Accession Number : ADA549271


Title :   TLK1 and Rad9 Cooperate in XRT-Refractory CaP


Descriptive Note : Annual rept. 1 Apr 2010-31 Mar 2011


Corporate Author : LOUISIANA STATE UNIV IN SHREVEPORT


Personal Author(s) : De Benedetti, Arrigo


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a549271.pdf


Report Date : Apr 2011


Pagination or Media Count : 26


Abstract : The main purpose of our work is to determine the expression pattern of TLKs and Rad9 in prostate cancer cell lines and in patients biopsies, and their relation to radiation resistance and (consequently) XRT failure. A second project was to identify compounds that inhibit the activity of TLKs and its phosphorylation of Rad9, and then determine the in vitro consequences of applying these compounds to the pattern of radiation sensitivity. A final goal, which is not really part of the listed tasks, is to understand better the mechanism of action of TLKs in DNA DSB repair. This is essential for the application of the use of the radiosensitizers one day to a human clinical trial, as basic information on their mechanism of action is critical. We have published the expression TLKs and Rad9 in prostate cancer cell lines (see attached PDF). We have also published two papers on the mechanism of action of TLKs and DSB repair (see attached). We have begun analyzing TMAs for the pattern of expression of TLKs and Rad9. This is in collaboration with MSKCC. We have probed the first TMA, but are waiting for quantitative analysis with the ARIOL system. We do have (indirectly) information on the patients, as per our approved IRB. We plan to analyze one or two more TMAs in the next fiscal year before we can make solid conclusions on patients failure to XRT. We have identified 4 structurally-related compounds from our screen (5000 clinically-relevant compounds) that are strong inhibitors of TLKs. These are certain interesting phenothiazines, and we are now studying their activity in a panel of CaP cell lines. They do synergize in killing with IR or doxorubicin, and they inhibit Rad9 (S328) phosphorylation in a direct in vitro reaction with recombinant TLK and Rad9 peptide, or in cell lines treated with doxorubicin.


Descriptors :   *PROSTATE CANCER , CELLS(BIOLOGY) , CLINICAL TRIALS , DEOXYRIBONUCLEIC ACIDS , FAILURE , IN VITRO ANALYSIS , PATIENTS , PHOSPHORYLATION , REPAIR , RESISTANCE , RESPONSE , SENSITIVITY


Subject Categories : Anatomy and Physiology
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE