For patients with hard-to-treat cancers, the hurdle often lies in the location.

For a pancreatic tumor situated close to vital organs, or a cancer embedded deep within the brain, drug developers have always faced a critical dilemma – even if a drug is capable of eradicating the tumor, how do you deliver it in a sufficiently high dose without causing irreversible harm?

Enter radionuclide therapy, a class of cancer medicines which deliver radioactive atoms or radionuclides, to tumors deep inside the body with extreme precision.

This idea originates from the 1940s when doctors began using radioactive iodine as a novel treatment for thyroid cancer due to iodine being preferentially absorbed by the tumor cells.

The past 13 years have seen a growing number of regulatory approvals, beginning with Xofigo, a therapy aimed at patients with advanced, treatment-resistant prostate cancer which has spread to the bones. The market for this class of cancer medicines is now rapidly growing and is projected to be worth $10.7 billion by 2030.

The development of these treatments has been accelerated by the discovery of various biomarkers, unique to cancer cells, enabling homing molecules to be designed that deliver radionuclides directly to tumors in highly concentrated doses.

A recent example is Pluvicto , a drug developed by Novartis for patients with metastatic prostate cancer, which uses PSMA, a protein highly expressed on prostate tumors, to target the radionuclide lutetium‑177 to the cancer cells. After being approved by the FDA in early 2022, it has emerged as a novel life-extending option for patients with advanced disease.

The success of this drug has resulted in PSMA becoming a focal point for other radionuclide therapies aimed at advanced prostate cancer. Bayer has two early-stage clinical trials in progress using PSMA to deliver higher energy radionuclides to patients with metastatic disease. One of these trials uses the alpha-emitting radionuclide actinium-225, a form of radiation that induces breakages in both DNA strands which is hard for a tumor to repair.

Other tumor biomarkers are starting to emerge for cancers which are notoriously tricky to treat, such as Claudin 18.2, a protein which is abundant in a significant proportion of gastric and gastrooesophageal cancers , and GPC3, a biomarker which is overexpressed in hepatocellular carcinoma (HCC), the most common type of liver cancer. Bayer also has a Phase 1 trial in progress using GPC3 to target radionuclide therapy in patients with advanced liver cancers.

“The breakthrough has not just been in developing the radiopharmaceuticals, but identifying biomarkers which are only present in the cancer cells, and either not present elsewhere or very minimal in healthy tissues,” says Shadi Esfahani, a nuclear medicine physician at Mass General Brigham in Boston.

Other biomarkers can provide even more nuanced information, such as highlighting whether a particular cancer is more aggressive. Discoveries such as ALDH1A1, an intracellular enzyme that is overexpressed in therapy-resistant cancer, can help pinpoint the presence of treatment-resistant tumors. As a result, targeted radionuclide therapy is set to become ever more varied and sophisticated in the coming years and could ultimately lead to a broad array of new treatment approaches, tailored to the nature and biology of different tumors.

Later this year, a UK-based biotech company called Nuclide Therapeutics, is planning a clinical trial in lung cancer patients, a population with notoriously low overall survival rates.

“The symptoms don’t often show until the disease has spread, making surgery difficult, and the cancer develops therapy resistance at a rapid rate,” says Tim Witney, professor of molecular imaging at King’s College London, and the company’s co-founder & CSO.

The concept behind Nuclide Therapeutics’ trial is to use radionuclides in two stages. The first stage will see patients receive a diagnostic agent containing a harmless, low energy radionuclide simply designed to be detected on a medical scanner. This initial step is to determine whether the patient has treatment-resistant tumors, and if so, how many. Such information will then be used to guide the subsequent therapy with higher energy radionuclides, designed to kill the cancer cells.

“The amount of radionuclide therapy can be adjusted according to what the imaging scan shows us,” says Witney. “If there are multiple lesions that appear problematic, we can increase the radioactive dose, or if the patient is shown to have other complications, the dose can be dialed down.”

Esfahani perceives this kind of stratification as the future of the field. At Mass General Brigham, she is involved in trials where diagnostic radionuclides are being used to first examine whether a patient’s tumors carry biomarkers linked to more aggressive disease. “This way, we can say, ‘Okay, these patients are good candidates,’ before we put them through this heavy treatment,” she says.

More advances are likely to come, with companies developing ever more advanced homing molecules. For example, Swedish biotech Affibody has developed so-called ‘affibody molecules’ for delivering radionuclides to tumors that are roughly 1/20th the size of a traditional monoclonal antibody, allowing them to penetrate deeper into tissues.

Drug developers are also continuing to tweak the characteristics of radionuclides themselves to find the optimal combination. “We’re trying to get the radioactive molecule into the tumor, it has to stay there long enough to do damage, and then it has to leave the patient’s body as quickly as possible,” says Dominik Ruettinger, global head of research and early development oncology at Bayer Pharmaceuticals. “These are the three key steps and we’re still experimenting.”

While targeted radionuclide therapy is now predominantly used in patients where first-line treatments have already failed, there’s a possibility it could start to be trialed as an adjuvant or add-on therapy to existing treatments. In particular, the damage inflicted by radiation on cancer cells is known to increase their visibility to the immune system, suggesting that targeted radionuclides could work particularly well in combination with immunotherapy.

While Esfahani recommends caution, she feels that as evidence grows, these treatments could play an increasing role in cancer medicine.

“These are radioactive treatments that are being given systemically, so we should always be cautious about the toxicity of these drugs,” she says. “Because of this, a lot of regulatory agencies prefer that they are first tested in people who have failed other treatments. But once there’s data that shows, ‘Ok, this is safe and also as effective as standard treatments,’ then radiopharmaceuticals could be moved up as a first-line option where it’s the patient’s and physician’s choice about which treatment they want to receive.”

I look forward to watching these clinical trials carefully over the coming years—and one day, hopefully, welcoming a new standard tool into our toolbox for treating cancer.

Thank you to David Cox for additional research and reporting on this article.