Lymphatic vessels in and around tumors are a key determinant in lymphatic metastasis. This study will provide tools for systemic delivery of tumor treatments through the lymphatic route. Peptide library-based vascular targeting, developed in the applicant's laboratory, will be used to profile molecular alterations in the lymphatic vasculature during tumorigenesis. Peptides that specifically recognize the lymphatics in a number of tumor types and stages of tumor development will be isolated. The design of the screening will favor peptides that recognize the lymphatics in a range of tumors, rather than being selective for an individual tumor model. The specificity of these and already existing lymphatic homing peptides will be ascertained by testing peptide binding to normal and cancerous tissues from mice and from human patients. The target molecules ('receptors') for the most promising peptides will be identified, and antibodies will be prepared against the receptors. The peptides identified and characterized as described above, and antibodies prepared against their receptors, will be tested for their effects on lymphatic vessels and tumor growth, and their ability to deliver peptide-drug or antibody drug conjugates to pre-malignant and malignant lesions. This approach specifically targets the treatments to areas that may not be readily accessible through the blood circulation. Destroying the lymphatic vessels in and around the tumor along with the adjacent tumor cells may be particularly effective in reducing lymphatic metastasis. Promising compounds emerging from these experiments will be tested in pre-clinical cancer models for treatment of cancer and prevention of metastasis. ? ?
| Fogal, Valentina; Richardson, Adam D; Karmali, Priya P et al. (2010) Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation. Mol Cell Biol 30:1303-18 |
| Sugahara, Kazuki N; Teesalu, Tambet; Karmali, Priya Prakash et al. (2010) Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328:1031-5 |
| Karmali, Priya Prakash; Kotamraju, Venkata Ramana; Kastantin, Mark et al. (2009) Targeting of albumin-embedded paclitaxel nanoparticles to tumors. Nanomedicine 5:73-82 |
| Teesalu, Tambet; Sugahara, Kazuki N; Kotamraju, Venkata Ramana et al. (2009) C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc Natl Acad Sci U S A 106:16157-62 |
| Sugahara, Kazuki N; Teesalu, Tambet; Karmali, Priya Prakash et al. (2009) Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16:510-20 |
| Fogal, Valentina; Zhang, Lianglin; Krajewski, Stan et al. (2008) Mitochondrial/cell-surface protein p32/gC1qR as a molecular target in tumor cells and tumor stroma. Cancer Res 68:7210-8 |
| Zhang, Lianglin; Giraudo, Enrico; Hoffman, Jason A et al. (2006) Lymphatic zip codes in premalignant lesions and tumors. Cancer Res 66:5696-706 |
