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August 2014

 

Is "The Fantastic Voyage" Becoming a Reality?  


 Akiva Mintz 

 
 

Akiva Mintz, section head of the division of radiologic science and associate professor at Wake Forest School of Medicine, highlights recent developments in α-particle therapy that have enabled investigators to exploit this highly potent form of cancer treatment by targeting tumor-restricted molecular biomarkers.

Although such drawbacks as toxicity and a lack of overwhelming response have dampened enthusiasm for molecular targeted radiation therapies, what are the lessons learned from these therapy efforts?

There were many lessons learned from these early pioneering studies. Perhaps the most important lesson is that cancer is very resilient and we need to optimize our delivery systems to obtain significant effects. The early trials used the available targeting technology, which included full antibodies derived from mice. That proved to be less than ideal because of the antibodies’ lack of rapid excretion from the blood, which limited their administered dose and tumor-to-normal organ ratios. Unlike the radioactive iodine used in a salt form for thyroid cancer, antibody-based strategies targeting other cancers failed to accumulate the requisite high local dose to the tumor before dose-limiting toxicities were seen.

Some of the antibodies have proven to be too large to allow them to rapidly clear the blood pool. How has that characteristic affected or influenced progress?

This is very significant, because these studies have shown that if the size of the targeting moiety is in a range smaller than antibodies and cleared by the kidneys, the tumor-to-normal tissue ratio is significantly improved. This allows a much higher dose of radioactivity to reach the tumor before the dose-limiting toxicities are seen.

What are some of the limitations of β-particle-emitter-based therapies?

While β-particle-emitter-based therapies have seen success in thyroid cancer and some lymphomas, they can be limited by their relatively long range, which can harm adjacent normal tissue in certain instances. Furthermore, due to their lower killing efficiency, large amounts are needed at the tumor site to successfully target radioresistant solid tumors, which may not be possible due to toxicities.

Why do α-particles succeed where β-particles fail?

Alpha-particles have very promising potential due to their much higher potency per a delivered particle (100 to 500-fold) compared to β-particles. Furthermore, their very short range makes them more precise compared to β-particles, which have a much longer range. However, in some cases this precision may be a drawback because if there are tumor cells nearby that do not have the targeted biomarker, the α-particles will not reach them. Therefore, it is critical for the targeting strategy to always reach the vast majority of the tumor cells.

Since at least the middle of the last century, both physicians and patients have dreamed of finding a way to target cancer cells for treatment without damaging healthy tissue. Are we seeing the beginnings of the then-science fiction film, Fantastic Voyage, coming to fruition? Will there be a “magic bullet?”

Cancer is a very resilient and adaptive disease, which prevents any magic bullet approach that will kill all cancers. Furthermore, we have learned that cancer is more of a collection of diseases, with every patient having a different variety that will likely have to be treated with different therapies. The most exciting technological advances are leading us to an era of precision personalized medicine, where each patient’s cancer is analyzed for its particular drivers and vulnerabilities using advanced genomic and diagnostic approaches. That information will allow oncologists to choose from a collection of therapies that will have the best chance of curing that particular cancer. This is especially important for α-particle- based therapies, because a priori knowledge of the expression of the targeted biomarker will be critical to the success of the therapy.

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