Targeted Alpha Particle Therapy Holds Promise for NETs

Researchers are shining a spotlight on a revolutionary approach to tackling neuroendocrine tumors (NETs), a rare but increasingly prevalent form of cancer. Published in Brain Medicine, the review article explores how targeted alpha therapy (TAT) could redefine treatment for patients where surgery is not an option. Authors Dr. Kalyan M Shekhda, Dr. Shaunak Navalkissoor, and Emeritus Professor Ashley B Grossman, unpack the physics and biology driving TAT's potential. Alpha particles, with their high linear energy transfer (LET), cause irreparable double-strand DNA breaks--far more lethal to cancer cells than the single-strand nicks from beta particles. Dr. Shekhda explains, "Alpha particles are like surgical strikes--short-range, high-impact, and devastating to tumors, even in low-oxygen environments where other therapies falter." Studies show their relative biological effectiveness outstrips beta emitters, raising a tantalizing question: could TAT turn the tide for patients with resistant NETs?

“What makes targeted alpha therapy particularly exciting is its potential as a precision tool for patients who have exhausted conventional treatment options. From our clinical experience, we're seeing that alpha particles can overcome resistance mechanisms that limit traditional therapies. The highly localized nature of alpha radiation means we can deliver potent treatment directly to tumor cells while minimizing collateral damage to healthy tissues,” says Dr. Shaunak Navalkissoor, co-author and nuclear medicine specialist at Royal Free Hospital.

Preclinical trials in animal models have been promising. Experiments with alpha-emitters like ²²⁵Ac-DOTATATE and ²¹²Pb-DOTAMTATE in mice and rats delayed tumor growth with minimal toxicity to kidneys or bone marrow. Clinical studies, while still very preliminary, echo this optimism. A phase I trial of ²¹²Pb-DOTAMTATE reported an 80% disease control rate in PRRT-naïve patients, earning it a coveted FDA Breakthrough Therapy Designation. Meanwhile, ²²⁵Ac-DOTATATE has shown a disease control rate nearing 90% in some cohorts with progressive NETs. But how do these early wins translate to long-term outcomes? Future trials will explore the longer-term effects of these therapies, and their possible adverse events, although to date any untoward effects seem to be uncommon and possibly no greater than with conventional PRRT.