During the past five years, we have discovered several novel genetic alterations in colorectal tumors that are central to its pathogenesis. The most interesting of these affected PIK3CA, a lipid kinase mutated in more than 30% of the tumors. The mutations were clustered in two hot-spots and were altered at similar frequencies and positions in several other common tumor types. The PIK3CA gene is therefore one of the two most highly mutated oncogenes ever identified in human cancers. Our future efforts will be devoted to its further exploration and will incorporate four major components: 1. We will use targeted homologous recombination to disrupt the genes that appear to mediate the biologic effects of PIK3CA in colorectal cancer cells. By comparison of the properties of these cells to those in which mutant or wild-type forms of PIK3CA have been disrupted, we will define the role of each gene in each phenotype associated with PIK3CA mutation. 2. We will determine the changes in transcription associated with PIK3CA mutation using SAGE and microarray technologies. Genes identified through the expression analyses will themselves be subject to targeted disruption to test their physiologic roles in colorectal cancer cells. 3. We will develop small molecular inhibitors of the p110a enzyme encoded by PIK3CA, preferably specific for the mutant form but at minimum specific for the a isoform. Cells in which PIK3CA pathway genes have been disrupted will provide unique tests of specificity of such compounds. 4. We will determine the molecular structure of wild-type and mutant forms of the PIK3CA gene product, both alone and in complex with small molecule inhibitors. Such structures will be used to guide drug discovery as well as to provide insights into the mechanisms through which PIK3CA mutations affect enzymatic function. Relevance to Public Health: These studies represent an integrated program of research that will illuminate key features of one of the most important pathways contributing to human neoplasia. It is likely to have substantial implications for the diagnosis and treatment of cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA043460-28
Application #
7990444
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mietz, Judy
Project Start
1983-08-01
Project End
2011-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
28
Fiscal Year
2011
Total Cost
$442,885
Indirect Cost
Name
Johns Hopkins University
Department
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
Makohon-Moore, Alvin P; Zhang, Ming; Reiter, Johannes G et al. (2017) Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat Genet 49:358-366
Masica, David L; Dal Molin, Marco; Wolfgang, Christopher L et al. (2017) A novel approach for selecting combination clinical markers of pathology applied to a large retrospective cohort of surgically resected pancreatic cysts. J Am Med Inform Assoc 24:145-152
Tomasetti, Cristian; Li, Lu; Vogelstein, Bert (2017) Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 355:1330-1334
Chen, Zan; Jiang, Hanjie; Xu, Wei et al. (2017) A Tunable Brake for HECT Ubiquitin Ligases. Mol Cell 66:345-357.e6
Miller, Michelle S; Maheshwari, Sweta; McRobb, Fiona M et al. (2017) Identification of allosteric binding sites for PI3K? oncogenic mutant specific inhibitor design. Bioorg Med Chem 25:1481-1486
Reiter, Johannes G; Makohon-Moore, Alvin P; Gerold, Jeffrey M et al. (2017) Reconstructing metastatic seeding patterns of human cancers. Nat Commun 8:14114
Tokheim, Collin J; Papadopoulos, Nickolas; Kinzler, Kenneth W et al. (2016) Evaluating the evaluation of cancer driver genes. Proc Natl Acad Sci U S A 113:14330-14335
Rettig, Eleni M; Talbot Jr, C Conover; Sausen, Mark et al. (2016) Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma. Cancer Prev Res (Phila) 9:265-74
Hao, Yujun; Samuels, Yardena; Li, Qingling et al. (2016) Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nat Commun 7:11971

Showing the most recent 10 out of 225 publications