Development of recombinant rhTL1A protein for cancer treatment

DESCRIPTION (provided by applicant): Breast cancer is the most common cause of cancer in women and the second most common cause of cancer death in women in the United States. In 2009, approximately 40,170 women in the US are estimated to die from breast cancer. In most cases, death results from metastasis of breast cancer cells. Cancer patients with metastasis cannot currently be cured. Therefore, the invention of therapy to treat breast cancer metastasis remains a critical medical challenge. We have recently discovered increased expression of DcR3 in metastatic breast cancer. DcR3 increases have already been reported in a variety of cancers and DcR3 is well known for its tumorigenic properties such as angiogenesis and anti-apoptosis. Therefore, the inhibition of DcR3 with specific inhibitors of DcR3 might provide new treatment modalities in breast cancer patients. TL1A, a novel cytokine of the TNF family, is known to bind to DcR3 with high affinity and specificity. The binding of TL1A to DcR3 results in the inhibition of DcR3 anti-cancer activity. Therefore, we speculate that the treatment of breast cancer patients with TL1A will inhibit excess DcR3 expression thus resulting in inhibition of tumor growth and metastasis. Therefore, we propose to investigate the therapeutic potential of soluble human recombinant TL1A (rhTL1A) in preventing DcR3-positive breast cancer metastasis by studying two aims in this study. First, we propose to develop safe and efficacious soluble recombinant TL1A (rhTL1A) protein using human mammalian cell protein expression system. Second, to test the efficacy of rhTL1A in inhibiting tumor growth and spread, we will inject DcR3 expressing human breast cancer cells to mice followed by rhTL1A treatment. The results will be decided on differences in sizes of primary tumors and the severity of metastasis between mice treated with or without rhTL1A. Undoubtedly, the positive outcome of our study will provide not only new insight into the mechanism underlying the development of breast cancer metastasis but also the rationale for developing a therapeutic rhTL1A for future clinical use. PUBLIC HEALTH RELEVANCE: Once breast cancer metastasizes to other parts of the body, there is no cure and in this year alone, it is estimated that 40,170 women in this country will die from breast cancer. Therefore, discovering effective therapeutic agents to combat metastatic breast cancer remains a critical medical challenge. We have discovered the high expression of soluble DcR3 in metastatic breast cancer. DcR3 has been known for its multiple pro-cancer properties. A novel cytokine, TL1A, was shown to inhibit DcR3 pro-cancer activity. Therefore, we hypothesize that TL1A can be developed as anti-cancer agent to target excess DcR3 in breast cancer patients. To test this hypothesis, we propose to evaluate the potential therapeutic effects of recombinant TL1A in an animal model of DcR3-positive breast cancer metastasis. We expect that the positive outcome of this study will provide a rationale for further developing a safe and efficacious TL1A protein drug that can provide survival benefits to breast cancer patients.