PILOT PROJECT 1: Every cancer begins its existence as a tiny cluster of abnormal tumor cells. Without its own blood supply to bring in oxygen and nutrients, the tumor cannot grow larger than 1-2 millimeters in diameter. To grow beyond this, tumors secrete 'angiogenic factors'into nearby tissues, where they stimulate endothelial cells to become angiogenic. These signals cause the endothelial cells to proliferate and migrate towards the tumor, which eventually provides the tumor with new blood vessels. The induction of angiogenesis in endothelial cells results in activation of specific molecular pathways. Using phage display technology, Erkki Ruoslahti's lab identified the F3 peptide (KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK) as a sequence that specifically binds to endothelial cells that are angiogenic based on the expression of nucleolin on their cell surface. We have recently demonstrated that this peptide sequence can target nanoparticles in a tumor specific manner (Clin Cancer Res. 12, 6677, 2007). In the present proposal we will investigate the utility of the F3 peptide as a tool for PET AND SPECT based molecular imaging of tumor angiogenesis.
In specific aim 1 we will synthesize a radiolabeled or fluorescently labeled F3 peptide by addition of a cysteine residue at the C-terminus and conjugation of the sulfydryl group with the appropriate maleimide reagent. The purification and characterization of radioligands will be performed by preparative reverse-phase HPLC, H1 NMR and mass spectral analysis.
In specific aim 2 we will characterize the target specificity and subcellular localization of labeled F3 peptide in vitro and utilize it for in vivo real time imaging of angiogenesis. We anticipate that successful completion of these aims will enable real time non-invasive and quantitative imaging of angiogenesis in a preclinical setting. This will lay the foundation for future clinical applications. Public Health: These studies will result in development of real time imaging tools that will allow non-invasive assessment of new tumor blood vessels during cancer progression. PILOT PROJECT 2: The treatment of oncogenic lesions residing in bone has advanced with an ever increasing array of therapies;however, response to treatment is considered """"""""immeasurable"""""""" according to existing clinical response criteria (RECIST). Bone is a common site of residence of metastatic tumors derived from prostate cancer. Imaging using skeletal scintigraphy, plain radiography, computed tomography, or magnetic resonance imaging remains essential, with positron emission tomography or single-photon emission computed tomography having potential applicability for evaluating bone metastases. However, no consensus exists as to the best modality for diagnosing these lesions or for assessing treatment response. In this clinical Project, we hypothesize that early changes in tumor microenvironment will occur following initiation of successful therapy. Since water molecules within tumor cells are in a restricted environment versus extracellular water, loss of cell membrane integrity would be anticipated to increase tumor diffusion values. We have recently developed a novel molecular imaging approach (functional diffusion map (fDM)) for quantifying therapeutic-induced changes of water Brownian motion within tumors. This Pilot Project will evaluate fDM as a molecular imaging biomarker for early detection of treatment response in patients with metastatic prostate cancer to the bone. Ten patients will receive diffusion MRI scans at baseline, week 2 and week 9-11 during systemic therapy with docetaxel + prednisone. Treatment and monitoring will be per standard of care which will include physical exams and laboratory evaluations including PSA prior to each cycle of therapy. All patients will undergo a standard bone scan at baseline and at week 9-11 of therapy. Additional staging will be performed as clinically indicated at baseline and following therapy at specified intervals to assess treatment response. The ultimate goal of this proposal is to establish fDM as a novel molecular imaging biomarker for the early assessment of treatment response in metastatic bone cancer. Public Health: A novel molecular imaging biomarker will be evaluated for its ability to detect early treatment response in bone cancer patients. The ultimate outcome of this Project would provide the rationale for the development of a novel imaging biomarker for bone cancer patients to quantify early treatment response. Validation of this biomarker would provide for individualization of patient care.
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