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By Ilya Gipp
As humanity's understanding of illnesses has grown, so has the desire for treatments that precisely target disease while sparing healthy tissues and organs. In cancer, where tumors arise from a patient's own once-healthy cells, the challenge of selectively targeting and destroying the disease becomes even more complex. The ability to identify unique tumor properties has long been seen as a key to finding a cure.
Surgery was the first method of cancer therapy, initially performed with crude instruments but always with the intent to preserve unaffected tissues. A more effective breakthrough in cancer treatment came in the late 19th and early 20th centuries with the birth of radiation therapy. Wilhelm Roentgen’s discovery of X-rays in 1895, followed by Marie and Pierre Curie’s pioneering work with radium, led to the use of radiation to shrink tumors. Although the greater radiosensitivity of cancerous tissues compared to healthy ones was only explained later, this discovery marked the beginning of modern oncology treatments.
March 31, 1941 — a date now celebrated as World Theranostics Day – marked a groundbreaking moment in medical history. On that day, Dr. Saul Hertz, a physician at Massachusetts General Hospital, became the first to administer artificially produced isotope – radioactive iodine to a patient. So surprising that as an endocrinologist, Hertz recognized the potential of Iodine-131, with its longer half-life, making it a practical and effective tool for therapy – an approach that continues to save lives today. Remarkably, long before the advent of molecular biology, this treatment achieved precise targeting simply through the natural affinity of iodine for thyroid tissue. The era of precision medicine had begun.
But the discovery didn’t stop there. In a textbook example of collaboration, Dr. Saul Hertz and physicist Arthur Roberts developed the "Multiscaler", a device designed to measure isotope uptake in tissues. This innovation not only quantified treatment efficacy but also laid the foundation for personalized medicine – an idea far ahead of its time. The use of radioisotope "imaging" during treatment also marked the first-ever application of theranostics in history.
Since Dr. Hertz’s groundbreaking invention, numerous radioisotope treatments have been developed beyond Iodine-131, including Strontium-89, Samarium-153, Lutetium-177, Bismuth-213, and Lead-212. Like brachytherapy, these treatments deliver sources of therapeutic radiation directly to tumors, but now at the molecular levels for even greater precision.
Subsequently, the concept of radiotheranostics relies on the unique presence or elevated expression of molecular targets in cancer cells, enabling the use of a "diagnostic-therapeutic pair." The approach involves a radiopharmaceutical pair, where one isotope is used for imaging, aiding in diagnosis, patient selection, and predicting treatment effectiveness, while the other is used for therapy, targeting the same cellular or biological marker for delivering the treatment. This therapy, also known as radioligand therapy, centers around radiotheranostics agents. Typically, an agent includes three components: a ligand that targets molecules expressed by cancer cells, a radionuclide that emits radiation for imaging and therapy, and a chelator that connects the radionuclide to the ligand.
In recent decades, two radiotheranostic agents have demonstrated improved clinical outcomes: Lutetium-177 DOTA-Tyr3-Octreotate, a radiolabeled somatostatin (177Lu-DOTATATE) for patients with differentiated neuroendocrine tumors; and Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA) for patients with advanced prostate cancers. Labeling DOTATATE or PSMA molecules with positron-emitting radiolabels like 18F or 68Ga enables clinicians to detect their distribution and predict therapy response using Positron Emission Tomography (PET). The beta-emission of 177Lu provides a therapeutic dose effect, while its small gamma component allows clinicians to verify the uptake of curative activity by Single Photon Emission Computed Tomography (SPECT) scanner.
It is therefore the development of radiotheranostics has significantly elevated the need for advanced imaging techniques and data processing. As these therapies rely on precise targeting of tumor cells, imaging plays a crucial role in both the diagnostic and therapeutic phases. As mentioned, PET and SPECT, nowadays combined with computed tomography scanning capabilities, are essential for visualizing the distribution of radiolabeled agents within the body, allowing clinicians to diagnose and predict therapy response for effective patient selection. Additionally, imaging enables real-time quantitative monitoring of treatment efficacy and helps in performing dosimetry, which should be vital for personalizing therapy and ensuring optimal patient outcomes. This integration of imaging technologies not only enhances the accuracy of cancer treatment but also opens new possibilities for tailored patient care.
Radiotheranostics is ready for a new era of innovation, driven by the development of next-generation agents designed to enhance tumor targeting, improve imaging precision, and deliver more effective, personalized treatments. As research advances, the future of radiotheranostics will be shaped by new radiopharmaceuticals and novel isotopes. The example of combined potential of radioligand and conventional radiation therapies opens doors to even more promising therapeutic strategies.
One of the most exciting developments in radiotheranostics is the emergence of Fibroblast Activation Protein Inhibitor (FAPI)-based tracers, which have the potential to transform cancer imaging and therapy. Unlike traditional FDG-PET imaging, FAPI-based agents selectively target fibroblast activation protein, overexpressed in a variety of solid tumors, making them valuable across multiple cancer types. Agents like 68Ga-FAPI-46 for imaging and 177Lu-FAPI for therapy are already showing promise in clinical research.
Meanwhile, already existing and clinically approved PSMA-targeted therapies continue to evolve, with highly anticipated shift toward alpha emitters like 225Ac-PSMA that deliver greater cytotoxicity while overcoming tumor resistance possibly seen with beta-emitting agents. Similarly, in neuroendocrine tumors, the transition from 177Lu-DOTATATE to 225Ac-DOTATATE may represent a step toward more potent and durable treatments.
Next generation radiotheranostics might move beyond single-target therapies, embracing bispecific radioligands that bind to multiple tumor markers simultaneously. This approach enhances specificity, reduces off-target effects, and broadens the range of treatable cancers. For example, HER2/EGFR-targeted radioligands hold promise for breast and lung cancer patients with resistant or heterogeneous tumors.
The future of radiotheranostics is not just about new agents or isotopes, but also about enhancing the role of imaging, as well as robust integration of additional patient information and its efficient use in clinical decisions. We should expect the growing need for greater accuracy and sensitivity of imaging equipment together with intelligent data processing algorithms. Advances in personalized dosimetry and AI-driven therapy optimization will ensure that each patient receives the most effective radioligand treatment tailored to their unique tumor biology. This patient-centric approach will further maximize efficacy, minimize side effects, and pave the way for even more individualized cancer therapy.
About the author: Dr. Ilya Gipp, MD, PhD is the oncology chief medical officer at GE HealthCare.
