The overall objective of this application is to perform necessary studies in preparation for conducting clinical trials in cancer of an immunoadhesin that neutralizes hepatocyte growth factor (HGF). Previously, a Met-Fc immunoadhesion was developed that inhibits the ability HGF to bind to its receptor Met, to induce proliferation of normal and cancer cells, and to induce angiogenesis. Moreover, Met-Fc inhibits growth of a glioma tumor cell line in a mouse xenograft model. The current goal is to conduct additional in vivo studies of Met-Fc in mouse cancer models as well as evaluate potential toxicities, pharmacokinetics, and in vivo tumor localization of Met-Fc. The information gained will pave the way to clinical trials and identify the most promising types of cancer to treat with Met-Fc.
The first aim i s to produce sufficient Met-Fc protein for preclinical in vivo studies. This material can be made in a Wave Bioreactor, but other methods for more efficient production will be explored, including development of a smaller version of Met-Fc and use of a fungal expression system.
The second aim i s to demonstrate that Met-Fc inhibits in vivo growth of tumor cells that both secrete HGF and express Met (HGF+/Met+) by using xenograft models in mice. Glioma tumors will also be tested in an intracranial mouse model to show that Met-Fc can cross the blood-brain barrier.
The third aim i s to demonstrate that Met-Fc inhibits in vivo growth of tumor cells that express Met but do not secrete HGF (HGF-/Met+), which may therefore utilize HGF secreted by stromal cells in a paracrine manner. Such tumors will be tested by co- injecting them into mice together with human MRC-5 fibroblast cells to provide a source of human HGF.
The fourth aim i s to demonstrate that Met-Fc inhibits tumor metastasis, which will be done by determining whether luciferase-labeled tumor cells from xenografted tumors migrate to other organs in mice treated with Met-Fc or control. The fifth aim is to evaluate the pharmacokinetics, biodistribution, tumor localization and possible toxic effects of Met-Fc in mice. Despite recent scientific advances, cancer remains a major medical problem, and brain tumors are a particularly deadly form of cancer. The objective of this program is develop an immunoadhesion (fusion protein) suitable for testing in human patients, which will have the potential to be an effective drug for the treatment of various cancers including glioma brain tumors. ? ? ?
