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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Relationship between psoriasis treatments and cardiovascular risk explained

psoriasis

Psoriasis is a chronic disease that causes patients to develop patches of dry, scaly, itchy skin. It is an autoimmune disorder, which means that it arises from a person’s immune system inappropriately targeting that person’s own body. It is a deeply unpleasant condition, and patients commonly take medications so that they can live their lives more comfortably.

Professor Min Chen of the Chinese Academy of Medical Sciences and the Peking Union Medical College has conducted extensive research on psoriasis. “There are many patients with psoriasis who also have cardiovascular diseases, such as hypertension, diabetes, hyperlipidemia and coronary heart disease,” she notes. The presence of such cardiovascular diseases is an important consideration when treating patients with psoriasis because, as Prof. Chen explains, “Some of the drugs for psoriasis may increase the risks of these diseases, while some can reduce them.” Now, in a recent review article published in Chinese Medical Journal, Prof. Chen and her colleagues provide a summary of the existing scholarly knowledge concerning the associations between the different treatments for psoriasis and risks of cardiovascular diseases.

The authors explore how various drugs influence the long-term risks of what is known as MACE, an acronym that encompasses myocardial infarction (i.e., heart attack), cerebrovascular accidents (i.e., strokes and similar events), and cardiovascular mortality. They note that some psoriasis treatments such as tumor necrosis factor-α (TNF-α) inhibitors and methotrexate may actually reduce long-term MACE risk. Conversely, they also note that some interleukin (IL) inhibitors may increase MACE risk. For example, the IL-12/23 inhibitor briakinumab increased MACE risks so much across multiple studies that investigators had to suspend all clinical trials. However, other IL inhibitors such as tildrakizumab and guselkumab do not appear to increase MACE risks. The widely used immunosuppressant cyclosporine A can cause damage to heart muscle tissues. Ultimately, these findings indicate that more research is needed before scientists can rank psoriasis treatments in terms of their effects on long-term MACE risks.

There is currently no consensus among medical scientists on whether systemic treatments for psoriasis can mitigate or worsen arterial plaques, vascular function, and vascular inflammation. There is some evidence that treatments for psoriasis counter inflammation of coronary tissues and can lessen the coronary plaque burdens that contribute to coronary artery disease. Conversely, it has also been found that treatment with TNF-α inhibitors may contribute to an undesirable thickening of the carotid arteries, which are found in the neck and provide blood to the head. Scientists do not yet know whether methotrexate, IL-17 inhibitors, and IL-12/23 inhibitors also have any effect on arterial wall thicknesses.

In addition to the heightened risk of cardiovascular diseases, patients with psoriasis are at an increased risk of developing various risk factors for cardiovascular diseases. These risk factors include obesity, diabetes mellitus, and high blood lipid levels, and the existing literature points to several varied relationships between psoriasis treatment options and risk factors for cardiovascular disease. For example, TNF-α inhibitors may contribute to increased body weight, but IL-17 and IL-12/23 inhibitors may help patients lose weight. Cyclosporine A can increase the risk of diabetes, worsen hypertension, and contribute to unhealthy lipid metabolism profiles.

In conclusion, different psoriasis treatments have different effects on cardiovascular diseases and their risk factors, necessitating a more thorough consideration of each patient’s clinical situation before picking a treatment. For example, TNF-α inhibitors and methotrexate are good therapeutic options for patients with psoriasis who are at high risk of experiencing MACE, and inhibitors of IL-17 and IL-12/23 may be beneficial for patients who have arterial plaques.

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Study identifies new potential treatments for COVID-19

A virtual screening of the DrugBank database has identified a variety of as yet unexplored ways to attack SARS-CoV-2, even as it mutates. The study identified drugs and possible cocktails that are shown to target vital proteins of the coronavirus.

Recently publishing in the journal Scientific Reports, researchers from KTH Royal Institute of Technology, in collaboration with Alagappa University (India), proposed a list of individual drugs and cocktails that deserve testing for the treatment of COVID-19.

The researchers at KTH tested their own screening protocol, as an alternative to software typically used in the biopharmaceutical industry to screen vast volumes of compounds in drug databases.

Theirs involved a double-scoring approach to identify lead compounds that show potential for COVID-19 therapy. The procedure appears to have succeeded in avoiding false-positives—a common problem in virtual screening.

A key part of the study is the identification of drugs that target—or bind to—multiple proteins that are essential for replication of the virus, and which are also involved in the initial stage of host-cell infection. Corresponding authors Vaibhav Srivastava and Arul Murugan say multi-targeting offers an effective route to deal with drug resistance, which would enable a drug to work around mutations of the virus.

The researchers at KTH tested their own screening protocol which appears to have reduced false positive matches.

“The virus is mutating rapidly, which means that it is modifying its proteins,” Srivastava says. “If we have a drug that can target several proteins, and if one becomes mutated, the drug will be effective on others.”

This attribute allowed the team to propose cocktails that have versatility. “It was possible for us to propose cocktails, or blends of drugs, in which each drug can bind to a specific target protein with high affinity,” he says.

For example, the study proposed one cocktail, baloxavir marboxil, natamycin and RU85053, which targets the three viral proteins respectively, 3CL Main protease, papain-like protease and RdRp. Such drug cocktails have proven effective in the treatment of other virally-transmitted diseases, such as HIV.

Murugan says that the reliability of their approach was validated by the fact that the screening also identified drugs that are already in clinical trial. Furthermore, he says that such studies can provide valuable insights regarding why certain drugs were found to be ineffective. For example, they state that the drug hydroxychloroquine was non-effective mainly due to its poor binding affinity towards viral proteins.

Other drugs that the study recommended for testing were tivantinib, olaparib, zoliflodacin, golvatinib, sonidegib, regorafenib and PCO-371.

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Point of care imaging can help patients receive sight saving treatments faster

Simple, non-invasive imaging at the point of care can aid the diagnosis of corneal infections, reducing the risk of sight loss and helping patients’ vision return to pre-infection levels.

Bacterial keratitis is one of the most common corneal infections in the western world, often caused by contaminated contact lenses, and results in frequent visits to emergency departments in eye clinics worldwide. It can have a major impact on patients’ day-to-day lives, causing visual impairment and resulting in two million cases of blindness in one eye every year. It can be caused by gram-negative and gram-positive bacteria, each of which have different implications for treatment.

Corneal infections are typically identified through microbial cultures from corneal scrapings, which means sending samples to a laboratory and takes around forty eighty hours to get the results back. This can lead to delays in providing the correct diagnosis and treatment, which are essential for getting the best possible outcome for patients.

This new study, led by the University of Southampton, examined 45 patients with bacterial keratitis using Optical Coherence Tomography, a non-invasive imaging technique that clinicians can use to examine patients at the point of care. The researchers also examined features of cytokines, proteins emitted from cells, in the patients’ tears to determine whether this is also an effective technique for assessing the inflammatory response.

The results, published in the scientific journal Nature Scientific Reports, showed that both techniques could rapidly distinguish between gram-negative and gram-positive infections. As gram-negative infections present a higher risk to vision, this could help clinicians prescribe the right antibiotics straight away and reduce the impact of anti-microbial resistance if the wrong treatment is applied.

Dr. Parwez Hossain, associate professor of ophthalmology at the University of Southampton said, “The availability of OCT machines nowadays means they could be widely used in optometry practices. This would be especially useful inthe majority of clinical practices around the world where they do not have access to laboratorymicrobiology facilities.”

The study also showed that faster application of topical steroids such as prednisolone could reduce the inflammatory response.

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Major trial uses blood test to match women with breast cancer to precision treatments

A blood test that can identify a variety of mutations in advanced breast cancer can reliably match women to effective targeted treatments, early results of a major clinical trial reveal.

The plasmaMATCH trial provides the strongest evidence yet that simple blood tests known as ‘liquid biopsies’ can benefit women with breast cancer by tracking their disease as it evolves and directing them to the most effective treatments.

Researchers showed that the blood test is now reliable enough to be offered to patients on the NHS once it has passed approval, raising the prospect of a major reshaping of care that could speed up access to the best available drugs.

A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, analysed blood samples from more than 1,000 women with breast cancer that had recurred after treatment or spread to another part of the body. The aim was to see whether the blood test could help improve treatment for the significant proportion of women whose breast cancer is caused by one of a variety of rarer mutations—as opposed to better-known defects like BRCA mutations.

The plasmaMATCH trial was largely funded by Stand Up To Cancer, a joint fundraising campaign from Cancer Research UK and Channel 4, with additional support from AstraZeneca, Breast Cancer Now and Puma Biotechnology, and the new findings are published in The Lancet Oncology today (Thursday).

Researchers at The Institute of Cancer Research (ICR) and The Royal Marsden were able to reliably detect mutations found in tumour DNA that had been shed into the bloodstream of women with advanced breast cancer. They then went on to match patients to targeted treatments according to the specific mutations in the tumour DNA.

The researchers looked at three targetable defects in genes called HER2, AKT1 and ESR1, which are known to drive breast cancer. A total of 142 women with these detectable mutations were then given experimental drugs targeted against the specific characteristics of their cancer.

Women with ESR1 mutations were treated with fulvestrant, while women with HER2 mutations received neratinib on its own or with fulvestrant. Women with AKT1 mutations were split into two groups, according to whether their cancer was oestrogen receptor positive or not, and were treated with capivasertib plus fulvestrant, or with capivasertib on its own.

Researchers found that some women with HER2 and AKT1 mutations responded to the treatments assigned to them—suggesting that liquid biopsies can successfully match patients with certain rare forms of advanced breast cancer to more effective treatments.

Five out of 20 women with rare HER2 mutations who were matched to neratinib saw a beneficial response—meaning cancer growth was slowed or stopped, or tumours were shrunk.

Meanwhile, four out of 18 patients with AKT1 mutations responded to capivasertib. However, the treatment targeting the ESR1 mutation was not found to be effective.

Researchers also validated the findings by checking tissue samples from the patients to confirm that the liquid biopsies had correctly identified the presence or absence of the mutations in over 93% of cases—sufficiently accurate to implement in routine care.

The team believes that findings from the plasmaMATCH trial will help make a strong case for the adoption of liquid biopsies into clinical practice for patients with advanced cancer—a case strengthened by the fact that liquid biopsies are easier to take, faster to analyse and less painful for patients than standard tissue biopsies.

Liquid biopsies also offer a more dynamic alternative that could keep track of cancers as they evolve over time and their range of mutations changes.

For the targeted drugs that have shown initial promise in this study, the next step is to carry out larger clinical trials to assess whether they are better than existing treatments. The hope is that larger trials will lead to more targeted treatments being approved, providing new treatment options for patients with rare subtypes of breast cancer.

Study leader Professor Nick Turner, Professor of Molecular Oncology at The Institute of Cancer Research, London, and Head of the Ralph Lauren Centre for Breast Cancer Research at The Royal Marsden, said:

“Our findings show that simple blood tests can quickly and accurately tell us the genetic changes present in a patient’s cancer, and use that information to select the most suitable available treatment.

“Using a liquid biopsy could be particularly important for patients with advanced breast cancer, to help select the most appropriate treatment.

“Tests that detect tumour DNA in the blood have huge potential and could transform how doctors select targeted therapies for patients with advanced cancer. Our study shows that these liquid biopsies can pick up the mutations that drive a patient’s breast cancer, and can successfully match patients with the best available precision medicine for their cancer.”

Study co-leader Professor Judith Bliss, Professor of Clinical Trials at The Institute of Cancer Research, London, and Director of its Cancer Research UK-funded Clinical Trials and Statistics Unit, said:

“The plasmaMATCH trial platform has allowed us to look at the activity of various different treatments at the same time. This efficient trial set-up has been a success and it is already starting to bring patients closer to new targeted treatments.”

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

“It’s exciting to see the first results emerging from the pioneering plasmaMATCH trial. The findings demonstrate the powerful potential of liquid biopsies to pick up mutations that although individually rare can collectively play an important role in causing many breast cancers. Crucially, the study shows that matching women to the best available precision medicine for their tumour, using a blood test rather than an invasive tissue biopsy, can have real clinical benefits.

“These findings should lay the foundation for liquid biopsies to become a standard part of patient care for patients with breast cancer, and help accelerate women’s access to the best available precision medicines.”

Michelle Mitchell, Chief Executive of Cancer Research UK, said:

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