One of the drugs, cyclophosphamide, is an outdated chemotherapy drug once used to treat small cell lung cancer. It was displaced in favor of platinum-based drugs in the 1980s. Both kinds of drugs work at first but falter after a few months as the cancer develops resistance. Platinum-based drugs became the standard of care mainly because they cause lesser side effects, but they have not substantially improved prognosis. Today, the typical patient survives less than a year and a half after diagnosis.

In this study, however, researchers showed that small cell lung cancer cells resist cyclophosphamide by activating a specific repair process, and demonstrated that throwing a wrench into the repair process makes the drug much more effective, at least in mice. The findings, available online in Cancer Discovery, suggest a pathway to better therapies for one of the least treatable forms of cancer.

“Small cell lung cancer has one treatment option — platinum-based chemotherapy — and that adds maybe two to six months of life,” said co-senior author Nima Mosammaparast, MD, PhD, an associate professor of pathology & immunology and of medicine at Washington University, and a researcher at Siteman Cancer Centerat Barnes-Jewish Hospital and Washington University School of Medicine. “The problem is that these tumors respond to treatment initially, but then they come back. This has not changed for 30 years. These tumors are just massively resistant to just about everything. So what this study shows is that we can actually combine a new target with an old drug to reduce resistance and potentially make the treatment much better and give these patients a much better chance.”

The study came together fortuitously. Co-senior author Nicolas Reynoird, PhD, a professor at Grenoble Alpes University, studies how internal signaling within cells — and deregulation of such signaling — can lead to cancer progression and drug resistance. A few years ago, his team discovered that a protein called RNF113A may play a role in small cell lung cancer, but the researchers could not determine what the protein does. Meanwhile, Mosammaparast was studying how cells repair injured DNA. In 2017, he published a paper in the journal Nature describing how cancer cells repair a kind of DNA damage known as alkylation damage, the kind caused by cyclophosphamide. The paper noted that RNF113A plays a role in the process. Reynoird essentially cold-called Mosammaparast, and the two teamed up — along with co-senior author Pawel K. Mazur, PhD, an associate professor of experimental radiation oncology at MD Anderson and a longstanding collaborator of Reynoird’s — to investigate how small cell lung cancer cells resist alkylation damage, and whether it’s possible to magnify the effects of alkylating chemotherapy drugs such as cyclophosphamide by interfering with that resistance.

The team discovered that RNF113A is regulated by a protein called SMYD3 that is highly expressed in small cell lung cancer and some other cancers. High levels of SMYD3 are associated with more invasive disease, increased resistance to alkylating chemotherapy and worse prognosis. Healthy lung tissue has very little SMYD3, which led the researchers to think that knocking it down might target cancerous cells while sparing healthy ones.

So they tried it. The researchers created mouse models of human disease by grafting cancerous cells from two people with small cell lung cancer onto separate groups of mice. One set of cells came from a patient who had not yet been treated, so the cells had not had a chance to develop resistance. The other came from a patient who had been treated with and become resistant to standard platinum-based therapy.

All of the mice grew tumors. When the tumors were big enough, the researchers treated the mice with an inhibitor of SMYD3, cyclophosphamide, both or an inactive solution. Inhibiting SMYD3 alone modestly slowed down the growth of the tumors. Cyclophosphamide initially halted the growth of tumors from both patients, but the tumors started to grow again after about two weeks, indicating that they had developed resistance. However, the combination of the two drugs stopped the tumors in their tracks. They did not restart growing for the duration of the experiment.

“We’re talking to a number of other groups about starting a phase 1 clinical trial as soon as possible,” Mosammaparast said. “One of the challenges we will face is convincing doctors to go back to an old drug. But the nice thing about this strategy is that it may work where current therapies have failed. This treatment worked just as well against the tumor from the patient who had already relapsed on platinum-based therapy as it did against the untreated patient. People with small cell lung cancer are in desperate need of better treatments, and I’m very excited about the possibilities here.”

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Materials provided by Washington University School of Medicine. Original written by Tamara Bhandari. Note: Content may be edited for style and length.

Antimicrobial resistance has become one of the greatest threats to public health globally. It occurs when bacteria, viruses, fungi and parasites change over time and no longer respond to medicines, making it difficult to treat infections. Because of this, there is a pressing need for the development of new antimicrobial drugs to combat infections.

A new study by scientists from the University of Portsmouth and Naresuan and Pibulsongkram Rajabhat Universities in Thailand explored whether hydroquinine, which is found in the bark of some trees, could inhibit any bacterial strains. Hydroquinine is already known to be an effective agent against malaria in humans, but until now there has been little investigation into its drug-resistant properties.

The findings, published in the Tropical Medicine and Infectious Disease journal, suggest the antimicrobial properties of the organic compound make it a potential candidate for future clinical investigation.

Dr Robert Baldock from the School of Pharmacy and Biomedical Sciences at the University of Portsmouth, said: “Using bacterial killing experiments, we found that hydroquinine was able to kill several microorganisms including the common multidrug-resistant pathogen pseudomonas aeruginosa.

“Characteristically, we also discovered that one of the main mechanisms used by these bacteria to escape killing activity of the drug was upregulated with treatment — indicating a robust response from the bacteria.

“By studying this compound further, our hope is that it may in future offer another line of treatment in combatting bacterial infections.”

Drug-resistant bacteria occur in more than 2.8 million infections and are responsible for 35,000 deaths per year. Common antibiotic-resistant “superbugs” cause diseases including sepsis, urinary tract infections, and pneumonia. Statistics show bloodstream infections with the bacteria — P. aeruginosa are associated with high mortality rates of between 30 and 50%.

The study recommends further investigation into the antimicrobial resistance properties and side effects of hydroquinine.

Dr Jirapas Jongjitwimol from the Department of Medical Technology at Naresuan University added: “Our future research aims to uncover the molecular target of hydroquinine. This would help our understanding of how the compound works against pathogenic bacteria and how it could potentially be used in a clinical setting.”

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Materials provided by University of Portsmouth. Note: Content may be edited for style and length.

The findings could have important implications in applied settings such as medical displays, cognitive assistants, and product and environmental design, according to the researchers.

“Since the way we perceive objects determines how we interact with them, it is important to visually process them quickly and with high detail” Sarah Shomstein, a professor of cognitive neuroscience at GW said. “However, the way our eyes perceive and process an object can be different depending on what we know about this object. Our study shows, for the first time, that if we recognize an object as a tool, we perceive it faster but with less detail. If we recognize an object as a non-tool, we perceive it slower but with higher detail.”

To determine how the human brain processes an object visually, Shomstein and Dick Dubbelde, a recent PhD graduate at GW and co-author on the study, showed participants several images of objects that can be easily manipulated by hand such as a coffee mug, snow shovel or screwdriver, and several images of objects that are infrequently manipulated by hand, such as a potted plant, a picture frame or a fire hydrant. For half of the experiment, a small gap could be cut out of the bottom of each object. For the other half of the experiment, the objects could flicker on the screen. The team asked participants to report the presence or absence of a gap or the flicker, which helped the researchers figure out the speed and detail of object processing, and also which regions of the brain were being used to process the object.

Researchers found that objects usually manipulated by your hands are perceived faster than non-manipulable objects, making it easier to see the flickering. Alternatively, objects that we usually do not manipulate are perceived with greater detail than manipulable objects, making it easier to see the small gaps.

“The differences in perception between ‘mugs’ and ‘plants’ in both speed and detail of perception means that these objects are sorted by the visual system for processing in different brain regions,” Dubbelde said. “In other words, your knowledge of the object’s purpose actually determines where in the brain object processing will occur and how well you will perceive it.”

The study also showed that if you interfere with object recognition by making it harder to recognize an object as either manipulable or not manipulable — for example, by turning it upside down — then the differences in the speed and detail perception of the objects disappear.

Shomstein and Dubbelde note that this study could possibly explain individual differences in object perception and underscores that what you know and what your personal experience is with any particular object has direct consequences for perception.

The National Science Foundation (BCS-1921415 and BCS-2022572) supported this work.

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Materials provided by George Washington University. Note: Content may be edited for style and length.