Accession Number : AD1020975


Title :   Targeting the Synthetic Essential Kinases of Breast Cancers


Descriptive Note : Technical Report,15 Apr 2015,14 Apr 2016


Corporate Author : Duke University Durham United States


Personal Author(s) : Chi,Jen-Tsan A


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1020975.pdf


Report Date : 01 May 2016


Pagination or Media Count : 39


Abstract : As breast tumors expand in size, they rapidly exceed the local oxygen supply. A limited oxygen supply (hypoxia)forces tumor glycolysis and produces large amount of lactic acid (lactic acidosis). The regions of hypoxia and lactic acidosis in tumors are resistant to most treatments and largely responsible for relapse. While the clinical relevance of these stresses is well recognized, they are usually not incorporated in the discovery and validation of tumor therapeutic targets. Thus, very few options currently exist to target the cells exposed to these stresses. Since targeting tumor stresses is expected to have significant clinical benefit, research in this area is an urgent and unmet need for the breast cancer. Using functional genomic screens, we have identified a set of protein kinases are contextually essential under hypoxia or lactic acidosis. We will first validate the inhibition of synthetic lethal kinases to eradicate breast cancer cells under hypoxia or lactic acidosis. Second, we will use FLECS (fluorescence linked enzyme chemoproteomic strategy) to identify and optimize the selective inhibitors of the top synthetic lethal kinases. Finally, we will validate the ability of the kinase inhibitors to reduce tumor growth and metastasis. Together, we will identify and validate a set of kinase inhibitors to eradicate breast tumors in both in vitro culture and xenograft models of breast tumors.


Descriptors :   breast cancer , cancer research , hypoxia , Ribonucleic acids , neoplasms , lactic acid , genomics , inhibition , inhibitors , metastasis , therapeutics


Distribution Statement : APPROVED FOR PUBLIC RELEASE