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1.  Imaging Tumor Burden in the Brain with 89Zr-Transferrin 
A noninvasive technology that indiscriminately detects tumor tissue in the brain could substantially enhance the management of primary or metastatic brain tumors. Although the documented molecular heterogeneity of diseases that initiate or eventually deposit in the brain may preclude identifying a single smoking-gun molecular biomarker, many classes of brain tumors are generally avid for transferrin. Therefore, we reasoned that applying a radiolabeled derivative of transferrin (89Zr-labeled transferrin) may be an effective strategy to more thoroughly identify tumor tissue in the brain, regardless of the tumor’s genetic background.
Transferrin was radiolabeled with 89Zr, and its properties with respect to human models of glioblastoma multiforme were studied in vivo.
In this report, we show proof of concept that 89Zr-labeled transferrin (89Zr-transferrin) localizes to genetically diverse models of glioblastoma multiforme in vivo. Moreover, we demonstrate that 89Zr-transferrin can detect an orthotopic lesion with exceptional contrast. Finally, the tumor-to-brain contrast conferred by 89Zr-transferrin vastly exceeded that observed with 18F-FDG, currently the most widely used radiotracer to assess tumor burden in the brain.
The results from this study suggest that 89Zr-transferrin could be a broadly applicable tool for identifying and monitoring tumors in the brain, with realistic potential for near-term clinical translation.
PMCID: PMC3747823  PMID: 23236019
89Zr; transferrin; positron emission tomography; glioma; molecular imaging
2.  Imaging androgen receptor signaling with a radiotracer targeting free prostate specific antigen 
Cancer Discovery  2012;2(4):320-327.
Despite intense efforts to develop radiotracers to detect cancers or monitor treatment response, few are widely used due to challenges with demonstrating clear clinical utility. We reasoned that a radiotracer targeting a validated clinical biomarker could more clearly assess the advantages of imaging cancer. The virtues and shortcomings of measuring secreted prostate specific antigen (PSA), an androgen receptor (AR) target gene, in prostate cancer (PCa) patients are well documented, making it a logical candidate for assessing whether a radiotracer can reveal new (and useful) information beyond that conferred by serum PSA. Therefore, we developed 89Zr-5A10, a novel radiotracer that targets “free” PSA. 89Zr-5A10 localizes in an AR-dependent manner in vivo to models of castration resistant prostate cancer, a disease state where serum PSA may not reflect clinical outcomes. Finally, we demonstrate that 89Zr-5A10 can detect osseous PCa lesions, a context where bone scans fail to discriminate malignant and non-malignant signals.
PMCID: PMC3351274  PMID: 22576209
PET; prostate cancer; prostate specific antigen; androgen receptor; biomarker; PSA; PCa; AR; CRPC; 18F-FDG; fPSA; mAbs; PET; MRI; PSMA; ITLC
3.  Annotating MYC oncogene status with 89Zr-transferrin imaging 
Nature medicine  2012;18(10):1586-1591.
A non-invasive technology that quantitatively measures the activity of oncogenic signaling pathways could broadly impact cancer diagnosis and treatment using targeted therapies. Here we describe the development of 89Zr-desferrioxamine transferrin (89Zr-Tf), a novel positron emission tomography (PET) radiotracer that binds the transferrin receptor 1 (TFRC, CD71) with high avidity. 89Zr-Tf produces high contrast PET images that quantitatively reflect treatment-induced changes in MYC-regulated TFRC expression in a MYC oncogene-driven prostate cancer xenograft model. Moreover, 89Zr-Tf imaging can detect the in situ development of prostate cancer in a transgenic MYC prostate cancer model, as well as prostatic intraepithelial neoplasia (PIN) prior to histological or anatomic evidence of invasive cancer. These preclinical data establish 89Zr-Tf as a sensitive tool for non-invasive measurement of oncogene-driven TFRC expression in prostate, and potentially other cancers, with prospective near-term clinical application.
PMCID: PMC3521603  PMID: 23001181
Zirconium-89; transferrin; TFRC; CD71; inflammation; prostate cancer; MYC; positron-emission tomography; PET/CT; oncogene
4.  TP73 allelic expression in human brain and allele frequencies in Alzheimer's disease 
BMC Medical Genetics  2004;5:14.
The p73 protein, a paralogue of the p53 tumor suppressor, is essential for normal development and survival of neurons. TP73 is therefore of interest as a candidate gene for Alzheimer's disease (AD) susceptibility. TP73 mRNA is transcribed from three promoters, termed P1 – P3, and there is evidence for an additional complexity in its regulation, namely, a variable allelic expression bias in some human tissues.
We utilized RT-PCR/RFLP and direct cDNA sequencing to measure allele-specific expression of TP73 mRNA, SNP genotyping to assess genetic associations with AD, and promoter-reporter assays to assess allele-specific TP73 promoter activity.
Using a coding-neutral BanI polymorphism in TP73 exon 5 as an allelic marker, we found a pronounced allelic expression bias in one adult brain hippocampus, while 3 other brains (two adult; one fetal) showed approximately equal expression from both alleles. In a tri-ethnic elderly population of African-Americans, Caribbean Hispanics and Caucasians, a G/A single nucleotide polymorphism (SNP) at -386 in the TP73 P3 promoter was weakly but significantly associated with AD (crude O.R. for AD given any -386G allele 1.7; C.I. 1.2–2.5; after adjusting for age and education O.R. 1.5; C.I. 1.1–2.3, N= 1191). The frequency of the -386G allele varied by ethnicity and was highest in African-Americans and lowest in Caucasians. No significant differences in basal P3 promoter activity were detected comparing -386G vs. -386A promoter-luciferase constructs in human SK-NSH-N neuroblastoma cells.
There is a reproducible allelic expression bias in mRNA expression from the TP73 gene in some, though not all, adult human brains, and inter-individual variation in regulatory sequences of the TP73 locus may affect susceptibility to AD. However, additional studies will be necessary to exclude genetic admixture as an alternative explanation for the observed associations.
PMCID: PMC420466  PMID: 15175114

Results 1-4 (4)