Neural crest stem cells differentiate into multiple tissues, including the peripheral and enteric nervous systems, the adrenal medulla, and melanocytes. Neural crest tumors derived from these precursors include neuroblastoma in children, neuroendocrine tumors of the gut and melanoma in adults. Neural crest tumors share common biological features, which may render them susceptible to similar treatments. Our work has demonstrated expression of somatostatin receptors in both primary tumors and cell lines. We have demonstrated the utility of radiolabeled somatostatin analogues in imaging neuroendocrine tumors. Our innovative technique for radioreceptor guided surgery has been utilized to successfully guide surgical extirpation of occult tumor in both adult and pediatric patients with neural crest derived tumors. Preliminary data demonstrates expression of somatostatin receptors in neuroblastoma, neuroendocrine tumors of the gut and melanoma. We therefore hypothesize that somatostatin receptors can be exploited as diagnostic and therapeutic targets in neural crest tumors. We propose to test this hypothesis in animal models of neuroblastoma followed by clinical trials in both male and female children and adults. We have designed and synthesized several unique somatostatin analogues with high affinity and potent physiologic effects at sst1 and sst2. We will characterize their affinity for other somatostatin receptors [sst3, sst4 and sst5] and test their growth inhibitory potential against neuroblastoma call lines and primary tumor cells in culture. Specific sst1 and sst2 analogues will be labeled with 123Iodine for scintigraphy, or 125Iodine for radioreceptor guided surgery will be tested in a xenograft model of disseminated neuroblastoma. Children with neuroblastoma will be entered into a clinical study to test the feasibility and specificity of somatostatin scintigraphy and radioreceptor guided surgery in detection and cytoreduction of neuroblastoma. This will provide image guided surgical therapy of neuroblastoma and will also provide whole body and tumor dosimetry data, which can then be applied to radiotherapy of neuroblastoma using (90)Y-DOTA-peptides, which target somatostatin receptors on malignant cells. Adults with neuroendocrine tumors will be entered into a study to test feasibility and specificity of radioreceptor guided surgery. Patients will be recruited from our nationally recognized, multidisciplinary neuroendocrine tumor clinic to participate in this trial of image guided surgical therapy.
| Sall, Jeffrey W; Klisovic, Dino D; O'Dorisio, M Sue et al. (2004) Somatostatin inhibits IGF-1 mediated induction of VEGF in human retinal pigment epithelial cells. Exp Eye Res 79:465-76 |
| Summers, Monica A; O'Dorisio, M Sue; Cox, Mary O et al. (2003) A lymphocyte-generated fragment of vasoactive intestinal peptide with VPAC1 agonist activity and VPAC2 antagonist effects. J Pharmacol Exp Ther 306:638-45 |
| Juweid, M E; Menda, Y; O'Dorisio, M S et al. (2002) 111In-pentetreotide versus bone scintigraphy in the detection of bony metastases of neuroblastoma. Nucl Med Commun 23:983-9 |
