Colorectal cancer (CRC) is the second most frequent cause of cancer-related deaths among American men and women. No available therapeutic agents have substantial effects against advanced CRCs. The chemokine receptor, CXCR4, and its ligand, SDF-1?, which are involved in angiogenesis and metastasis, are targets for therapy of CRCs. We have found, with patient-derived xenografts that the HIV-1 Nef protein promotes apoptosis through CXCR4, and we have identified a 10-amino acid motif within this protein that drives apoptosis. We isolated this region of the protein and developed a peptide, NefM1, to target CXCR4 and thus to inhibit CRCs. We hypothesize that the NefM-1 peptide will inhibit the growth of primary human CRCs and prevent hepatic metastases. This hypothesis will be tested through two specific aims.
Aim -I will assess the capacity of NefM-1 to inhibit, in severe combined immunodeficiency (SCID) mice, the growth and angiogenesis of various human CRC xenografts derived from surgical specimens.
Aim -II will evaluate the capacity of NefM-1 to inhibit hepatic metastases from these xenografts. As shown by us and others, patient-derived CRC xenografts grow and propagate as primary tumors in subcutaneous tissues and as metastatic tumors in the gonad fat pads of SCID mice. Thus, we will use this model to establish the effects of NefM-1 on xenografts and on metastasis of human CRCs. In our preliminary studies, we have demonstrated a significant inhibitory effect of the NefM-1 peptide on the growth of patient-derived xenografts as well as xenografts of established CRC cell lines. Results derived with this model will determine the extent to which this peptide inhibits growth of primary tumors and metastasis of CRCs. Furthermore, the results will be utilized for a future R01 application that wil involve (a) evaluation, for various human malignancies, of the molecular mechanisms involved with the anti-cell growth, anti-angiogenic, and anti-metastatic pathways that are targets for this peptide and (b) development of new, effective treatment modalities.
Colorectal cancer (CRC) is the second most frequent cause of cancer-related deaths among American men and women and the most common etiology of CRC-related death is hepatic metastasis. The investigators have identified an apoptotic peptide, NefM-1, and they propose to validate its inhibitory effects on tumor growth, angiogenesis, and metastasis using mice xenografts developed from human CRC surgical specimens.