Accelerating cancer treatments with the power of isotopes

Accelerating cancer treatments with the power of isotopes

Cancer is one of the most dreaded diagnoses most people can imagine receiving.

However, no two cancer patients—even if they have the same kind of cancer—experience exactly the same disease.

Successful treatment requires an approach tailored to the specific nature of an individual’s disease. The more customized the therapy is, the more effective it will be at killing cancer cells and sparing healthy tissue.

One way to deliver a knockout punch to tumor cells is to use medical isotopes or radionuclides—radiologically active atoms that can provide a highly targeted dose directly at a tumor site. While not applicable for all cancers, targeted radionuclide therapy is providing doctors with a new weapon in their arsenal against cancer.

The use of radionuclides in medicine is not new: Every year, doctors perform more than 40 million medical procedures that rely on the use of medical isotopes. However, most of these procedures are currently for diagnosing disease rather than treating it.

Producing radionuclides requires specialized facilities—they can’t be manufactured in just any lab. At the U.S. Department of Energy’s (DOE) Argonne National Laboratory, for example, high-powered linear accelerators are dispatched to generate these radionuclides, and specialized radiological facilities are needed to purify them. Traditionally used for physics experiments, these accelerators have the capability to study and even create radionuclides for use by researchers and doctors.

How medical isotopes work

Once produced, medical radionuclides can fall into three major categories. The first is diagnostic, where the radioisotope allows doctors to visualize a tumor’s precise location and contours within the body with greater clarity than an MRI scan provides. Another is therapeutic, where doctors use the radionuclide to deliver cancer-killing radiation directly to tumor cells. The third is theragnostic, which combines the power of both in such a way that the theragnostic radionuclide agent allows a doctor to both visualize and treat a tumor simultaneously.

When added into new generations of medicines that contain medical isotopes, or radiopharmaceuticals, that selectively seek out cancer cells, or that provide additional benefits in radiotherapy, these theragnostic isotopes will give doctors more options in the fight against disease and will ultimately give patients more hope.

Argonne’s long history of expertise in nuclear physics, nuclear chemistry, chemical separations and accelerator physics has paid dividends in the creation of both a radionuclide research and development program and a specialized process for supplying a particular radionuclide, copper-67, to the medical community.

“Copper-67 is an especially valuable radioisotope because it is theragnostic and because we have a way to produce it in quantities that would be useful to hospitals,” said Dave Rotsch, an Argonne chemist and deputy program manager of Argonne’s radioisotope program. “Because Argonne has unique facilities and expertise that allow us to produce these isotopes, hospitals are expressing interest.”

Argonne’s critical research role

Argonne’s work in radioisotopes is supported by the DOE Isotope Program, which is the global leader in producing and distributing radioactive and enriched stable isotopes that are deemed critical or are in short supply. DOE’s Isotope Program is taking advantage of the capabilities found at national laboratories like Argonne and putting them to use developing advanced production and processing technologies for these much-needed isotopes.

In addition to this effort, the DOE’s National Nuclear Security Administration funds Argonne to support and accelerate the U.S. production of another isotope, molybdenum-99. Argonne continues to provide target testing and development, irradiation, and Monte Carlo calculation services for multiple commercial partners to accelerate domestic production of molybdenum-99. The laboratory also helps develop and optimize separation methods for those partners.

“Argonne has a long history of showing that we can make important contributions in radioisotopes—originally in R&D, but now in actually producing them as well,” said Argonne physicist and deputy program manager Jerry Nolen.

One key facility involved in producing radioisotopes is Argonne’s Low-Energy Accelerator Facility (LEAF). To make medical isotopes, the LEAF delivers a powerful beam of electrons, which are converted to gamma rays, which are highly energetic photons, or packets of light.

These gamma rays, in turn, strike a highly pure, stable target material, like zinc-68. The resulting photo-nuclear reaction ejects one or more protons or neutrons to make the desired radioisotope: copper-67 in this case.

Only a small fraction of the target mass is converted to the isotope of interest, which means that the target can be used over and over again.

“It’s a little bit like doing alchemy,” Rotsch said. “Essentially, by hitting our target with photons, we’re converting one element into another or one isotope into another.”

The copper-67 and other byproduct isotopes are separated in gaseous form in a process that involves vaporizing the zinc in the target material and condensing it on a cold surface. The copper is then dissolved into a solution and further purified through a process that allows researchers to selectively isolate copper-67 (or whatever isotope they might want) based on the chemical differences of the atoms that are present in the solution.

A world of medical isotopes

Copper-67 is not the only isotope of interest being studied by researchers at Argonne. Rotsch and his colleagues are also investigating scandium-47, another exciting theragnostic isotope, and actinium-225, which has shown great promise for treating cancer.

“With most standard treatments, like chemotherapy, you don’t know to which drug, or drugs, a patient will respond the best, so it can sometimes be a guess-and-check game,” Rotsch said.

Radiopharmaceuticals allow doctors to observe a tumor’s uptake of a diagnostic version of the radiopharmaceutical. Based on these results, Rotsch explained, the doctor can more effectively develop and prescribe a treatment plan with a therapeutic or theragnostic radiopharmaceutical.

Artificial intelligence also could help doctors pair radioisotope candidates with individual tumors. Using the genetic profile of a tumor on a computer, researchers and medical professionals could run simulations of how a radiopharmaceutical would attach to and attack the tumor. This would provide a good idea of which therapies would be most effective even before implementing them, said Kawtar Hafidi, Argonne associate laboratory director for Physical Sciences and Engineering.

“Argonne is unique in the suite of facilities and expertise that it offers, from the accelerators to the radiochemical separations to the computing,” she said. “By combining all of these resources, we can really make a range of treatments more effective.”

From Argonne’s perspective, the ultimate goal, Hafidi said, is to create an integrated program that allows scientists to develop isotopes as fluidly as possible and create pathways for new treatments that have yet to be conceived.

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Accelerating gains in abdominal fat during menopause tied to heart disease risk

heart

Women who experience an accelerated accumulation of abdominal fat during menopause are at greater risk of heart disease, even if their weight stays steady, according to a University of Pittsburgh Graduate School of Public Health-led analysis published today in the journal Menopause.

The study—based on a quarter century of data collected on hundreds of women—suggests that measuring waist circumference during preventive health care appointments for midlife women could be an early indicator of heart disease risk beyond the widely used body mass index (BMI)—which is a calculation of weight vs. height.

“We need to shift gears on how we think about heart disease risk in women, particularly as they approach and go through menopause,” said senior author Samar El Khoudary, Ph.D., M.P.H., associate professor of epidemiology at Pitt Public Health. “Our research is increasingly showing that it isn’t so important how much fat a woman is carrying, which doctors typically measure using weight and BMI, as it is where she is carrying that fat.”

El Khoudary and her colleagues looked at data on 362 women from Pittsburgh and Chicago who participated in the Study of Women’s Health Across the Nation (SWAN) Heart study. The women, who were an average age of 51, had their visceral adipose tissue—fat surrounding the abdominal organs—measured by CT scan and the thickness of the internal carotid artery lining in their neck measured by ultrasound, at a few points during the study. Carotid artery thickness is an early indicator of heart disease.

The team found that for every 20% increase in abdominal fat, the thickness of the carotid artery lining grew by 2% independent of overall weight, BMI and other traditional risk factors for heart disease.

They also found that abdominal fat started a steep acceleration, on average, within two years before the participants’ last period and continued a more gradual growth after the menopausal transition.

Saad Samargandy, Ph.D., M.P.H., who was a doctoral student at Pitt Public Health at the time of the research, explained that fat that hugs the abdominal organs is related to greater secretion of toxic molecules that can be harmful to cardiovascular health.

“Almost 70% of post-menopausal women have central obesity—or excessive weight in their mid-section,” said Samargandy, also the first author of the journal article. “Our analysis showed an accelerated increase of visceral abdominal fat during the menopausal transition of 8% per year, independent of chronological aging.”

Measuring abdominal fat by CT scan is expensive, inconvenient and could unnecessarily expose women to radiation—so El Khoudary suggests that regularly measuring and tracking waist circumference would be a good proxy to monitor for accelerating increases in abdominal fat. Measuring weight and BMI alone could miss abdominal fat growth because two women of the same age may have the same BMI but different distribution of fat in their body, she added.

“Historically, there’s been a disproportionate emphasis on BMI and cardiovascular disease,” said El Khoudary. “Through this long-running study, we’ve found a clear link between growth in abdominal fat and risk of cardiovascular disease that can be tracked with a measuring tape but could be missed by calculating BMI. If you can identify women at risk, you can help them modify their lifestyle and diet early to hopefully lower that risk.”

Late last year, El Khoudary led a team in publishing a new scientific statement for the American Heart Association that calls for increased awareness of the cardiovascular and metabolic changes unique to the menopausal transition and the importance of counseling women on early interventions to reduce cardiovascular disease risk factors.

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