Overview- 'The imaging data and how it will be related to apoptosis alteration could have been more stronglystated, and 'Investigators demonstrate their ability to carry out the extensive imaging experiments proposed,but they do not really explain why they are necessary or how they will help in the planned human trials.' Weagree that in the previous application we did not provide adequate biological rationale for the proposed imagingmodalities (including apoptosis, proliferation, EGFR expression, and VEGFR expression). Here, we haverevised the Background and Significance section to explicitly state the biological rationale for each of theproposed imaging metrics with respect to the utilized treatments. This rationale is further emphasized by theinclusion of additional preliminary in vitro and in vivo data that has been generated since the previoussubmission. Although beyond the scope of the proposed pre-clinical investigations, we envision that highlyeffective non-invasive imaging readout(s) of treatment response will provide valuable information towardsoptimizing individualized patient therapy. More directly, non-invasive imaging metrics could be employedclinically as markers of treatment response in place of invasive biopsy procedures. Thus, in the revisedapplication, we have addressed the clinical utility and intended use of the imaging metrics developed here andprioritize their clinical implementation.'The potential impact of sequential CT studies and radiation dose was not discussed and should either bedropped or further considered.' The potential impact of sequential CT, as well as the effective radiation dose,is discussed in the revised application (Background and Significance and Research Design and Methods), andwe now emphasize that only two CT scans will be collected per animal during the study. These scans will beused for anatomical co-registration with PET images ([18F]-FLT or [18F]-FDG) as are routinely done in PET/CT.'Criteria for determining the relationships of imaging variables to response are not well described, and thereappears to be limited use of statistical input.' In the revised experimental plan, we have carefully describedprocedures that will be used to validate the proposed imaging metrics, particularly at the tissue level usingseveral well-accepted immunohistochemical (IHC) methods. Dr. Kay Washington, an expert in Gl pathology,has been added as key personnel and will be responsible for the IHC analysis of tissues. Furthermore, ourstatistical analysis plan has been revised considerably and will be strengthened by the new Statistics Core thatwill be directed by Dr. Yu Shyr.'Reduced enthusiasm [was expressed] for the lack of focus in Research Project 1.' We have made a majorconcerted effort to focus the aims of Project 1. We hypothesize that the most relevant biological readouts to bestudied in Project 1 include apoptosis, proliferation, EGFR expression and VEGFR expression. Therefore, wehave considerably focused the project by reducing the total number of imaging metrics studied, eliminatingtangentially relevant metrics such as PBR imaging with NIR-conPK11195 and DCE MRI. Furthermore, wehave focused our therapeutic strategies. Previously, the therapeutic regimen described in Aim 1 relied on thehypothesis that sequential administration of two mechanistically distinct EGFR axis inhibitors would result inimproved therapeutic efficacy. Additionally, Aim 2 focused on a novel combination of EGFR and HDACinhibition. While we remain optimistic with respect to these innovative strategies, we recognize that the focusof this application is upon the development of novel imaging methods and not the establishment of innovativetherapeutic regimens. Therefore, our experimental plan now utilizes a much simpler therapeutic strategy withestablished readouts of clinical response.
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