Experimental drug turns cancer's favorite fuel against it - Chemistry & Biochemistry

PFKL is an enzyme in cancer cells that metabolizes sugar. This image shows the protein structure of PFKL bound to two parts of the experimental cancer drug XJ-4-85 (blue and orange). When XJ-4-85 binds the sites K677 and K315 on PFKL (inset), it boosts sugar metabolism and releases a payload (not shown) that shuts down fatty acid metabolism. Credit: Eric Lynch (University of Washington) and Xiaoding Jiang (University of Texas at Austin).

Cancer cells have a voracious appetite for sugar—using it to fuel their rapid growth. This is why many scientists have tried to develop drugs that block cancer cells' metabolism by cutting off their sugar supply.

Now a team led by researchers at The University of Texas at Austin report in Nature Chemical Biology that they have found a completely different approach. Instead of starving cancer cells, they trick them into consuming even more sugar than usual. At the same time, the drug blocks their backup fuel source—fat.

By attacking both fuel sources at once, the experimental drug puts cancer cells under so much stress that many of them die. They demonstrated the drug's effectiveness in treating an aggressive form of melanoma in mice.

"I like to think of this technology like a two-headed dragon," said Xiaolu (Lulu) Lim Ang Cambronne, an associate professor of molecular biosciences at UT and co-corresponding author. "We are putting one part of the cell into overdrive while simultaneously weakening another part. It appears to be extremely potent."

A chemical alternative to ADCs

In lab experiments, the drug was effective against several types of human cancer cells, including melanoma, leukemia, breast cancer, lung cancer, liver cancer and neuroblastoma. In mice with melanoma, most cancer cells died, while noncancerous cells were much less affected.

Drugs that attack cancer with this kind of one-two punch are not entirely new. A growing class of compounds called antibody-drug conjugates (ADCs) use an antibody to target cancer cells, then deliver a payload of chemotherapy directly to the tumor. But ADCs have many limitations.

"Antibodies are difficult to make, and because they're so large, they're only able to target proteins on the surface of cancer cells," said Ken Hsu, an associate professor of chemistry at UT and co-corresponding author. "We think of this new compound as a fully chemical counterpart to ADCs. They are much easier to manufacture. And because they are smaller, they are able to target even proteins that are inside cells."

How the two-part drug works

The drug has two parts. The targeting agent, a molecule called XJ-4-85, acts on an enzyme called PFKL, speeding up glycolysis (the breakdown of sugar) inside cancer cells. After XJ-4-85 binds, it releases its payload, a compound that acts on another enzyme called CPT2. CPT2 normally helps cells break down fatty acids for energy. By disrupting both of the cells' major energy sources at the same time, it shuts down cancer growth.

"The way this drug works was totally unexpected," said Xiaoding Jiang, a postdoctoral fellow in the Hsu Lab, who designed the molecule. "A lot of research was required to figure out what it was doing on the molecular level. We were also surprised to see how selectively it binds to cancer cells."

Early promise, broader potential

The research is still in its early stages. Although the results are promising, much more laboratory testing is needed before the drug can be studied in people.

Beyond this particular drug, the researchers say the research also illustrates a broader approach for designing these two-part medicines, which they call "electrophile-drug conjugates" or EDCs. "They have the potential to be useful beyond cancer, for other kinds of diseases as well," Cambronne said.

The team members emphasize the importance of collaboration in making this discovery possible, bringing together experts from across UT—and beyond. "This project took a village," Hsu said. 

Provided by University of Texas at Austin 

by University of Texas at Austin

edited by Sadie Harley, reviewed by Robert Egan 

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ADHD, Explained: Symptoms, Treatment, and What Living With It Actually Looks Like

ADHD is one of the most commonly diagnosed conditions in childhood, yet still one of the most misread once someone reaches adulthood. It’s often reduced to a stereotype, the kid who can’t sit still in class. That image misses most of what the condition actually looks like for the estimated 8.4% of children and 4.4% of adults in the U.S. who meet diagnostic criteria, a great many of whom are never formally diagnosed, especially women and adults whose symptoms show up as chronic disorganization rather than visible hyperactivity. This post lays out what ADHD actually is, what it isn’t, what treatment realistically involves, and where the evidence is still thin.

What ADHD actually is

Attention-deficit/hyperactivity disorder is a neurodevelopmental condition marked by persistent patterns of inattention and/or hyperactivity-impulsivity that interfere with functioning or development. It isn’t a mood that comes and goes with a bad night’s sleep, the symptoms need to be present before age 12, show up across multiple settings (school or work, home, relationships), and cause real, measurable impairment.

The DSM-5 recognizes three presentations:

·         Predominantly inattentive presentation — difficulty sustaining attention, following through on tasks, organizing, and frequent forgetfulness, without significant hyperactivity.

·         Predominantly hyperactive-impulsive presentation — fidgeting, restlessness, excessive talking, and impulsive decisions, without pronounced inattention.

·         Combined presentation — meeting criteria for both, which is the most commonly diagnosed type.

Diagnosis requires at least six symptoms of inattention and/or hyperactivity-impulsivity for children under 17, or five for adolescents 17 and older and adults, evaluated by a clinician using structured interviews and rating scales. There’s no blood test or brain scan that confirms it. The lower symptom threshold for adults reflects something longitudinal research keeps finding: the raw frequency of symptoms tends to soften with age, but the functional impairment they cause often doesn’t shrink at the same rate.

What the symptoms actually look like

Inattentive symptoms can include: difficulty sustaining focus on tasks, careless mistakes, trouble following through on instructions, losing things regularly, being easily distracted, forgetfulness in daily activities, and difficulty organizing tasks. In adults, this frequently shows up as chronic procrastination, missed deadlines, losing keys or phones, and zoning out mid-conversation.

Hyperactive-impulsive symptoms can include: fidgeting, difficulty staying seated, feeling internally restless, excessive talking, blurting out answers, interrupting others, and difficulty waiting one’s turn. In adults, hyperactivity often turns inward, less running-around-the-room, more a constant internal sense of restlessness or being “on the go.”

ADHD frequently co-occurs with other conditions, anxiety, depression, and learning disabilities are among the most common, which can complicate both diagnosis and treatment. Women and girls, in particular, tend to be diagnosed significantly later than men, partly because inattentive presentations are easier to overlook than the more visibly disruptive hyperactive-impulsive ones.

What causes it (and what doesn’t)

There’s no single known cause, but ADHD is one of the more strongly heritable psychiatric conditions studied:

·         Genetics — twin and family studies put heritability estimates around 70-80%, among the highest of any psychiatric condition, though (as with bipolar disorder) no single “ADHD gene” exists; it involves many genes of small effect.

·         Brain chemistry and structure — differences in dopamine and norepinephrine signaling, particularly in circuits involved in attention and executive function, are consistently implicated. Imaging studies have found modest differences in the development of certain brain regions, though these findings describe group averages, not individual diagnostic markers.

·         Prenatal and early-life factors — premature birth, low birth weight, and prenatal exposure to alcohol or tobacco are associated with higher risk.

·         Environmental exposures — early childhood lead exposure has a documented association with ADHD symptoms.

What it is not: a result of poor parenting, too much screen time, or sugar. It’s also not simply a lack of willpower or discipline, and it’s not the same as being an easily distracted person on a bad week.

Treatment: what’s actually involved

Unlike some conditions, ADHD has one of the largest evidence bases in psychiatry for medication effectiveness. Most treatment plans draw from a few categories:

Medication. Stimulants are the first-line, best-studied treatment:

·         Stimulants — methylphenidate-based (Ritalin, Concerta) and amphetamine-based (Adderall, Vyvanse) medications increase dopamine and norepinephrine availability. They’re effective for the large majority of people who try them, though finding the right medication and dose is often trial and error.

·         Non-stimulants — atomoxetine, viloxazine, and guanfacine or clonidine are used when stimulants aren’t well tolerated, are contraindicated, or when there’s significant co-occurring anxiety.

A meaningful caution: stimulant medications carry risk of misuse and are controlled substances, which is part of why ongoing prescriber oversight matters, particularly for young adults.

Behavioral therapy and psychotherapy. For young children, behavioral parent training is often recommended as a first step, sometimes before medication. For older kids and adults, cognitive behavioral therapy adapted for ADHD focuses on building organizational systems, time-management strategies, and addressing the negative self-talk that often accumulates after years of being told to “try harder.”

Self-management and accommodations. External structure — reminders, timers, body-doubling, breaking tasks into smaller pieces — along with workplace or school accommodations (extended time, reduced distraction environments) are realistic, evidence-supported complements to clinical treatment, not substitutes for it.

Research consistently shows that combining medication with behavioral strategies produces better outcomes than either approach alone, particularly for managing the functional impairment (missed deadlines, strained relationships) rather than just the checklist symptoms.

What doesn’t work, or isn’t well supported

To be equally direct about the limits:

·         Elimination diets and sugar restriction don’t have strong evidence as standalone treatments for the general ADHD population, despite popular claims; a small subset of children may be sensitive to specific additives, but this isn’t broadly generalizable.

·         “Just focus harder” or willpower-based approaches misunderstand ADHD as a motivation problem rather than a difference in executive-function circuitry.

·         Brain-training apps and games marketed as ADHD treatments generally lack robust evidence of transferring to real-world functioning.

·         Self-diagnosis from social media checklists is increasingly common but risks both over- and under-identifying real ADHD, since many symptoms overlap with anxiety, sleep deprivation, and other conditions that need different treatment.

Living with it

Outcomes vary widely depending on when ADHD is identified and how consistent treatment and accommodations are. Longitudinal research suggests that while symptom frequency often decreases into adulthood, a substantial share of people diagnosed in childhood continue to experience real functional impairment well into their mid-20s and beyond. Many people with ADHD build successful careers and relationships once they find a workable combination of treatment, structure, and self-understanding, the disorder doesn’t have to mean a lifetime of the same struggles that showed up at age eight, even though getting there can take real trial and error.

If any of this resonates with your own experience, the next step is an evaluation with a doctor or mental health professional, not a self-diagnosis from a blog post or a social media quiz.

Sources

·         National Institute of Mental Health — ADHD

·         CDC — ADHD: About

·         PMC — ADHD in DSM-5: a field trial in young adults

·         Cleveland Clinic — ADHD

Source: ADHD, Explained: Symptoms, Treatment, and What Living With It Actually Looks Like