A core challenge in oncology has always been the “one-size-fits-all” approach. Systemic chemotherapy floods every tissue with cytotoxic agents, and a sobering statistic reveals its contribution to overall survival in the US is only 4.3%. Even when treatments work, they come with poor drug solubility, short half-life, multidrug resistance, and nontargeted side effects.

“Theranostics,” a portmanteau of “therapeutics” and “diagnostics,” empowers nuclear medicine physicians the power to tag malignant cells with molecular beacons, visualize their distribution, and deliver targeted radiation directly to them. That potential has some touting the treatment as a candidate for the “fifth pillar” of cancer care alongside surgery, chemotherapy, radiotherapy, and immunology.

“Theranostics uses a tumor-selective molecule that’s injected intravenously and finds all the tumors in the body,” said Jamey P. Weichert, PhD, professor of radiology and director of the Contrast Agent Laboratory at the University of Wisconsin in Madison, Wisconsin. “That’s why there’s been a lot of interest in this area.”

That interest is rising. Venture capital investments in US radiopharmaceutical startups surged 550%, from $63 million in 2017 to $408 million in 2023, with US-based companies securing $1.2 billion in total venture financing during this period. “Every Big Pharma [company] is trying to get into the theranostics game now,” Weichert added. “Even small biotech companies are getting gobbled up by these Big Pharmas for billions of dollars.”

For patients with late-stage cancers, it already delivers the tangible gift of more time with a better quality of life. The NETTER-1 trial established the efficacy of ¹⁷⁷Lu-DOTATATE (Lutathera) in patients with advanced neuroendocrine tumors (NETs), offering a median progression-free survival of more than 20 months compared with the standard of care. This led to its FDA approval in January 2018. Similarly, the phase 3 VISION trial evaluated ¹⁷⁷Lu-prostate-specific membrane antigen (PSMA)-617 (Pluvicto) in patients with metastatic castration-resistant prostate cancer. The drug demonstrated a 5.3-month improvement in median progression-free survival and a 4-month extension in overall survival, leading to FDA approval in March 2022.

Now, the race is on to refine these therapies and bring a new weapon to the broader cancer fight.

The Anatomy of a Molecular Smart Bomb

Modern theranostic drugs are sophisticated four-part molecular “smart bombs.” First, a targeting ligand sniffs out and locks onto specific molecular signatures on cancer cells. This is attached to a radioactive isotope — the therapeutic compound itself. To prevent this unstable atom from escaping, a chelator acts like a cage, holding it securely. Finally, a linker acts as a molecular shock absorber, fine-tuning the drug’s stability and how long it stays in the bloodstream.

The process begins with a diagnostic scan. A radiopharmaceutical with a diagnostic isotope (like gallium-68) is injected. It emits positrons that a PET scanner detects, creating a detailed map showing where tumors are hiding. If the scan confirms the tumors are treatable, a second, therapeutic radiopharmaceutical is administered. It uses the same targeting molecule but is armed with a cancer-killing isotope (like lutetium-177) that releases destructive beta or alpha particles, delivering targeted radiation while minimizing damage to healthy tissue.

“You have the imaging component…to find disease, particularly metastatic disease,” explained James Kelly, PhD, chief of radiopharmaceutical sciences at Weill Cornell Medicine, New York City. “And then there’s the therapeutic component, which delivers ionizing radiation directly to the cancerous lesions.”

A Tale of Two Continents

Theranostics gained traction in Europe long before the US. Lisa Bodei, MD, Director of Molecular Imaging and Therapy at Memorial Sloan Kettering Cancer Center, New York City, notes that in Europe, “nuclear medicine was very much connected with internal medicine and endocrinology,” while the US “was more devoted to PET” imaging.

This interdisciplinary approach was crucial at the Erasmus University Rotterdam, Rotterdam, the Netherlands, where Eric P. Krenning, MD, PhD, pioneered peptide receptor radionuclide therapy. Working closely with endocrinologists, he had the insight to radiolabel octreotide, a drug for NETs. If it could be labeled to visualize where it traveled, why not attach therapeutic radiation to treat tumors wherever they appeared? Europe’s regulatory environment, with exceptions to compassionate use laws in countries like the Netherlands and Italy, also allowed researchers to conduct studies with greater ease than their American counterparts.

Steven Rowe, MD, PhD, chief of the Molecular Imaging and Therapeutics Division at the University of North Carolina, Chapel Hill, was captivated by this potential and now uses PSMA-targeted agents to treat his patients with prostate cancer. Once a patient is deemed a candidate, the care team spends about 2 weeks securing insurance approvals and coordinating logistics. The infusion itself takes about 5 minutes within a 20-minute appointment. Patients return every 6 weeks for up to six infusions, with regular lab tests to monitor for toxicity.

Still, theranostics is not a cure. “These are palliative therapies,” Rowe said. “About 70% of patients will respond, and maybe 40%-50% will have a good response, where they have a fairly prolonged progression-free survival.”

Choosing the Right Isotope

Beta-emitting isotopes, used in Pluvicto and Lutathera, hit a sweet spot of tumor penetration, clearance, and predictable dosimetry (radiation dose measurement). But the next generation of drugs will use more powerful alpha-emitting isotopes like actinium-225.

Alpha particles burn out after traveling just a few cell diameters, making them perfect for small tumors but less effective against larger masses. Bodei notes that while physicians have decades of experience with beta emitters, actinium remains relatively uncharted territory. It is also difficult to produce at scale, and its decay products create safety challenges. “Supply is an issue…[actinium] is the one that folks have the most experience with toxicities from,” said Rowe.

Its decay pathway also complicates imaging. “Once actinium decays to francium, francium is no longer conjugated and can move around the body,” said Kelly. This makes accurate dosimetry difficult. Kelly’s lab is exploring pairing cerium-134 with actinium to better visualize its uptake. Despite the challenges, alpha therapy is a major focus because “it’s much stronger” and “has been demonstrated to be efficacious even in patients who are resistant to the classic treatment” with beta emitters, said Bodei.

Other promising alpha-emitters include lead-212 and astatine-211, though neither is approved yet, and both have issues. Lead-212 is easier to source, but its daughter nuclides can detach, whereas astatine-211 has ideal decay properties but requires specialized production.

Big Things Have Small Beginnings

The influx of capital and excitement has taken theranostics farther than many expected. Weichert and his team at the University of Wisconsin received $20 million from the National Cancer Institute to advance their work. In a 2021 study, they used a carrier molecule (NM600) linked to radioactive yttrium to deliver low-dose radiation directly to tumors. This transformed immunologically “cold” tumors — those that evade immune surveillance — into “hot” lesions that attracted and activated tumor-killing immune cells.

In mice with checkpoint inhibitor-resistant tumors, this treatment eliminated tumors in about half the cases. More importantly, it generated robust immunological memory; when “cured” mice were rechallenged with the same tumor, their immune systems mounted a rapid response that prevented regrowth.

Having secured institutional review board approval, Weichert’s team is poised to begin human clinical trials. If successful, their work could alter how nuclear medicine views the relationship between radiation and immunity. “This is only the beginning,” said Weichert. “I should have retired 5 years ago. I just cannot retire right now because of what we’re doing here.”