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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA158377-03
Application #
8477014
Study Section
Special Emphasis Panel (ZRG1-DTCS-A (81))
Program Officer
Timmer, William C
Project Start
2011-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$505,800
Indirect Cost
$189,675
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104