Multiple myeloma (MM) is the second most commonly diagnosed hematologic cancer and remains incurable with current therapies. Biomedical imaging techniques such as 18F-fluorodeoxyglucose (FDG)/Positron Emission Tomography (PET), skeletal survey, bone scintigraphy and Magnetic Resonance Imaging (MRI) are routinely used for staging and post-treatment follow up in MM patients. More importantly, imaging of the skeleton with the aim of detecting lytic bone lesions is needed to discriminate MM from its precursor states such as smoldering MM (sMM) and monoclonal gammopathy of undetermined significance (MGUS). Many effective chemotherapy agents are available for MM patients, but the optimal use of these agents is not clear and a vast majority of patients relapse and die from their disease. All currently available imaging modalities take months to demonstrate tumor responses and therefore are of limited utility for clinical trials requiring rapi evaluation of treatment responses. FDG is a marker of cell metabolism that has limited sensitivity (61%) for intramedullary lesions in MM. Receptor-mediated interactions between myeloma cells and BM milieu support tumor survival. Very late antigen-4 (VLA-4;also called alpha4beta1 integrin) is one of the critical mediators of myeloma cell adhesion to the BM stroma. VLA-4 promotes myeloma cell trafficking, proliferation, differentiation and drug resistance. Clinically, high-levels of VLA-4 predict a poor prognosis in MM patients. In this proposal, we will develop a high-affinity and high-specific activity, copper-64 labeled VLA-4 targeted PET radiopharmaceutical (64Cu-LLP2A) to assess disease progression and response to treatment in pre-clinical models of mouse and human MM by quantitatively imaging VLA-4. The goal of aim 1 is twofold: a) to optimize the first-generation agent to enhance solubility and improve pharmacokinetics;and b) to synthesize optical and scrambled analogs for in vitro and in vivo binding specificity evaluations.
Aim 2 a will develop an imaging method using 64Cu- LLP2A/PET that can detect myeloma cells and myeloma induced bone lesions when they are significantly smaller than those currently detected with existing diagnostic tests and imaging methods. Finally, Aim 2b will focus on the monitoring of therapeutic responses using bortezomib (a proteasome inhibitor) and zoledronic acid (a bisphosphonate) at early and late time points.
These aims will help in the accurate assessment of early stage disease and treatment response by sensitive and specific VLA-4 targeted PET imaging.
The goal of this project is to evaluate a novel multiple myeloma (MM) molecular imaging approach to image early stage disease using a VLA-4 targeted PET probe in mouse models which closely emulate human myeloma bone disease and progression. The described studies will directly compare this innovative imaging methodology in pre-clinical models with FDG/PET, the current imaging standard, and will lay the groundwork for first-in-man clinical trials.
|Hathi, Deep K; DeLassus, Elizabeth N; Achilefu, Samuel et al. (2018) Imaging Melphalan Therapy Response in Preclinical Extramedullary Multiple Myeloma with 18F-FDOPA and 18F-FDG PET. J Nucl Med 59:1551-1557|
|Ghai, Anchal; Maji, Dolonchampa; Cho, Nicholas et al. (2018) Preclinical Development of CD38-Targeted [89Zr]Zr-DFO-Daratumumab for Imaging Multiple Myeloma. J Nucl Med 59:216-222|
|Fontana, Francesca; Ge, Xia; Su, Xinming et al. (2017) Evaluating Acetate Metabolism for Imaging and Targeting in Multiple Myeloma. Clin Cancer Res 23:416-429|
|Soodgupta, Deepti; Zhou, Haiying; Beaino, Wissam et al. (2016) Ex Vivo and In Vivo Evaluation of Overexpressed VLA-4 in Multiple Myeloma Using LLP2A Imaging Agents. J Nucl Med 57:640-5|
|Sun, Jessica; Miller, Jessica P; Hathi, Deep et al. (2016) Enhancing in vivo tumor boundary delineation with structured illumination fluorescence molecular imaging and spatial gradient mapping. J Biomed Opt 21:80502|
|Xu, Baogang; Shokeen, Monica; Sudlow, Gail P et al. (2015) Utilizing the Multiradionuclide Resolving Power of SPECT and Dual Radiolabeled Single Molecules to Assess Treatment Response of Tumors. Mol Imaging Biol 17:671-9|
|Maji, Dolonchampa; Solomon, Metasebya; Nguyen, Annie et al. (2014) Noninvasive imaging of focal atherosclerotic lesions using fluorescence molecular tomography. J Biomed Opt 19:110501|
|Soodgupta, Deepti; Hurchla, Michelle A; Jiang, Majiong et al. (2013) Very late antigen-4 (?(4)?(1) Integrin) targeted PET imaging of multiple myeloma. PLoS One 8:e55841|