtypes targeted for novel therapy in the FOCUS4 trial. Our studies demonstrate that dual PI3K/mTOR inhibition is highly effective in invasive adenocarcinoma models characterized by combinatorial mutations in Apc and Pten; Apc and Kras; and Apc, Pten and Kras. MEK inhibition was effective in the combinatorial Apc and Kras setting, but had no impact in either Apc Pten mutants or in Apc Pten Kras triple mutants. Furthermore, we describe the importance of scheduling for combination studies and show that although no additional benefit is gained in Apc Pten mice, combination of PI3K/mTOR and MAPK inhibition leads to an additive benefit in survival in Apc Kras mice and a synergistic increase in survival in Apc Pten Kras mice. This is the first study using robust colorectal cancer genetically engineered mouse models to support the validity of PI3K/mTOR and MEK inhibitors as tailored therapies for colorectal cancer and highlight the potential importance of drug scheduling in the clinic.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , MAP Kinase Kinase Kinases/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Animals , Antineoplastic Agents/therapeutic use , Benzimidazoles/pharmacology , Benzimidazoles/therapeutic use , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Disease Models, Animal , Drug Screening Assays, Antitumor , Genes, APC , Imidazoles/pharmacology , Imidazoles/therapeutic use , Mice, Transgenic , PTEN Phosphohydrolase/genetics , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins p21(ras)/genetics , Quinolines/pharmacology , Quinolines/therapeutic use , Tumor BurdenSubject(s)
Pleural Effusion, Malignant/therapy , Pleurodesis/methods , Sclerosing Solutions/administration & dosage , Humans , Mitoxantrone/administration & dosage , Propionibacterium acnes , Quinacrine/administration & dosage , Randomized Controlled Trials as Topic , Talc/administration & dosage , Tetracycline/administration & dosageABSTRACT
Current US FDA-approved monoclonal antibodies targeting the EGF receptor (EGFR) include cetuximab and panitumumab. In this article, we discuss the clinical evidence concerning the use of monoclonal antibodies targeting the EGFR in the setting of advanced colorectal cancer and the emergence of predictive molecular biomarkers. In addition, we also consider the evidence surrounding the evolution of anti-EGFR-resistance mechanisms evoked by targeted anti-EGFR therapy and potential therapeutic strategies that may counteract resistant tumor growth.
