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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA089888-01
Application #
6293440
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Program Officer
Stone, Helen B
Project Start
2000-09-30
Project End
2002-09-29
Budget Start
2000-09-30
Budget End
2001-09-29
Support Year
1
Fiscal Year
2000
Total Cost
$289,638
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Cuneo, Kyle C; Geng, Ling; Fu, Allie et al. (2008) SU11248 (sunitinib) sensitizes pancreatic cancer to the cytotoxic effects of ionizing radiation. Int J Radiat Oncol Biol Phys 71:873-9
Huamani, Jessica; Willey, Christopher; Thotala, Dinesh et al. (2008) Differential efficacy of combined therapy with radiation and AEE788 in high and low EGFR-expressing androgen-independent prostate tumor models. Int J Radiat Oncol Biol Phys 71:237-46
Geng, Ling; Cuneo, Kyle C; Cooper, Michael K et al. (2007) Hedgehog signaling in the murine melanoma microenvironment. Angiogenesis 10:259-67
Cuneo, Kyle C; Fu, Allie; Osusky, Katherine et al. (2007) Histone deacetylase inhibitor NVP-LAQ824 sensitizes human nonsmall cell lung cancer to the cytotoxic effects of ionizing radiation. Anticancer Drugs 18:793-800
Geng, Ling; Cuneo, Kyle C; Fu, Allie et al. (2006) Histone deacetylase (HDAC) inhibitor LBH589 increases duration of gamma-H2AX foci and confines HDAC4 to the cytoplasm in irradiated non-small cell lung cancer. Cancer Res 66:11298-304
Cuneo, Kyle C; Geng, Ling; Tan, Jiahuai et al. (2006) SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation. Int J Radiat Oncol Biol Phys 64:1197-203
Yazlovitskaya, Eugenia M; Edwards, Eric; Thotala, Dinesh et al. (2006) Lithium treatment prevents neurocognitive deficit resulting from cranial irradiation. Cancer Res 66:11179-86
Kuhn, Sam J; Hallahan, Dennis E; Giorgio, Todd D (2006) Characterization of superparamagnetic nanoparticle interactions with extracellular matrix in an in vitro system. Ann Biomed Eng 34:51-8
Kim, Dong Wook Nathan; Huamani, Jessica; Niermann, Kenneth J et al. (2006) Noninvasive assessment of tumor vasculature response to radiation-mediated, vasculature-targeted therapy using quantified power Doppler sonography: implications for improvement of therapy schedules. J Ultrasound Med 25:1507-17

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