The Importance of Nuclear Medicine and Molecular Imaging and its Potential to Drive Precision Medicine
By Diana Roettger, PhD, Olga Kubassova, PhD and Faiq Shaikh, MD
Nuclear and molecular imaging has a tremendous potential of catalyzing the precision medicine revolution and impact targeted drug development due to their ability to identify disease at the molecular level and detect earliest signals that can be used as biomarkers for predicting disease progression and amenability to therapy. The latter allows it to facilitate and monitor personalized therapy. As the focus switches from structural classification of disease (especially in oncology) to genetic and molecular classification, molecular imaging is poised to be critically important in disease identification as well as risk stratification and therefore prognostication.
In early drug development phases, nuclear and molecular imaging are critical to answering specific questions around whether the new drug candidate reaches the target and, if so, in sufficient quantity or whether the expected mechanism of action can be observed.
In the translational arena, molecular imaging is being used to explore many of the critical processes on key biology processes, such as angiogenesis, proliferation, tissue invasion, fibrosis, apoptosis/necrosis, etc. which are targets of novel therapies in development. Molecular imaging provides surrogate endpoints for these processes that in turn guide translation of novel therapeutic approaches.
Nuclear medicine is the branch of medicine that deals with the use of radioactive substances in research, diagnosis and treatment response assessment. Molecular imaging supports the visualization, characterization and quantification of biologic processes taking place at the cellular and subcellular levels within living subjects, such as immunologic processes, receptor activity and signal transduction.
Molecular imaging is a term often used interchangeably with nuclear medicine, probably because it shares the imaging modalities, but there is a conceptual difference. There is a wide range of imaging modalities that are used in molecular imaging, including MRI (using peptides, antibodies, small ligands, and small protein domains as targets), optical imaging (fluorescence, bioluminescence, absorption or reflectance), Near Infrared Imaging (using peptide probes), and SPECT/PET (using minibodies, ligands for receptors, reporter genes, etc.).
Nuclear medicine is the field of medicine that involves the use of radioisotopes to detect and follow the treatment response in cancerous and noncancerous disease entities in humans. The radioactive emissions from these agents administered in various compartments of the body are captured using gamma, SPECT or PET cameras, and provide information regarding the physiologic/biochemical processes and detect perturbations therein. Their ability to do so is based on the physicochemical properties of the ligand that the radioisotope is attached to.
In that sense, it is truly functional imaging and therefore instrumental in detecting disease processes that do not manifest structurally (at least right away) on anatomic imaging (such as CT or MRI)
‘To make objective decisions on the efficacy of a specific compound or to better understand its mechanism of action, it is important to combine novel Quantitative Image Analysis and Radiomic approaches.’
Through the right use of imaging it is possible to derive useful insights to pathophysiologic process that drive disease entities, such as fibrosis, hypoxia, vasculogenesis, apoptosis, necrosis, immune cell recruitment and infiltration.
At IAG, we understand the complexity and the importance of nuclear medicine and molecular imaging and its potential to drive precision medicine forward. Working with variety of imaging modalities such as MRI, PET, SPECT, CT, optical imaging and tracers labelled with 18F, 11C, 15O, 13N, 32Rb, 99mTc, 89Zr, 177Lu allows to determine an optimal trial design and outcome measures for various indications (oncologic, inflammatory, immunologic and genetic).
There are a host of molecular imaging agents under study and in trials in the realm of inflammatory disorders. There are investigational agents in each subclass (radiolabeled biologicals, specific molecular markers, etc.) that are of great interest especially for drug development for Rheumatoid arthritis. One such example is that of (R)-[(11)C]PK11195, which is a radioactive Carbon (11-Carbon) labeled agent that binds to peripheral benzodiazepine receptors expressed on macrophages, and is imaged using PET. This agent allows quantitative analysis of the degree of inflammation in joints with RA. There are several trials underway that are evaluating its usefulness in synovitis, RA and arthralgia.
Figure 1: This image shows in parallel, PET images of arthritic knees in rats using [11C]DPA-713, [18F]DPA-714 and (R)-[11C]PK11195 along with their corresponding TAC of arthritic and contralateral knees. Results are presented as mean ± SD of seven, five and five arthritic rats for [11C]DPA-713, [18F]DPA-714 and (R)-[11C]PK11195, respectively. (Reference: Promising potential of new generation translocator protein tracers providing enhanced contrast of arthritis imaging by positron emission tomography in a rat model of arthritis. Gent CY, Weijers CFM, Molthoff AD, Windhorst MC. Published 2015).
In the realm of oncology, one very exciting prospect is that of Antibody-drug conjugate (ADC). ADCs are extremely specific in attacking the target antigen and pack the cytotoxic potential of a chemotherapeutic drug. Currently, 2 ADCs are approved for standard care and more than 50 are in clinical development. CEACAM6, an ADC-targeting carcinoembryonic antigen–related cell adhesion molecule is one such ADC agent, and when radiolabeled with a positron emitting radioisotope, the 64Cu-anti-CEACAM6 mAb can monitor the delivery and biodistribution of the drug and monitor response. Early studies in mice with human xenograft pancreatic adenocarcinoma have shown promising results, especially in predicting toxicity and efficacy profiles of its ADC.
Figure 2: microPET whole body images (coronal plane) of BxPC3 tumor-bearing mice at different time points after tail vein injection of 3.7 MBq of 64Cu-DOTA-2A3, 64Cu-DOTA-2A3- mFc, 64Cu-DOTA-9A6, or 64Cu-DOTA-IgG (different types of anti-CEACAM6 ADC agents). Tumors were indicated by white arrows at the last time point. The displayed plane was selected to best show the tumor cross section. (Referece: Niu G, Murad YM, Gao H, et al. Molecular targeting of CEACAM6 using antibody probes of different sizes. J Control Release. 2012;161(1):18-24).
There are countless other molecular imaging agents/probes in the preclinical space making their way into translational and ultimately clinical medicine. It is very exciting to be in a position to apply advanced computational models to use them to their maximum potential.
A list of important publications in this area is provided below. To discuss your trial in details, email to the authors to firstname.lastname@example.org
- Pysz MA, Gambhir SS, Willmann JK. Molecular imaging: current status and emerging strategies. Clin Radiol. 2010 Jul;65(7):500-16. doi: 10.1016/j.crad.2010.03.011.
- WunderRH, Straub S, Gay J, et al. Funk Molecular imaging: novel tools in visualizing rheumatoid arthritis. Rheumatology, Volume 44, Issue 11, 1 November 2005, Pages 1341–1349.
- Put S, Westhovens R, Lahoutte T, Matthys P. Molecular imaging of rheumatoid arthritis: emerging markers, tools, and techniques. Arthritis Research & Therapy201416:208.
- Rudin M, Weissleder R. Molecular imaging in drug discovery and development. Nat Rev Drug Discov.2003 Feb;2(2):123-31.
- Waaijer SJH, Kok IC, Eisses B, et al. Molecular Imaging in Cancer Drug Development. J Nucl Med.2018 May;59(5):726-732. doi: 10.2967/jnumed.116.188045. Epub 2018 Jan 25.
About the Authors:
Diana Roettger, Head of Therapeutic Innovation at IAG.
Diana is a medical computer scientist and passionate to bring AI and imaging data analytics to the development of new drugs. She is an expert in imaging clinical trial design, regulatory pathways and novel imaging biomarkers that accelerate drug development bring earlier evidence of efficacy in inflammatory, immuno-oncology and neuro-oncology indications.
Olga Kubassova, CEO of IAG and a Venture Partner.
She is a a mathematician with over 10 years expertise in actively managing innovation in life science companies. Olga is a healthcare innovator and biotech investor with passion for improving people’s health. She has co-authored over 60 publications, books and book chapters, has become a scientific adviser to the UK government and EU funding bodies. Olga’s ambition is to bring truly disruptive technologies, artificial intelligence and best of machine learning to clinical practice and research, while expanding IAG’s footprint and partnerships.
Faiq Shaikh, Head of Research & Enterprise at IAG.
Faiq Shaikh, Head of Research and Enterprise (Oncology & Radiomics) is a dual-fellowship trained Molecular Imaging physician and an experienced translational and clinical researcher focusing on Quantitative image analysis of multimodality imaging in the realms of Immuno-oncology and Infectious/inflammatory imaging. He has co-authored over 35 publications, abstracts and book chapters. Faiq is catalysing the incorporation of advanced imaging methodologies, including radiomics in clinical trials.
About IAG, Image Analysis Group
IAG is a strategic partner to bio-pharmaceutical companies developing new treatments to improve patients’ lives. Our dynamic Strategy, Trial Solutions and Bio-Partnering divisions work closely to meet critical needs of biotechnology companies: funding, clinical development and monetization of their assets. We fuse decades of therapeutic insights, risk-sharing business model and agile culture to accelerate novel drug development. IAG broadly leverages its core imaging expertise, proprietary technology platform DYNAMIKA and capabilities to support an objective early go no/ go decision and drive excellence for tomorrow’s innovative therapeutic agents with speed.