Episode 4, Precision radiopharmaceuticals: the time is now.
Over the past few decades, we have witnessed a paradigm shift in the diagnosis and treatment of cancer towards precision medicine. The deep and detailed understanding of the molecular mechanisms involved the tumor biology have led to the generation of targeted therapies.
Tumor biomarker is a term used to describe unique tumor features. Not surprisingly, one of the most important challenges in the precision medicine era is the identification of biomarkers for both diagnosis and treatment since often they may act as the Achilles heel in tumors cells.
Radiomolecular theranostic is a radioactive technique that represents a major step forward in diagnostic and personalized therapy. It’s based on radiolabeled molecules (“radioligands” or “tracers”), with a dual function, to bind to a specific biomarker in tumor cells and, simultaneously, use the absorbed radiation for diagnostic and/or tumor treatment. This precisely therapeutic approximation enables targeted delivery of radiation into the tumor niche and limits the damage on the surrounding healthy cells.
While future use of theranostic molecules may extend to different tumor types, to date, most of the experience and success has been in neuroendocrine tumors, pancreatic tumors and metastatic prostate cancer. Currently, a growing number of clinical trials are testing radioligands for use in diagnosis and/or treatment for advanced cancer of prostate, lung, thyroid, pancreas, breast, ovarian and neuroendocrine tumors among others.
In recent years, there has been an explosion of interest in radiopharmaceuticals. In June 2021, Novartis reported phase 3 data showing that men with castration-resistent prostate carcinoma lived longer when received Lu177-PSMA-617 (Luthatera) in addition to standard-of-care treatment. Novartis acquired the rights to Lutathera in 2018 and many other companies and investors followed Novartis’s lead.
One of the great reasons behind small biotech companies making possible the blossoming of clinical studies is by a virtue of radiotherapeutic drug development. Companies can collect pharmacokinetic data by imaging, using weakly radioactive molecules directed at the same cancer target as the therapeutic agent, and then design treatment protocols informed by knowledge of the precise amounts of drug absorbed by both tumor and normal tissue. Any resulting toxicities are thus more predictable and manageable than with most other drug platforms.
Although radiopharmaceuticals have shown enormous potential benefit, it’s still facing early days and companies are exploring different approximations to mitigate unwanted side effects such as the modification of the constant region of antibodies, the use of different radionuclides (alpha emitters such as At-211, Ac-225 and Th-227), and the identification of new targets in tumor or in the adjacent cells.
Another challenge is facing the field is the drug combination, pairing radiotherapeutics with, for example, checkpoint inhibitors, chemotherapy drugs or other radioactive agents. The approved dosage regimen for Lutathera and the dosing protocol used in phase 3 studies of Lu177-PSMA-617, in standard-of-care treatment, were each chosen for historical reasons. To minimize unwanted side effects and to maximize therapeutic benefit, in the future, studies to assess the administration of targeted radiopharmaceuticals in non-conventional ways will be required, rather than by historical knowledge of the therapeutic precursor of the radiopharmaceutical, either by playing with the dosage and schedules or by personalizing treatment plans on the basis of an individual’s imaging results.