PILOT PROJECT 1: Every cancer begins its existence as a tiny cluster of abnormal tumor cells. Withoutits own blood supply to bring in oxygen and nutrients, the tumor cannot grow larger than 1-2 millimeters indiameter. To grow beyond this, tumors secrete 'angiogenic factors' into nearby tissues, where theystimulate endothelial cells to become angiogenic. These signals cause the endothelial cells to proliferateand migrate towards the tumor, which eventually provides the tumor with new blood vessels. Theinduction of angiogenesis in endothelial cells results in activation of specific molecular pathways. Usingphage display technology, Erkki Ruoslahti's lab identified the F3 peptide(KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK) as a sequence that specifically binds to endothelial cellsthat are angiogenic based on the expression of nucleolin on their cell surface. We have recentlydemonstrated that this peptide sequence can target nanoparticles in a tumor specific manner (Clin CancerRes. 12, 6677, 2007). In the present proposal we will investigate the utility of the F3 peptide as a tool forPET AND SPECT based molecular imaging of tumor angiogenesis.
In specific aim 1 we will synthesize aradiolabeled or fluorescently labeled F3 peptide by addition of a cysteine residue at the C-terminus andconjugation of the sulfydryl group with the appropriate maleimide reagent. The purification andcharacterization of radioligands will be performed by preparative reverse-phase HPLC, H1 NMR and massspectral analysis.
In specific aim 2 we will characterize the target specificity and subcellular localization oflabeled F3 peptide in vitro and utilize it for in vivo real time imaging of angiogenesis. We anticipate thatsuccessful completion of these aims will enable real time non-invasive and quantitative imaging ofangiogenesis 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-invasiveassessment of new tumor blood vessels during cancer progression.PILOT PROJECT 2: The treatment of oncogenic lesions residing in bone has advanced with an everincreasing array of therapies; however, response to treatment is considered 'immeasurable' according toexisting clinical response criteria (RECIST). Bone is a common site of residence of metastatic tumors derivedfrom prostate cancer. Imaging using skeletal scintigraphy, plain radiography, computed tomography, ormagnetic resonance imaging remains essential, with positron emission tomography or single-photonemission computed tomography having potential applicability for evaluating bone metastases. However, noconsensus exists as to the best modality for diagnosing these lesions or for assessing treatment response. Inthis clinical Project, we hypothesize that early changes in tumor microenvironment will occur followinginitiation of successful therapy. Since water molecules within tumor cells are in a restricted environmentversus extracellular water, loss of cell membrane integrity would be anticipated to increase tumor diffusionvalues. 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 willevaluate fDM as a molecular imaging biomarker for early detection of treatment response in patients withmetastatic prostate cancer to the bone. Ten patients will receive diffusion MRI scans at baseline, week 2and week 9-11 during systemic therapy with docetaxel + prednisone. Treatment and monitoring will be perstandard of care which will include physical exams and laboratory evaluations including PSA prior to eachcycle 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 specifiedintervals to assess treatment response. The ultimate goal of this proposal is to establish fDM as a novelmolecular 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 treatmentresponse in bone cancer patients. The ultimate outcome of this Project would provide the rationale for thedevelopment 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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| Nyati, Shyam; Schinske-Sebolt, Katrina; Pitchiaya, Sethuramasundaram et al. (2015) The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-? signaling. Sci Signal 8:ra1 |
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| Bowman, Brittany M; Sebolt, Katrina A; Hoff, Benjamin A et al. (2015) Phosphorylation of FADD by the kinase CK1? promotes KRASG12D-induced lung cancer. Sci Signal 8:ra9 |
| Khondee, Supang; Rabinsky, Emily F; Owens, Scott R et al. (2015) Targeted therapy of colorectal neoplasia with rapamycin in peptide-labeled pegylated octadecyl lithocholate micelles. J Control Release 199:114-21 |
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