In their investigation of the most common type of kidney cancer, called clear cell renal cell carcinoma (ccRCC), Qing Zhang, Ph.D., and his colleagues identified a possible way to treat tumors while sparing nearby healthy tissue.

Their study uncovers a mechanism by which either the loss of a protein that protects against cancer or an oxygen-poor (hypoxic) environment can promote tumor growth via the cancer cell’s oxygen-sensing pathway, he explains. Their work points to inhibiting an enzyme called TBK1, which becomes more active once the protein is lost, as a potential cancer-fighting strategy.

Because kidney cancer is often resistant to the most advanced treatments, new therapies are critically needed, says Zhang, associate professor of pathology and a corresponding author of the study published online recently by Cancer Discovery.

The American Cancer Society estimates that in 2019, kidney cell and renal pelvic cancers affected about 74,000 people in the U.S., resulting in nearly 15,000 deaths. Recently, it has been shown that treatment with one member of a drug class called hypoxia-inducible factor 2 alpha (HIF2α) inhibitors can block tumor growth in some kidney cancers. However, only a subset of tumors respond to that therapy and a significant number of patients develop resistance to it. “We need to identify additional strategies that would work alone or in combination with the HIF2α inhibitors,” Zhang says.

Previous studies had found that 70 to 80 percent of kidney cancers show a loss of function of a critical tumor suppressor gene called von Hippel Lindau (VHL). “It had previously been shown that loss of the protein product of that gene mimics the hypoxic conditions under which many solid tumors seem to thrive,” Zhang says.

Based on that knowledge, the researchers aimed to identify enzymes with potential therapeutic action against kidney cancer with VHL protein loss.

“We identified one particular enzyme, called TBK1 (TANK-binding kinase 1), that is highly activated in kidney cancer patients with VHL loss,” says Zhang of the study that began while he was at the University of North Carolina at Chapel Hill and continued after his arrival at UT Southwestern last year.

TBK1 is an enzyme best known for its role in innate immunity, where it is important in the STING cellular sensing pathway that detects viral invaders. To study the enzyme’s activity in the context of cancer, the scientists conducted a series of experiments on several VHL protein-deficient ccRCC cell lines to see what would happen when TBK1 activity was reduced. Specifically, they used CRISPR gene-editing technology to remove the gene that makes TBK1, pharmacologically reduced the enzyme’s activity, and used small molecules to degrade TBK1 protein.

“We found that inhibiting TBK1 activity slowed or blocked cancer cell growth,” Zhang says.

In comparison experiments of cancerous and healthy cells that used small molecules to block TBK1 activity, the researchers found the strategy inhibited tumor growth in VHL-deficient ccRCC cells while leaving healthy cells with normal VHL protein levels unaffected. “That indicates this strategy holds the potential for selective lethality, killing the cancer cells without harming the healthy ones,” says Zhang, a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar.

Because hypoxia is thought to occur in most tumors, the study may have broader implications. The researchers found that hypoxia can increase TBK1 activity through the same mechanism as VHL loss, i.e., through the cell’s oxygen-sensing pathway, he says. “We believe targeting and manipulating TBK1 activity — possibly with drugs already under investigation for other cancers — may benefit patients with other forms of cancer,” he says.

TBK1 is central to cell signaling in the innate immune system’s antiviral response, so the researchers wanted to learn whether the protein’s immune system activity was connected to the effects they observed in kidney cancer. To do that, they studied TBK1-depleted cancer cells to see if the proteins created by genes governing the cell’s innate immune response pathway were affected. They were not. That finding indicated that TBK1’s novel role in cancer is distinct from the enzyme’s function in the immune system.

Next steps include trying to optimize the efficiency of the small molecules used in this study and testing them in ccRCC tumor cells grown in mice, Zhang says. Additionally, recent studies from other laboratories indicated depletion of TBK1 can boost the effectiveness of a class of anti-cancer drugs called immune checkpoint inhibitors. So that is another area of interest for future studies, he adds.

“We propose that TBK1 is a promising potential therapeutic target for kidney cancer,” Zhang says.

Purdue University researchers are aiming to stump counterfeiters with an edible “security tag” embedded into medicine. To imitate the drug, a counterfeiter would have to uncrack a complicated puzzle of patterns not fully visible to the naked eye.

Fake medicine is a thriving business, making up at least 10% of global pharmaceutical commerce while also claiming thousands of lives each year.

In the U.S., counterfeit drugs range from cancer and diabetes treatment to erectile dysfunction medication. Counterfeit opioids have caused deaths in 46 states.

Tagging drugs would not only guard against fakery, but also help pharmacies better verify the legitimacy of a drug before selling to consumers.

“Every single tag is unique, offering a much higher level of security,” said Young Kim, an associate professor in Purdue’s Weldon School of Biomedical Engineering.

The tag acts as a digital fingerprint for each drug capsule or tablet, using an authentication technique called “physical unclonable functions,” or PUF, that was originally developed for information and hardware security.

PUFs have the ability to generate a different response each time that they are stimulated, rendering them unpredictable and extremely difficult to duplicate. Even the manufacturer wouldn’t be able to re-create an identical PUF tag.

Kim’s group is the first to create an edible PUF — a thin, transparent film made of silk proteins and fluorescent proteins genetically fused together. Because the tag is easily digestible and made entirely of proteins, it can be consumed as part of a pill or tablet.

Shining various LED light sources on the tag excites the fluorescent silk microparticles, causing them to generate a different random pattern each time. The microparticles emit cyan, green, yellow or red fluorescent colors.

Digital bits can then be extracted from an image of those patterns to produce a security key, which a pharmacy or patient would use to confirm that a drug is authentic.

The researchers are currently converting this process to a smartphone app for both pharmacies and consumers.

“Our concept is to use a smartphone to shine an LED light on the tag and take a picture of it. The app then identifies if the medicine is genuine or fake,” said Jung Woo Leem, a postdoctoral associate in biomedical engineering at Purdue.

The tag also has the potential to hold much more information than simply a confirmation of what the drug is, Leem said, such as the dose and expiration date.

Leem found that the tag works for at least a two-month period without the proteins degrading. Next, the team will need to confirm that the tag could last as long as a drug does and that it doesn’t affect a medicine’s key ingredients or potency.

The work is published in the journal Nature Communications. A YouTube video is available at https://youtu.be/0bN1qODhRPU.

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

Air pollution has negative effects on physical health, and recent work has begun to also show negative effects on mental health. Life stress, particularly early in life, is one of the best-known contributors to mental health problems. The new study is one of the first to examine the combined effects of air pollution and early life stress on school-age children. Results appear in the Journal of Child Psychology and Psychiatry.

“Prenatal exposure to polycyclic aromatic hydrocarbons, a neurotoxicant common in air pollution, seems to magnify or sustain the effects of early life social and economic stress on mental health in children,” says first author David Pagliaccio, PhD, assistant professor of clinical neurobiology in psychiatry at Columbia Psychiatry.

“Air pollutants are common in our environment, particularly in cities, and given socioeconomic inequities and environmental injustice, children growing up in disadvantaged circumstances are more likely to experience both life stress and exposure to neurotoxic chemicals,” says senior author Amy Margolis, PhD, assistant professor of medical psychology in psychiatry at Columbia Psychiatry.

“These exposures have a combined effect on poor mental health outcomes and point to the importance of public health programs that try to lessen exposure to these critical risk factors, to improve not only physical, but psychological health,” says Julie Herbstman, PhD, associate professor of environmental health science and director of the Columbia Center for Children’s Environmental Health at Columbia Mailman School of Public Health.

Data were from the CCCEH Mothers and Newborns longitudinal birth cohort study in Northern Manhattan and the Bronx, which includes many participants who self-identify as African American or Dominican. Mothers wore an air monitoring backpack during the third trimester of pregnancy to measure exposure to air pollutants in their daily lives. When their children were 5 years old, mothers reported on stress in their lives, including neighborhood quality, material hardship, intimate partner violence, perceived stress, lack of social support, and general distress levels. Mothers then reported on their child’s psychiatric symptoms at ages 5, 7, 9 and 11.

The combined effect of air pollution and early life stress was seen across several measures of thought and attention problems/ADHD at age 11. (Thought problems included obsessive thoughts and behaviors or thoughts that others find strange.) The effects were also linked to PAH-DNA adducts — a dose-sensitive marker of air pollution exposure.

The researchers say PAH and early life stress may serve as a “double hit” on shared biological pathways connected to attention and thought problems. Stress likely leads to wide-ranging changes in, for example, epigenetic expression, cortisol, inflammation, and brain structure and function. The mechanism underlying the effects of PAH is still being interrogated; however, alterations in brain structure and function represent possible shared mechanistic pathways.

Earlier studies making use of the same longitudinal cohort data found that prenatal exposure to air pollution combines with material hardship to significantly increase ADHD symptoms in children. A separate study found a combination of air pollution and poverty lowered child IQ.