isct: Advanced Preclinical Metabolic Imaging and Cell Engineering

Advanced Preclinical Metabolic Imaging and Cell Engineering

Cell metabolism plays an essential role in understanding nutrient uptake and oxidation of crucial substrates in tissues. Recently many reports emerged in metabolic imaging as it allows to image-guide new targeted therapies in cancer, diabetes, stroke, and liver failure. At the WSIC, we address these biochemical/biomedical challenges using cutting-edge, state-of-the-art, and highly translatable metabolic imaging.

Figure 1. A) Axial view T1-weighted imaging and the respective B) in vivo CEST MR imaging of mice bearing a small cell lung cancer (SCLC) tumor at the lower flank after an i.v. injection of a SR.

Hyperpolarized Metabolism & Cancer Profilling

Metabolic cancer profiling is a crucial focus at our laboratory, particularly towards the understanding of resistance to cancer immunotherapy. We are uniquely positioned to detect and predict real-time therapy response by molecular and metabolic imaging. For instance, we have a clinical SpinLabTM DNP hyperpolarizer that is a unique piece of instrumentation in Germany to perform metabolic imaging. We have gained a vast amount of experience with this innovative multimodality imaging system over the last few years. Now we combine metabolic imaging with both PET and MRI (HyperPET) so that in a single 1-2 hour imaging session, we study: perfusion, hyperpolarized metabolism, cellularity and therapy in solid tumors. We have also implemented a Magnetic Resonance Imaging (MRI) technique able to map extracellular pH and lactate levels in tissues in vivo by Chemical Exchange Saturation Transfer (Figure 1) (Zhang et al., J Am Chem Soc. 2017 Dec 6;139(48)). All these techniques are currently applied in clinics. They offer unique information about metabolic activity in tissues.

Metabolic Clustering and Modulation of the Tumour Microenvironememt

Understanding tumor microenvironment, heterogeneity, and metabolism will provide critical insights that will lead to symptomatic improvement of the diagnostic and to personalized cancer therapies. We aim to address the challenges associated with tumor heterogeneity and aggressiveness with novel hybrid positron emission tomography / magnetic resonance imaging (PET/MRI) sensors, state-of-the-art hybrid imaging, multiparametric data analysis & machine learning, and a quantitative functional imaging sensing approach. Our expertise will open venues to understand and modulate - with inhibitors currently undergoing clinical trials - tumor heterogeneity, aggressiveness, and malignancy. It will also create opportunities for the development of personalized treatments through specialized diagnostic methods capable of detecting relevant metabolic biomarkers (e.g., metabolites, pH, signaling metals, reactive oxygen species).

Quantitative Functional Imaging Metabolic Sensors

The development of “smart” and responsive multimodal sensors that detect events in the extracellular space offers the possibility of adding accurate molecular imaging information in addition to outstanding temporal and spatial resolution. Here, we combine expertise from several colleagues at the Radiochemistry group to design the next generation of functional quantitative imaging probes (e.g., hybrid PET/MRI sensors). We aim to develop sensors that detect changes in specific enzymatic activity, temperature, metal ion concentrations, oxygen pressure, and reactive species, pH, and metabolites. The Department of Preclinical Imaging and Radiopharmacy has state-of-the-art instrumentation ideal for this research (hybrid PET/MRI, PET/CT, and SPECT/CT scanners), modern small animal imaging facilities, GMP-capable radiochemistry with fully equipped laboratories which enable finally a clinical translation.

Metal Metabolism for Medical Imaging

Perturbed metal homeostasis is associated with pathological conditions such as dementia, cancer, and inherited metabolic abnormalities. Intracellular pathways involving essential metals have been extensively studied. However, whole-body fluxes and transport between different compartments remain poorly understood. Recently we have demonstrated in a collaborative effort with the Harvard Medical School and the UT Southwestern that zinc and copper play a critical role in identifying stages of malignancy in prostate cancer (PCa) by MRI and synchrotron radiation X-Ray fluorescence (SR-XRF) (Jordan et al., Inorg Chem. 2019 Oct 21;58(20)). Preliminary results from the WSIC also suggest that copper, zinc, and manganese play an essential role in triple-negative breast cancer, pancreatic cancers, and hepatocellular carcinomas (HCC). We aim here at the preclinical translation of metal metabolism using hybrid molecular imaging, personalized diagnostics, and specialized methods developed in-house: PET/MRI, HyperPET, functional quantitative imaging, PET/MRI sensors.

Our research has been recently recognized by the Alexander von Humboldt Foundation through the prestigious Sofja Kovalevskaja Award. The overreaching goal of the proposed research is to quantitatively access, predict, and modulate metabolic tumor heterogeneity with non-invasive multifunctional/multimodal/multiparametric methods. We will use cutting-edge hybrid technology, machine learning, and highly translatable smart molecular imaging hybrid probes to access new metabolic cancer features. This 5-year program will enable to non-invasively surveil, predict, select, and image-guide with high precision tumor metabolic therapies functionally. The work is also of critical importance for understanding the response of immune checkpoint inhibitor therapies, cellular immunotherapies (e.g., CAR-T cells or adoptive T cell transfer), and combinatorial therapies. Can therapy resistance be predicted and modulated by the tumor microenvironment?