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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA139003-03
Application #
8193048
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Timmer, William C
Project Start
2009-08-03
Project End
2014-07-31
Budget Start
2012-09-17
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$636,010
Indirect Cost
$217,487
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tabernero, Josep; Garcia-Carbonero, Rocio; Cassidy, James et al. (2013) Sorafenib in combination with oxaliplatin, leucovorin, and fluorouracil (modified FOLFOX6) as first-line treatment of metastatic colorectal cancer: the RESPECT trial. Clin Cancer Res 19:2541-50
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