I. RATIONALE We have demonstrated that ascites (peritoneal fluid) from human ovarian cancer patients is a potent inducer of proliferation of ovarian cancer cells in vitro and in vivo. We have purified a novel mediator from ascites, ovarian cancer activating factor (POCAF), which consists of multiple forms of lysophosphatidic acid (LPA). However, OCAF is much more potent than conventional lPA in activating ovarian cancer cells. The increased activity of OCAF appears to be due to unexpectedly high levels of sn-2 linoleoyl LPA in OCAF isolated from ovarian cancer patients. This is supported by our preliminary data which indicates that synthetic sn-2 linoleoyl LPA is more active than its sn-1 or saturated fatty acyl-containing counterparts in activating ovarian cancer cells. Our preliminary data indicates that the elevated levels of OCAF present in plasma of a significant percentage of ovarian cancer patients are sufficient to stimulate proliferation of ovarian cancer cells in vitro and to protect cells from the action of the most effective drug for ovarian cancer, cisplatinum, suggesting that OCAF may play a major role in the dismal prognosis associated with ovarian cancer. In contrast to peptide growth factors, OCAF is a small molecule readily amenable to drug """"""""discovery"""""""" and delivery. We have identified two potential receptor antagonists and obtained several potential inhibitors of POCAF production and one potential agonist of OCAF production. An understanding of the role of OCAF in the initiation and progression of ovarian cancer may lead to more effective management for ovarian cancer. II. HYPOTHESIS That OCAF produced by ovarian cancer cells contributes to outcome by increasing proliferation or decreasing sensitivity of ovarian cancer cells to chemotherapy. As a corollary, measurement of OCAF levels or altering OCAF production or action may contribute to early diagnosis, help establish prognosis, monitor response to therapy, or aid in development of novel, effective therapies for ovarian cancer. III.
SPECIFIC AIMS 1. To characterize production and action of OCAF in ovarian cancer Subaim 1. What is the identity of the active mediator(s) in OCAF? Subaim 2. What is the cellular source of OCAF? Subaim 3. What is the mechanism of production of OCAF? Subaim 4. Is responsiveness to or production of OCAF acquired during transformation? Subaim 5. To clone and characterize the OCAF receptor 2. To determine the role of OCAF in ovarian cancer pathogenesis Subaim 1. To develop OCAF receptor and production agonists and antagonists.
Sub aim 2. Does OCAF alter proliferation or sensitivity to chemotherapy 3. To establish whether measurement of OCAF levels can be used for early diagnosis, establishing prognosis, or monitoring response to therapy.
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