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.
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|Truillet, Charles; Cunningham, John T; Parker, Matthew F L et al. (2016) Non-invasive measurement of mTORC1 signaling with 89Zr-transferrin. Clin Cancer Res :|
|Doran, Michael G; Carnazza, Kathryn E; Steckler, Jeffrey M et al. (2016) Applying â¸â¹Zr-Transferrin To Study the Pharmacology of Inhibitors to BET Bromodomain Containing Proteins. Mol Pharm 13:683-8|
|Huang, Chun-Hao; Lujambio, Amaia; Zuber, Johannes et al. (2014) CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev 28:1800-14|
|Zeglis, Brian M; Houghton, Jacob L; Evans, Michael J et al. (2014) Underscoring the influence of inorganic chemistry on nuclear imaging with radiometals. Inorg Chem 53:1880-99|
|Cheal, Sarah M; Punzalan, Blesida; Doran, Michael G et al. (2014) Pairwise comparison of 89Zr- and 124I-labeled cG250 based on positron emission tomography imaging and nonlinear immunokinetic modeling: in vivo carbonic anhydrase IX receptor binding and internalization in mouse xenografts of clear-cell renal cell carcino Eur J Nucl Med Mol Imaging 41:985-94|
|Doran, Michael G; Watson, Philip A; Cheal, Sarah M et al. (2014) Annotating STEAP1 regulation in prostate cancer with 89Zr immuno-PET. J Nucl Med 55:2045-9|