A. Background Information ? We developed a technology called PlatinDx that, based upon preclinical data, can potentially identify chemoresistance in breast cancer patients before they receive oxaliplatin therapy. PlatinDx utilizes tracing of subtherapeutic """"""""microdoses"""""""" of 14C-labeled oxaliplatin with accelerator mass spectrometry (AMS), which has attomole (10-18 mole) sensitivity for 14C. We hypothesize that DNA damage caused by a single subtoxic microdose of oxaliplatin can predict patient outcomes such as tumor shrinkage and survival. The goal of the project is to define the appropriate chemical (~1/100th the therapeutic dose) and radiochemical dose (a chest x-ray exposure) for the microdose composition, to establish protocols for the procedure and to gather preliminary clinical data. Breast cancer patients will receive a 14C-oxaliplatin microdose a few hours prior to normal biopsy. DNA will be isolated from white blood cells and left over tumor biopsy tissue. Drug-DNA damage levels will be measured by AMS and compared to outcomes such as tumor shrinkage, recurrence and severity of side effects. The data will be compared to ERCC1 expression and other biomarkers using the Response Genetics RT-PCR assay as a benchmark. The resulting feasibility data will allow the design of an SBIR Phase II diagnostics study. B. Phase I Technical Objectives The proposed Phase I clinical study will determine the feasibility of using [14C]oxaliplatin combined with AMS for clinical diagnostics trials using breast cancer patients. A clinical study is proposed due to substantial preclinical data (presented below). C. All patient recruitment for this SBIR Phase I study will be conducted by UC Davis. D. Experiments using accelerator mass spectrometry (AMS) will be performed by Accelerated Medical Diagnostics staff at the Lawrence Livermore National Laboratory.
