This proposal describes a training program to advance my academic career in biomarker development for oncology. The purpose of this award is to encourage my independent research program, and this period will be used to expand my scientific knowledge and mentoring skills. During the K99 award period, I will be mentored by Dr. Charles Sawyers and co-mentored by Dr. Jason Lewis. Dr. Sawyers is an internationally recognized expert in clinical oncology, in particular, the development and assessment of targeted molecular therapeutics for hematological and prostate cancers, and has a longstanding interest in technologies that define drug pharmacology in vivo. Dr. Lewis is an Inorganic Chemist and Radiochemist with substantial experience in the preclinical validation and clinical translation of novel radiopharmaceuticals for imaging and therapy. Drs. Sawyers and Lewis have mentored many scientists and clinical fellows, several of whom have transitioned to successful academic careers. Memorial Sloan Kettering Cancer Center (MSKCC) will provide institutional support to me, including the resources to conduct laboratory research, opportunities to foster career development and continuing education, and an open scientific environment to foster the interaction required for me to achieve my goals. The overall goal of this research proposal is for me to learn the theory and practice of Radiochemistry in the context of developing new applications for zirconium-89 labeled transferrin (89Zr-Tf), a novel radiotracer for PET I co-invented at MSKCC. The proposal extends directly from my previous experience, as 89Zr-Tf is one of three novel radiotracers for Positron Emission Tomography (PET) that I developed through collaborations to measure androgen receptor (AR) or MYC signaling in prostate cancer. This research has established that genetic or pharmacologically driven changes in oncogenic signaling pathways can be non-invasively measured with PET imaging, further underscoring a role for molecular imaging in oncology.
The specific aim of this proposal during the 2-year K99 award period is to use 89Zr-Tf to study the role of MYC in tumor response to targeted therapies (Specific Aim 1).
The specific aims for the 3-year R00 award period extend from this aim, and are (1) to demonstrate that 89Zr-Tf can measure pharmacologically triggered changes in PI3K pathway signaling in prostate cancer models (Specific Aim 2, and (2) to determine whether 89Zr-Tf uptake is reflective of aberrant PI3K pathway signaling in preclinical models of glioblastoma multiforme (Specific Aim 3), two pathologies for which novel imaging biomarkers are urgently needed.
Discovering cancer biomarkers that quantitatively measure tumor biology can significantly improve cancer diagnosis and treatment monitoring. This proposal is dedicated to the development of a novel biomarker for cancer imaging that targets biology promoting the pathogenesis of leukemia, prostate cancer, and glioblastoma. Because this diagnostic strategy invokes clinically validated imaging technologies, the potential for near-term clinical impact on cancer diagnosis and treatment monitoring is high.
|Lue, Hui-Wen; Podolak, Jennifer; Kolahi, Kevin et al. (2017) Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade. Genes Dev 31:2067-2084|
|Aggarwal, Rahul; Behr, Spencer C; Paris, Pamela L et al. (2017) Real-Time Transferrin-Based PET Detects MYC-Positive Prostate Cancer. Mol Cancer Res 15:1221-1229|
|Truillet, Charles; Cunningham, John T; Parker, Matthew F L et al. (2017) Noninvasive Measurement of mTORC1 Signaling with 89Zr-Transferrin. Clin Cancer Res 23:3045-3052|
|Mari Aparici, Carina; Behr, Spencer C; Seo, Youngho et al. (2017) Imaging Hepatocellular Carcinoma With 68Ga-Citrate PET: First Clinical Experience. Mol Imaging 16:1536012117723256|
|Truillet, Charles; Thomas, Eloise; Lux, Francois et al. (2016) Synthesis and Characterization of (89)Zr-Labeled Ultrasmall Nanoparticles. Mol Pharm 13:2596-601|
|Doran, Michael G; Carnazza, Kathryn E; Steckler, Jeffrey M et al. (2016) Applying ??Zr-Transferrin To Study the Pharmacology of Inhibitors to BET Bromodomain Containing Proteins. Mol Pharm 13:683-8|
|Flavell, Robert R; Truillet, Charles; Regan, Melanie K et al. (2016) Caged [(18)F]FDG Glycosylamines for Imaging Acidic Tumor Microenvironments Using Positron Emission Tomography. Bioconjug Chem 27:170-8|
|Behr, Spencer C; Aggarwal, Rahul; Seo, Youngho et al. (2016) A Feasibility Study Showing [68Ga]Citrate PET Detects Prostate Cancer. Mol Imaging Biol 18:946-951|
|Drake, Christopher R; Sevillano, Natalia; Truillet, Charles et al. (2016) Site-Specific Radiofluorination of Biomolecules with 8-[(18)F]-Fluorooctanoic Acid Catalyzed by Lipoic Acid Ligase. ACS Chem Biol 11:1587-94|
|Carroll, V N; Truillet, C; Shen, B et al. (2016) [(11)C]Ascorbic and [(11)C]dehydroascorbic acid, an endogenous redox pair for sensing reactive oxygen species using positron emission tomography. Chem Commun (Camb) 52:4888-90|
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