The development of antiangiogenic therapy has resulted n therapeutic advances in many of the major epithelial malignancies. In some, however, the incremental;advance has been limited, and the basis for susceptibility and resistance has proven difficult to identify. Here we propose to build upon a hypothesis that autophagy is a protective mechanism that permits tumor cell survival in the face of bevacizumab-induced oxygen and nutrient deprivation, and we show in animal models that the effectiveness of bevacizumab is enhanced by autophagy inhibition. We have elucidate some of the likely signaling pathways involved in the protective effect, and seek more definitive evidence of the participation especially of JNK1 as a resistance factor. In parallel with this analysis in preclinical models, we propose a direct translation to the clinic, with a trial of hydroxychloroquine in combination with standard therapy for colorectal cancer.
By understanding mechanisms of resistance to antiangiogenic interventions, the treatment of colorectal cancer can be improved. If effective, the intervention will be relevant to a broad variety of cancers.
|Vasilevskaya, Irina A; Selvakumaran, Muthu; Roberts, David et al. (2016) JNK1 Inhibition Attenuates Hypoxia-Induced Autophagy and Sensitizes to Chemotherapy. Mol Cancer Res 14:753-63|
|Selvakumaran, Muthu; Amaravadi, Ravi K; Vasilevskaya, Irina A et al. (2013) Autophagy inhibition sensitizes colon cancer cells to antiangiogenic and cytotoxic therapy. Clin Cancer Res 19:2995-3007|