Problems that cause significant negative impacts on cancer patients' quality of life and on their survival include current therapies that lead to unwanted side effects due to their action on normal cells. Furthermore, invading carcinoma cells can be resistant to therapies due to the migration-proliferation dichotomy. Monoclonal antibody (Mab) therapies, such as those against EGF, VEGF, c-Met and their respective receptors, can target invading carcinoma cells. However, these molecular targets are on normal cells. While there are cancer cell-specific mutations that can be targeted, these mutations do not cause the majority of solid tumor cancers. To address these problems our goal is to develop the first Migration Inducting Gene-7 (Mig7) Mabs using our proprietary knowledge of the unusual programmed ribosomal shift site that is located at two stop codons nine amino acids into the translation of Mig7 protein. These stop codons are read through during Mig7 translation. Prior research shows that our polyclonal antibody to Mig7 significantly inhibits cancer cell invasion. Data suggest that Mig7 protein is an important Mab target because cell surface Mig7 protein expression leads to metastasis by causing cancer cells to aggressively invade. However, a Mig7 Mab therapy does not exist. Mig7 protein is found in 96% of malignant cases of carcinoma and melanoma examined. Exhaustive studies characterizing Mig7 expression show that no normal or inflammatory cells express Mig7 post-gestation. Mig7 protein specifically localizes to cancer cells of: primary tumors, invading cancer cells, abnormal vessels of tumors, blood of untreated cancer patients, and metastatic sites; indicating a broad range of Mab targeting opportunities. Therefore, a Mig7 specific Mab is needed for future clinical use. Our approach to developing and testing Mig7 Mabs will focus on our knowledge of Mig7 protein as well as our quantitative functional assays and endometrial carcinoma nude mouse model of metastasis to lymph nodes (LNs). Our goal in Phase I is to develop Mig7 function inhibiting Mabs. Therefore, our aims are to: 1) Generate cell lines expressing Mabs to four proprietary Mig7 peptides, including the peptide immunogenic in rabbit, and determine specificity to each peptide, 2) Quantify the Mig7 Mab effect on Mig7 function of carcinoma cell invasion in vitro using our transwell invasion assay that is predictive of metastatic potential in vivo, and 3) Quantify Mig7 Mab effects on metastasis to LNs in our xenograft mouse model of endometrial carcinoma (EC) experimental metastasis. In the future Phase II proposal, Mig7 Mabs will be humanized and tested for additional mechanisms of action to enable filing an IND. Our development of the Mig7 Mab therapy will be unique because one does not exist and, like Mig7 expression, it will be highly carcinoma-specific. Importantly, Mig7 Mab therapies may overcome some current drug resistance during therapy. The antigen binding region of this Mab could also be used to make other promising cancer therapies such as chimeric antigen receptor T cells and anti-immune suppression more specific to carcinoma cells.
Cancer-specific Migration inducting gene-7 (Mig7) protein promotes metastasis by activating several essential pathways in this lethal aspect of cancer. Mig7 polyclonal antibody is effective to inhibit these functions, however, Mig7 monoclonal antibodies, proposed in this Phase I project, are required for development into therapies. A novel, broadly carcinoma-specific monoclonal antibody therapy capable of simultaneously targeting several metastasis-promoting pathways, multiple mechanisms of drug resistance as well as negative side effects of current therapies should have a major impact on future cancer therapies and improve patient quality of life.
