X-ray guided drug delivery systems developed at Vanderbilt University include peptides and single chain antibodies that bind specifically to radiation-induced vascular proteins. The goal of developing this technology is to achieve site-specific drug delivery to the tumor microvasculature, which circumvents the limitation of tumor-type specificity using antibodies to tumor antigens such as CEA or Her2. The present clinical feasibility study addresses radiation-induced activation of integrins alpha-2b and beta-3. We have found that these activated integrins accumulate in the tumor blood vessels after irradiation. Ligands that bind to alpha-2b-beta3 (a2bB3) include fibronectin and fibrinogen and peptide fragments from those proteins. One such peptide is RGD, which is present on each of these ligands and binds to a2bB3 within irradiated tumors. The commercialized synthetic form of RGD, apcitide, (Acutect, Diatide), conjugates Tc-99m to allow for imaging of activated platelets. In the present study, we will utilize apcitide-Tc-99 to image a2bB3 integrin activation in cancer. The study design has three components. First is the optimization of the schedule of administration of apcitide-Tc-99 and high dose irradiator using stereotactic radiotherapy for metastatic disease. Secondly, we will de-escalate radiation therapy dose by use of the continual reassessment method (CRM) in which apcitide-Tc-99 is administered and the response is assessed (imaged). Model fitting will be performed and reduced dose for the next patient will be estimated. Finally, we will stratify dose de-escalation by the site of disease and tumor subtypes. Once optimization, threshold dose and limitations of radiation-induced peptide binding are determined, we will design clinical trials using therapeutic radionuclides or liposomes.
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