Resistance of rectal cancer to radiotherapy manifests as local recurrence, and represents a common but poorly understood problem. Radiation exposure induces apoptosis through diverse signaling pathways, but these death-inducing stimuli can be overriden by powerful cell survival mechanisms termed inducible resistance pathways. Inducible resistance pathways may be abnormally active in some cancers, but these mechanisms have not been studied in the setting of clinical radiotherapy to date. The long-term goal of this project is to better understand the importance of treatment-induced anti-apoptotic signaling in patients being treated with radiation for rectal cancer. This goal will be realized by examining tumor biopsies taken very early after a single fraction of radiation in patients undergoing preoperative therapy. We will analyze signaling pathways with antibodies that are capable of distinguishing the active state of the molecules. We will then perturb these pathways, first in animal models and then in patients, using agents that specifically antagonize the signaling pathways in question. We will then determine the molecular and clinical effects of this perturbation in biopsy samples. Our central hypothesis is that radiation therapy upregulates one or more prosurvival pathways resulting in clinically significant radioresistance and that therapeutic response will be improved by abrogating these signaling responses using targeted drugs. The research projects described form the core of a 5-year career development plan for Dr. Bert O'Neil, an Assistant Professor in the Division of Hematology/Oncology. His mentors, Drs. Joel Tepper, Albert Baldwin, and Richard Goldberg are leaders in the fields of clinical research on Gl malignancies and the basic science of apoptosis and transcriptional regulation. They propose a combined didactic and translational research experience to foster Dr. O'Neil's development into an independent clinician investigator with expertise in the molecular mechanisms of resistance to cancer therapy and apoptosis signaling. They have assembled a carefully selected group of collaborators to assist in the research and in Dr. O'Neil's career development. Rectal cancer is a major health problem whose treatment can result in life-changing morbidity such as the requirement for permanent colostomy as part of therapy. This is partly due to the relative ineffectiveness of radiation on rectal cancer compared with other cancer types, a phenomenon we are trying to better understand via this proposal. The long-term goal of our research is to apply drugs that target tumor but not normal tissue in addition to radiation to improve the effectiveness of radiation on rectal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23CA118431-03
Application #
7468348
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
2006-08-11
Project End
2011-07-31
Budget Start
2008-08-25
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$136,705
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Raftery, Laura; Tepper, Joel E; Goldberg, Richard M et al. (2013) A two-cohort phase I study of weekly oxaliplatin and gemcitabine, then oxaliplatin, gemcitabine, and erlotinib during radiotherapy for unresectable pancreatic carcinoma. Am J Clin Oncol 36:250-3
Davies, Janine M; Trembath, Dimitri; Deal, Allison M et al. (2011) Phospho-ERK and AKT status, but not KRAS mutation status, are associated with outcomes in rectal cancer treated with chemoradiotherapy. Radiat Oncol 6:114
O'Neil, Bert H; Goff, Laura W; Kauh, John Sae Wook et al. (2011) Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 29:2350-6
O'Neil, Bert H; Funkhouser, William K; Calvo, Benjamin F et al. (2011) Nuclear factor ýý-light chain-enhancer of activated B cells is activated by radiotherapy and is prognostic for overall survival in patients with rectal cancer treated with preoperative fluorouracil-based chemoradiotheraphy. Int J Radiat Oncol Biol Phys 80:705-11
Tsai, Andrea Lan; Burke, Charles T; Kennedy, Andrew S et al. (2010) Use of yttrium-90 microspheres in patients with advanced hepatocellular carcinoma and portal vein thrombosis. J Vasc Interv Radiol 21:1377-84
Puvvada, Soham D; Funkhouser, William K; Greene, Kevin et al. (2010) NF-kB and Bcl-3 activation are prognostic in metastatic colorectal cancer. Oncology 78:181-8
O'Neil, Bert H; Raftery, Laura; Calvo, Benjamin F et al. (2010) A phase I study of bortezomib in combination with standard 5-fluorouracil and external-beam radiation therapy for the treatment of locally advanced or metastatic rectal cancer. Clin Colorectal Cancer 9:119-25
Skelton, Matthew R; O'Neil, Bert (2008) Targeted therapies for hepatocellular carcinoma. Clin Adv Hematol Oncol 6:209-18
O'Neil, Bert H; Venook, Alan P (2007) Hepatocellular carcinoma: the role of the North American GI Steering Committee Hepatobiliary Task Force and the advent of effective drug therapy. Oncologist 12:1425-32
O'Neil, Bert H; Tepper, Joel E (2007) Current options for the management of rectal cancer. Curr Treat Options Oncol 8:331-8

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