Radiolabelled Theranostic Agents for Targeted Cancer Diagnosis and Treatment
Cancer Theranostics: Strategies and Applications
Medical imaging is being revolutionised through personalised medicine to avoid unnecessary and expensive treatments. The nuclear medicine imaging approach is to use theranostics [targeted therapeutic (Rx) + companion diagnostic (DX)], for example, Zevalin, to establish tools for specific molecular targeting.
The aim is to visualise potential biological targets and develop a personalised treatment plan for the patient. The advent of the development of radiopharmaceuticals and diagnostic procedures will drive these theranostic agents (Zevalin) to be utilised in various nuclear medicine departments. This article aims to provide an overview of theranostics, highlighting radioiodine therapy in patients with thyroid cancer and then progressing through multiple approaches for the treatment of advanced cancer by applying targeted therapies.
Theranostics is an emerging field of nuclear medicine with the aim to target disease states by applying a specific targeted therapy based on precise diagnostic tests. This strategy is focused on the patient to produce a favourable outcome from medical imaging by treating the disease state. This approach moves away from a conventional medicine platform to a personalised and precision methodology. The theranostics model involves bridging nanoscience with diagnostic and therapeutic applications to generate a single agent to facilitate diagnosis, drug delivery and treatment response monitoring.
Therapeutic Bullets for Targeted Cancer Therapy
The premise behind theranostics is to take advantage of specific biological pathways in the human body to enable the acquisition of diagnostic images. The transformation of these digital images will increase the chance that the therapeutic dose will specifically target the disease site and therefore limit the damage to the surrounding tissues. This approach of using a specific diagnostic test identifies a particular molecular target on tumour cells, allowing a therapeutic agent to bind to the receptor sites and specifically target the regions in the tumour volume.
Theranostics nuclear medicine imaging has started to revolutionise medicine in how we diagnose and develop treatment plans for patients, especially in oncology. This is in contrast to the more orthodox treatment approach based on the “one-medicine-fits-all” concept. The economic benefits are vast because the patient will receive the correct treatment plan, which would include the right amount of dose to produce a favourable pharmacotherapy outcome in the form of theranostics.
Today, theranostics is used in medical and research establishments to focus on the development of personalised treatment plans by using targeted therapies to eliminate specific disease subtypes, and this may include the genetic profiling of patients. The collaborative approach between nuclear medicine imaging and biosciences will enable successful protocols in the optimisation of drug efficacy, including safety profiles. The merit of this approach is to rationalise the drug development process and reduce costs. The dual diagnostic and therapy tool will form a central part in elucidating the disease subtypes and understanding its progression within a particular patient. All the information obtained will create an overall rationale to progress the treatment plan, including the type of drugs to be administered, dosing schedules and an understanding of how the patient responds to treatment.
Theranostics can trace its roots back to the pioneering work of Glenn Seaborg and John Livingood, who, in 1938, at the University of California, Berkeley, discovered radioactive iodine-131. This radioisotope became the gold standard in diagnosing and treating thyroid cancer in nuclear medicine imaging departments worldwide.
Hybrid Imaging Systems in Nuclear Medicine: PET/CT and SPECT/CT Integration
During the past decade, a similar model has been developed for neuroendocrine tumours, which use the radionuclide gallium-68. This positron emission tomography (PET) radiotracer is chelated to DOTA-octreotate and is utilised in tumour diagnosis and produces a higher sensitivity compared to Indium-111 octreotide imaging. The disease state in patients can be assessed by targeting the somatostatin receptor volume by using the gallium-68 DOTA-TATE and image with a hybrid scanner such as PET-CT (Positron Emission Tomography-Computer Tomography).
Patients with disease states that respond to gallium-68 DOTA-TATE PET-CT imaging can receive a treatment plan involving lutetium-177 octreotate therapy for the treatment of carcinoid and endocrine pancreatic tumours. In these cases, the patient will receive 4 to 6 hours of intravenous infusion of lutetium-177 octreotate before leaving the hospital on the advice of the medical physicist. The beta-emitting therapeutic radiopharmaceutical is known as Lutetium Octreotate Therapy and is available in five medical centres throughout North America, including several European nuclear medicine departments.
Since the discovery of this radiotherapeutic method by Harvey and Claringbold using a chemo-targeted radiopeptide therapy approach and building on the platform, theranostic technologies are emerging by building on the platform of radio-sensitising chemotherapy.
The theranostics approach to personalised medicine is gaining pace through a series of milestones, including:
- Lutetium PSMA therapy for the treatment of resistant prostate cancer or metastatic cancer
- Yttrium-90 SIRT therapy for liver cancer
- Iodine-131 therapy for thyrotoxicosis and thyroid cancer
- Radium-223 therapy for metastatic prostate cancer in bones
- Yttrium-90 radiosynovectomy therapy for inflammatory synovitis of joints.
Theranostics offers many challenges in the implementation of targeted therapy towards cancer due to tumour heterogeneity between individuals. The application of molecular characteristics contributes to tumour reclassification and the best-targeted therapies to be used to ensure the most promising outcome for each patient. To understand the targeted approach, functional imaging such as PET and CT scanning or its hybrids have been used with the versatile radiotracer [18F]fluorodeoxyglucose (FDG) to evaluate the glucose metabolism in tumour cells. Building on this platform has identified other radiopharmaceutical targets which are capable of tumour characterisation, microenvironment, angiogenesis, proliferation, apoptosis and receptor expression.
Several studies have explored specific imaging probes to study receptor expression in tumours. These include PET-CT and Single Photon Emission Computed Tomography (SPECT-CT). However, these hybrid scanners have proved to be invaluable by exchanging between diagnosis and therapy functionality using a specific therapeutic radionuclide. Moreover, these molecular imaging techniques have demonstrated a great potential to link target identification with therapy and personalise it towards the patient’s treatment plan. Furthermore, creating the potential for in vivo tissue characterisation and improve prediction, including prognostication. These components lead to a roadmap for biopsy and therapy monitoring.
The unique feature of Zevalin® is that it can target the CD20 antigen on B-cell non-Hodgkin’s lymphoma (Zevalin) to allow imaging during radiotherapy. Zevalin works by fixing the radiometal indium-111 into a tiuxetan chelate. The monoclonal antibody ibritumomab can detect B-cells and transport the beta/alpha-emitting radiometal to destroy the lymphoma. SPECT imaging can confirm that the antibody is distributed within the body. The indium-111 is swapped with radionuclide yttrium-90 transporting beta particles to kill the B-cells.
Theranostic Aspects of Zevalin: Bridging Molecular Imaging and Targeted Radiotherapy
Zevalin® therapy has shown useful indications for B-cell non-Hodgkin’s lymphoma, including relapsed or refractory low-grade or follicular forms. Since 2002, Zevalin® has been used for the treatment of this indication, including B-cell non-Hodgkin’s lymphoma and rituximab refractory follicular non-Hodgkin’s lymphoma. In 2008, Zevalin® was given FDA approval for follicular lymphoma in the European Union.
The theranostics integration platform enables ‘drug’ selection to target specific cancers through a personalised medicine approach and is the result of the information processed from a diagnostic test. Targeted therapy strategies are becoming prevalent in oncology (Zevalin) and nuclear medicine imaging by moving towards an ultimate goal of personalised medicine.
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