Colorectal cancer is a leading cause of cancer death in the United States with 135,000 new cases and 55,000 deaths each year. The great majority of these cases are initiated by mutations in the APC tumor suppressor gene. Mutations of APC result in the formation of benign tumors that progress to malignancy through subsequent mutations in oncogenes and other tumor suppressor genes. During this progression, tumors subvert normal physiological processes to support their growth. Chief among these processes is the provision of a blood supply through stimulation of angiogenesis.
The aims of this application are directed at continuing our successful analyses of the APC pathway and the angiogenic processes that support colorectal tumor growth. ? ? Aim #1. Expression analysis of the APC pathway. While a great deal has been learned about the APC pathway, the precise molecular details of how APC normally functions to suppress tumorigenesis remain controversial.
This aim i s intended to couple the power of somatic cell knockout technology with advances in gene expression technology to provide an unprecedented view of the changes in gene expression associated with APC and Beta-catenin mutations. ? ? Aim#2. Functional analysis of the APC pathway. As the APC pathway continues to be defined and extended, it will be critical to carefully define the biological functions of each component. While over-expression and RNA mediated inhibition can aid in these analyses, genetic knockouts provide the most rigorous way to assess these parameters in somatic cells.
This aim i s intended to use genetic knockouts to carefully dissect the biochemical and biological functions of members of the APC pathway including APC, Beta-catenin, c-MYC, CDK4, Cyclin D1 and EB1. ? ? Aim #3. Molecular characterization of tumor angiogenesis. We have previously identified a series of genes that is preferentially expressed in the vessel endothelial cells from human colorectal cancers (TEMs).
This aim i s intended to define the function of selected TEMs through identification of interacting proteins, gene expression analysis and mouse knockouts. ? ? The combination of the above studies should provide important insights into the processes that drive and support colorectal tumor development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA057345-15
Application #
7077635
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mohla, Suresh
Project Start
1992-09-01
Project End
2007-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
15
Fiscal Year
2006
Total Cost
$486,852
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Le, Dung T; Durham, Jennifer N; Smith, Kellie N et al. (2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409-413
Holdhoff, Matthias; Cairncross, Gregory J; Kollmeyer, Thomas M et al. (2017) Genetic landscape of extreme responders with anaplastic oligodendroglioma. Oncotarget 8:35523-35531
Anglesio, Michael S; Papadopoulos, Nickolas; Ayhan, Ayse et al. (2017) Cancer-Associated Mutations in Endometriosis without Cancer. N Engl J Med 376:1835-1848
Hoang, Margaret L; Chen, Chung-Hsin; Chen, Pau-Chung et al. (2016) Aristolochic Acid in the Etiology of Renal Cell Carcinoma. Cancer Epidemiol Biomarkers Prev 25:1600-1608
Hoang, Margaret L; Kinde, Isaac; Tomasetti, Cristian et al. (2016) Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing. Proc Natl Acad Sci U S A 113:9846-51
Robles, Ana I; Traverso, Giovanni; Zhang, Ming et al. (2016) Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers. Gastroenterology 150:931-43
Tie, Jeanne; Wang, Yuxuan; Tomasetti, Cristian et al. (2016) Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med 8:346ra92
Roberts, Nicholas J; Norris, Alexis L; Petersen, Gloria M et al. (2016) Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer. Cancer Discov 6:166-75
Tie, J; Kinde, I; Wang, Y et al. (2015) Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol 26:1715-22
Jiao, Yuchen; Lumpkins, Kimberly; Terhune, Julia et al. (2015) Intraductal papillary mucinous neoplasm in a neonate with congenital hyperinsulinism and a de novo germline SKIL gene mutation. Pancreatology 15:194-6

Showing the most recent 10 out of 153 publications