Epithelial ovarian cancer (EOC) is a chemosensitive disease, yet remissions are often of short duration. The overall objective of this project is to evaluate novel methods of remission re-induction and maintenance, many of which are developed in other projects in this submission. The central theme relates to the recent identification of MUC16 and its possible role in the clinical behavior of ovarian cancer and chemotherapy resistance as well as using MUC16 as a potential therapeutic immunologic target. Investigational strategies are organized around a disease states model developed during the current PPG which allows groups of patients to be considered homogeneous for the purpose of evaluating therapeutic interventions.
Specific aim 1 relates to the importance of achieving second complete clinical remission (cCR), in platinum sensitive patients, as an essential precursor to the evaluation of maintenance or consolidation therapy. The hypothesis is that molecularly targeted agents will increase the cCR, and separate clinical trials will evaluate the addition of Bortezomib (a proteosome inhibitor) and 17 allyl-aminogeldanamycin (targets Her-2 and AKT kinases). Exploration of the MUC16 contribution to chemotherapy resistance is also including in this aim. Patients in cCR have a predictably short response, and a series of cytostatic and immune based strategies are well suited for evaluation in this minimal disease state which serve as the focus of Specific Aim 2. Our first trial is a Phase II study of ACA125, an anti idiotype vaccine. We have previously identified a high frequency of Lewis Y positivity on ovarian cancer. We have initiated a Phase I trial of a Yt-hu3S193 humanized anti lewis Y antibody, given IP as consolidation. Regarding immune based therapies for remission, the culmination of a series of antibody producing monovalent vaccines explored in the current PPG has defined a consistently immunogenic polyvalent construct. A phase II efficacy trial will be performed in the complete remission population. Simultaneously, Phase I pilot trials evaluating T-cell activating vaccines; and the development of a MUC16 targeted vaccine are central to other projects in this submission.
Specific Aim 3 relates to the importance of modeling CA-125 trajectory as a predictor of EOC biology which has been demonstrated in the current PPG, and the model will be prospectively validated.
This aim has been enhanced by the inclusion of a new marker, YKL-40 in the prospective clinical trial on serum markers.
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