Angiogenesis inhibitors are the most successful of the targeted therapies tested to date. The VEGF antibody bevacizumab is now approved for treatment of colorectal, non-small cell lung, and breast cancers. Common to each of these diseases, there is limited efficacy of bevacizumab as a single agent, but in combination with chemotherapy it yields marked improvement in disease-free survival, and in colon and lung cancers, overall survival. The basis for this interaction of antiangiogenic therapy and chemotherapy is the focus of our research. We have developed a number of preclinical models applicable to the study of anti-angiogenic therapy colon cancer, and have discovered that the pathway to activation of jun N-terminal kinase (JNK) determines sensitivity or resistance to treatment, in particular at the level of the kinases SEK1 and MKK7, activation of which demonstrates opposing influences. We have found a substantial mutation rate in these kinases in the tumors of patients with colon cancer, and propose to extend these findings to (a) define the mechanism of how signaling to JNK determines sensitivity to bevacizumab;(b) validate the impact of SEK1 and MKK7 variation in a large set of clinical samples from E3200;(c) perform a clinical trial in patients with colorectal cancer to relate these preclinical findings to clinical consequences of bevacizumab therapy. This work has the potential to make antiangiogenic therapy more effective in colorectal cancer, as well as to identify patient populations in whom alternative treatment options should be explored.

Public Health Relevance

Our current treatment algorithms provide for treating all patients with advanced colorectal cancer (and in the future, possibly those with stages II and III) with combined chemotherapy and bevacizumab. While the therapeutic benefit has been marked, it has come with costs both economic and in terms of toxic side effects of the treatment. Improving patient care requires us to identify which patients will respond to these therapies, and to avoid unwanted effects and to investigate alternative approaches in those who will not.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Timmer, William C
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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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
Vasilevskaya, Irina A; Selvakumaran, Muthu; Hierro, Lucia Cabal et al. (2015) Inhibition of JNK Sensitizes Hypoxic Colon Cancer Cells to DNA-Damaging Agents. Clin Cancer Res 21:4143-52
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Bates, David O; Catalano, Paul J; Symonds, Kirsty E et al. (2012) Association between VEGF splice isoforms and progression-free survival in metastatic colorectal cancer patients treated with bevacizumab. Clin Cancer Res 18:6384-91