How Radiopharmaceuticals Are Revolutionizing Cancer Therapy

Radiation therapy was first used to treat cancer over 100 years ago, with about half of all cancer patients today still receiving it at some point during their treatment.

Up until recently, radiation therapy was given much as it was more than 100 years ago – delivering beams of radiation from outside the body to kill tumors inside the body. However, even with external, effective radiation, healthy cells can become damaged as well as cancerous tissue. The resulting side effects of radiation therapy depend on the area of the body treated but can include loss of taste, skin changes, hair loss, diarrhea and sexual problems.

Therapeutic radiopharmaceuticals, commonly referred to as radioligand therapy (RLT), a class of drugs that deliver radiation therapy directly to cancer cells, have attracted great research interest over the last few years. Although these drugs are not new – radioactive iodine was first used to treat thyroid cancer in the 1940s – recent discoveries are changing the way we treat cancer, offering a highly targeted way to destroy tumors while minimizing damage to healthy tissue.

Ratio Therapeutics employs a suite of innovative technologies to develop targeted radiotherapeutics for the treatment of cancers. Technology Networks spoke with Ratio’s Dr. Jack Hoppin, chairman and chief executive officer, and Dr. John Babich, director, president and chief scientific officer, to learn more about the recent radiopharmaceutical revolution.

How do radiopharmaceuticals work?

Radiopharmaceutical therapies involve the targeted delivery of radiation to tumor cells or the tumor microenvironment using a radioactive drug. The drugs are composed of a radioactive isotope attached to a targeting molecule (e.g., monoclonal antibodies, proteins or small molecules) that binds specifically to cancer cells.

“The benefit of administering a radioactive drug through the blood system [via intravenous infusion] is that you can go after multiple metastatic lesions in a patient,” Babich said. “With external beam therapy, you are typically limited to a limited number of tumors in the body.”

Radiopharmaceuticals exert anticancer effects by inducing cytotoxic DNA damage through, for example, reactive oxygen species generation, induction of single and double-strand breaks and inhibition of DNA repair processes.¹ Therapeutic radioactive isotopes emit ionizing radiation – in the form of alpha or beta particles – which penetrates the cancer cells, damaging their DNA and leading to cell death. This radiation can also alter the tumor environment, limit angiogenesis and regulate the immune response, improving the overall therapeutic effect.²

A successful RLT relies on the ability to identify a molecular target or antigen on the surface of tumor cells matched to a radioligand that binds to that target. This allows for the selective delivery of a cytotoxic payload with minimal off-target effects. If the wrong antigen is selected, it sets a precedent for failure in the therapy design and radiopharmaceutical development.³ As RLT is administered into the blood system, the whole body is subject to some form of radiation before it reaches the tumors – even if only for a short time.

“It is important to have a substantial ratio between how much radioactivity goes into the tumor and how much of it goes everywhere else in the normal tissues, and that is a difficult problem to control,” Babich said.

“The drug binding to the tumor is accomplished by having a molecule that binds with a strong affinity to the cell surface target. But then we want the rest of the molecule to wash out of the body as fast as possible – not get hung up in the kidneys where it would emit radiation to the kidneys and other tissues,” he continued.

A double-pronged approach

Radiopharmaceuticals can be used for diagnostic or therapeutic purposes. The physical and molecular properties of a radiopharmaceutical influence its distribution within the body, whereas its radioactive decay qualities determine its suitability for diagnostic or therapeutic purposes. Therapeutic radionuclides are chosen to deliver a high radiation dose to the specific tissue, whereas diagnostic radionuclides are chosen to help visualize the distribution of the labeled compound in the body to identify disease.¹  In the case of RLT, a diagnostic radiopharmaceutical that binds the same target as the therapeutic radiopharmaceutical is used to identify patients who may benefit for the RLT.

“I think that it's so unique, the notion of a companion diagnostic – we all know that biomarkers drive better drug discovery development, and we have the ultimate biomarkers by far,” Hoppin said. “RLT is incredibly predictive. There's no other class of drug where you do measurements to forecast the absorbed dose quantitatively. There are some great biomarkers out there for sure, but this is a totally different sport and I think that it is part of the rise of RLT.”

“One of the things that's really exciting about this is you can identify the patients who will likely do well or who may have a benefit from RLT. But you can also rule out and not waste time with a particular therapy that might not be useful to a patient, thereby allowing them to pursue other treatments,” Babich added.

Challenges of radiopharmaceuticals

Like any drug discovery, RLT comes with a multitude of challenges encompassing drug discovery, manufacture and administration, in addition to regulatory and safety issues. One of these challenges is the availability of radioactive isotopes – a crucial factor in RLT production.

“The field of nuclear medicine therapy initially started in treating thyroid and neuroendocrine cancers. Both were a small market, so the availability of isotopes for the treatment of these diseases was reasonable,” said Babich. “As the program for treating neuroendocrine tumors became mature, it was obvious that we needed a better supply of different types of isotopes, however, the infrastructure to allow this was initially lacking.”

“With the RLT treatments for neuroendocrine tumors and prostate cancer doing well clinically and in the marketplace, it is envisioned that RLT could hold promise for other cancers – such as lung or breast – prevalent in large numbers of people. In order to meet the needs of the larger markets, isotope production has attracted significant investments in order to support use in clinical trials and ultimately the commercialization of these drugs,” he continued.

The regulation of RLT is also highly complex, with all radiopharmaceuticals – alpha, beta and gamma – presenting different regulatory challenges.

“Gamma emitters are very well characterized, and we know a lot about their safety and clinical use in imaging. By contrast, we know less about the long-term toxicity of novel alpha and beta emitting therapeutic radiopharmaceuticals. This makes them a more unique regulatory challenge during clinical development,” Hoppin explained. “The MHRA (Medicines and Healthcare products Regulatory Agency, UK) and EMA (European Medicines Agency) are coming up to speed with how to deal with radiopharmaceuticals and having large populations being treated in a study.”

“The regulators are cautious, as they should be, because they don't know the full impact beyond the limited number of patients involved in clinical trials – safety profiles are extrapolated from a relatively small number of individuals included in such clinical trials,” Babich added.

Long-term safety studies are also needed. People treated with external radiation therapy may experience some side effects called late effects – such as the development of second cancers – months or years after treatment. Although research to date has not shown a high rate of late effects from radiopharmaceutical treatment, like any new therapeutic class this needs to be continuously monitored with the emergence of these new drugs.

The future of radiopharmaceuticals

Radiopharmaceuticals represent a rapidly evolving frontier in cancer care, with research efforts increasingly focused on designing molecules that target tumors with remarkable specificity. As scientists continue to engineer fit-for-purpose, “designer” radioligands, we can expect to see ongoing improvements in therapeutic indices, meaning treatments will become more effective and safer for patients.

One of the most promising avenues in the field is the convergence of radioligand therapy and immuno-oncology. “There is promise in combining radiation therapy with immune-oncology treatments and plenty of discovery research is underway exploring this combination of therapies. An escalation of the innovations of the fit-for-purpose, designer molecules for the space of RLTs, means you're going to see better and better therapeutic indices,” Hoppin said.

Importantly, the benefits of radiopharmaceuticals extend beyond efficacy alone. Traditional cancer therapies, while life-extending, often come with harsh side effects that diminish patients' quality of life.

“We all are very familiar with friends and family that have gone through cancer treatment, right? It really knocks people. What we believe and see is that RLT can extend life while maintaining quality of life,” Babich concluded.

Looking ahead, the field of radiopharmaceuticals is not just advancing – it’s accelerating. With each innovation, we move closer to a future where cancer treatment is not only more effective but also more personalized, humane and hopeful.