News
Research!America’s National Health Research Forum
Posted on by Lawrence Tabak, D.D.S., Ph.D.

Rice-Sized Device Tests Brain Tumor’s Drug Responses During Surgery
Posted on by Lawrence Tabak, D.D.S., Ph.D.

Scientists have made remarkable progress in understanding the underlying changes that make cancer grow and have applied this knowledge to develop and guide targeted treatment approaches to vastly improve outcomes for people with many cancer types. And yet treatment progress for people with brain tumors known as gliomas—including the most aggressive glioblastomas—has remained slow. One reason is that doctors lack tests that reliably predict which among many therapeutic options will work best for a given tumor.
Now an NIH-funded team has developed a miniature device with the potential to change this for the approximately 25,000 people diagnosed with brain cancers in the U.S. each year [1]. When implanted into cancerous brain tissue during surgery, the rice-sized drug-releasing device can simultaneously conduct experiments to measure a tumor’s response to more than a dozen drugs or drug combinations. What’s more, a small clinical trial reported in Science Translational Medicine offers the first evidence in people with gliomas that these devices can safely offer unprecedented insight into tumor-specific drug responses [2].
These latest findings come from a Brigham and Women’s Hospital, Boston, team led by Pierpaolo Peruzzi and Oliver Jonas. They recognized that drug-screening studies conducted in cells or tissue samples in the lab too often failed to match what happens in people with gliomas undergoing cancer treatment. Wide variation within individual brain tumors also makes it hard to predict a tumor’s likely response to various treatment options.
It led them to an intriguing idea: Why not test various therapeutic options in each patient’s tumor? To do it, they developed a device, about six millimeters long, that can be inserted into a brain tumor during surgery to deliver tiny doses of up to 20 drugs. Doctors can then remove and examine the drug-exposed cancerous tissue in the laboratory to determine each treatment’s effects. The data can then be used to guide subsequent treatment decisions, according to the researchers.
In the current study, the researchers tested their device on six study volunteers undergoing brain surgery to remove a glioma tumor. For each volunteer, the device was implanted into the tumor and remained in place for about two to three hours while surgeons worked to remove most of the tumor. Next, the device was taken out along with the last piece of a tumor at the end of the surgery for further study of drug responses.
Importantly, none of the study participants experienced any adverse effects from the device. Using the devices, the researchers collected valuable data, including how a tumor’s response changed with varying drug concentrations or how each treatment led to molecular changes in the cancerous cells.
More research is needed to better understand how use of such a device might change treatment and patient outcomes in the longer term. The researchers note that it would take more than a couple of hours to determine how treatments produce less immediate changes, such as immune responses. As such, they’re now conducting a follow-up trial to test a possible two-stage procedure, in which their device is inserted first using minimally invasive surgery 72 hours prior to a planned surgery, allowing longer exposure of tumor tissue to drugs prior to a tumor’s surgical removal.
Many questions remain as they continue to optimize this approach. However, it’s clear that such a device gives new meaning to personalized cancer treatment, with great potential to improve outcomes for people living with hard-to-treat gliomas.
References:
[1] National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Brain and Other Nervous System Cancer.
[2] Peruzzi P et al. Intratumoral drug-releasing microdevices allow in situ high-throughput pharmaco phenotyping in patients with gliomas. Science Translational Medicine DOI: 10.1126/scitranslmed.adi0069 (2023).
Links:
Brain Tumors – Patient Version (National Cancer Institute/NIH)
Pierpaolo Peruzzi (Brigham and Women’s Hospital, Boston, MA)
Jonas Lab (Brigham and Women’s Hospital, Boston, MA)
NIH Support: National Cancer Institute, National Institute of Biomedical Imaging and Bioengineering, National Institute of Neurological Disorders and Stroke
New Approach to ‘Liquid Biopsy’ Relies on Repetitive RNA in the Bloodstream
Posted on by Lawrence Tabak, D.D.S., Ph.D.

It’s always best to diagnose cancer at an early stage when treatment is most likely to succeed. Unfortunately, far too many cancers are still detected only after cancer cells have escaped from a primary tumor and spread to distant parts of the body. This explains why there’s been so much effort in recent years to develop liquid biopsies, which are tests that can pick up on circulating cancer cells or molecular signs of cancer in blood or other bodily fluids and reliably trace them back to the organ in which a potentially life-threatening tumor is growing.
Earlier methods to develop liquid biopsies for detecting cancers often have relied on the presence of cancer-related proteins and/or DNA in the bloodstream. Now, an NIH-supported research team has encouraging evidence to suggest that this general approach to detecting cancers—including aggressive pancreatic cancers—may work even better by taking advantage of signals from a lesser-known form of genetic material called noncoding RNA.
The findings reported in Nature Biomedical Engineering suggest that the new liquid biopsy approach may aid in the diagnosis of many forms of cancer [1]. The studies show that the sensitivity of the tests varies—a highly sensitive test is one that rarely misses cases of disease. However, they already have evidence that millions of circulating RNA molecules may hold promise for detecting cancers of the liver, esophagus, colon, stomach, and lung.
How does it work? The human genome contains about 3 billion paired DNA letters. Most of those letters are transcribed, or copied, into single-stranded RNA molecules. While RNA is best known for encoding proteins that do the work of the cell, most RNA never gets translated into proteins at all. This noncoding RNA includes repetitive RNA that can be transcribed from millions of repeat elements—patterns of the same few DNA letters occurring multiple times in the genome.
Common approaches to studying RNA don’t analyze repetitive RNA, so its usefulness as a diagnostic tool has been unclear—until recently. Last year, the lab of Daniel Kim at the University of California, Santa Cruz reported [2] that a key genetic mutation that occurs early on in some cancers causes repetitive RNA molecules to be secreted in large quantities from cancer cells, even at the earliest stages of cancer. Non-cancerous cells, by comparison, release much less repetitive RNA.
The findings suggested that liquid biopsy tests that look for this repetitive, noncoding RNA might offer a powerful new way to detect cancers sooner, according to the authors. But first they needed a method capable of measuring it. Due to its oftentimes uncertain functions, the researchers have referred to repetitive, noncoding RNA as “dark matter.”
Using a liquid biopsy platform they developed called COMPLETE-seq, Kim’s team trained computers to detect cancers by looking for patterns in RNA data. The platform enables sequencing and analysis of all protein coding and noncoding RNAs—including any RNA from more than 5 million repeat elements—present in a blood sample. They found that their classifiers worked better when repetitive RNAs were included. The findings lend support to the idea that repetitive, noncoding RNA in the bloodstream is a rich source of information for detecting cancers, which has previously been overlooked.
In a study comparing blood samples from healthy people to those with pancreatic cancer, the COMPLETE-seq technology showed that nearly all people in the study with pancreatic cancer had more repetitive, noncoding RNA in their blood samples compared to healthy people, according to the researchers. They used the COMPLETE-seq test on blood samples from people with other types of cancer as well. For example, their test accurately detected 91% of colorectal cancer samples and 93% of lung cancer samples.
They now plan to look at many more cancer types with samples from additional patients representing a broad range of cancer stages. The goal is to develop a single RNA liquid biopsy test that could detect multiple forms of cancer with a high degree of accuracy and specificity. They note that such a test might also be used to guide treatment decisions and more readily detect a cancer’s recurrence. The hope is that one day a comprehensive liquid biopsy test including coding and noncoding RNA will catch many more cancers sooner, when treatment can be most successful.
References:
[1] RE Reggiardo et al. Profiling of repetitive RNA sequences in the blood plasma of patients with cancer. Nature Biomedical Engineering DOI: 10.1038/s41551-023-01081-7 (2023).
[2] RE Reggiardo et al. Mutant KRAS regulates transposable element RNA and innate immunity via KRAB zinc-finger genes. Cell Reports DOI: 10.1016/j.celrep.2022.111104 (2022).
Links:
Daniel Kim Lab (UC Santa Cruz)
Cancer Screening Overview (National Cancer Institute/NIH)
Early Detection (National Cancer Institute/NIH)
NIH Support: National Cancer Institute, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Cryo-EM Scores Again
Posted on by Lawrence Tabak, D.D.S., Ph.D.

Human neurons are long, spindly structures, but if you could zoom in on their surfaces at super-high resolution, you’d see surprisingly large pores. They act as gated channels that open and close for ions and other essential molecules of life to pass in and out the cell. This rapid exchange of ions and other molecules is how neurons communicate, and why we humans can sense, think, move, and respond to the world around us [1].
Because these gated channels are so essential to neurons, mapping their precise physical structures at high-resolution has profound implications for informing future studies on the brain and nervous system. Good for us in these high-tech times that structural biologists keep getting better at imaging these 3D pores.
In fact, as just published in the journal Nature Communications [2], a team of NIH-supported scientists imaged the molecular structure of a gated pore of major research interest. The pore is called calcium homeostasis modulator 1 (CALHM1). Pictured below, you can view its 3D structure at near atomic resolution [2]. Keep in mind, this relatively large neuronal pore still measures approximately 50,000 times smaller than the width of a hair.

The structure comes from a research team led by Hiro Furukawa, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. He and his team relied on cryo-electron microscopy (cryo-EM) to produce the first highly precise 3D models of CALHM1.
Cryo-EM involves flash-freezing molecules in liquid ethane and bombarding them with electrons to capture their images with a special camera. When all goes well, cryo-EM can reveal the structure of intricate macromolecular complexes in a matter of weeks.
Furukawa’s team had earlier studied CALHM1 from chickens with cryo-EM [3], and their latest work reveals that the human version is quite similar. Eight copies of the CALHM1 protein assemble to form the circular channel. Each of the protein subunits has a flexible arm that allows it to reach into the central opening, which the researchers now suspect allows the channels to open and close in a highly controlled manner. The researchers have likened the channels’ eight flexible arms to the arms of an octopus.
The researchers also found that fatty molecules called phospholipids play a critical role in stabilizing and regulating the eight-part channel. They used simulations to demonstrate how pockets in the CALHM1 channel binds this phospholipid over cholesterol to shore up the structure and function properly. Interestingly, these phospholipid molecules are abundant in many healthy foods, such as eggs, lean meats, and seafood.
Researchers knew that an inorganic chemical called ruthenium red can block the function of the CALHM1 channel. They’ve now shown precisely how this works. The structural details indicate that ruthenium red physically lodges in and plugs up the channel.
These details also may be useful in future efforts to develop drugs designed to target and modify the function of these channels in helpful ways. For instance, on our tongues, the channel plays a role in our ability to perceive sweet, sour, or umami (savory) flavors. In our brains, studies show the abnormal function of CALHM1 may be implicated in the plaques that accumulate in the brains of people with Alzheimer’s disease.
There are far too many other normal and abnormal functions to mention here in this brief post. Suffice it to say, I’ll look forward to seeing what this enabling research yields in the years ahead.
References:
[1] On the molecular nature of large-pore channels. Syrjanen, J., Michalski, K., Kawate, T., and Furukawa, H. J Mol Biol. 2021 Aug 20;433(17):166994. DOI: 10.1016/j.jmb.2021.166994. Epub 2021 Apr 16. PMID: 33865869; PMCID: PMC8409005.
[2] Structure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red. Syrjänen JL, Epstein M, Gómez R, Furukawa H. Nat Commun. 2023 Jun 28;14(1):3821. DOI: 10.1038/s41467-023-39388-3. PMID: 37380652; PMCID: PMC10307800.
[3] Structure and assembly of calcium homeostasis modulator proteins. Syrjanen JL, Michalski K, Chou TH, Grant T, Rao S, Simorowski N, Tucker SJ, Grigorieff N, Furukawa H. Nat Struct Mol Biol. 2020 Feb;27(2):150-159. DOI: 10.1038/s41594-019-0369-9. Epub 2020 Jan 27. PMID: 31988524; PMCID: PMC7015811.
Links:
Brain Basics: The Life and Death of a Neuron (National Institute of Neurological Disorders and Stroke/NIH)
Alzheimer’s Disease (National Institute on Aging/NIH)
Furukawa Lab (Cold Spring Harbor Lab, Cold Spring Harbor, NY)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of Mental Health
Next Page