If further research confirms these findings, clinical laboratory identification of cancer cells could lead to new treatments for certain childhood cancers
Can cancer cells be changed into normal healthy cells? According to molecular biologists at the Cold Spring Harbor Laboratory (CSHL) in Long Island the answer is, apparently, yes. At least for certain types of cancer. And clinical laboratories and anatomic pathologists may play a key role in identifying these specific cancer cells and then guiding physicians in selecting the most appropriate therapies.
The cancer cells in question are called rhabdomyosarcoma (RMS) and are “particularly aggressive,” according to ScienceAlert. Generally, and most sadly, the cancer primarily affects children below the age of 18. It begins in skeletal muscle, mutates throughout the body, and is often deadly.
“Treatment usually involves chemotherapy, surgery, and radiation procedures. Now, new research by scientists at Cold Spring Harbor Laboratory demonstrates differentiation therapy as a new treatment option for RMS,” Genetic Engineering and Biotechnology News (GEN) reported.
For those young cancer patients, this new research could become a lifesaving therapy as further studies validate the approach, which has been in development for six years.
“Every successful medicine has its origin story,” said Christopher Vakoc, MD, PhD (above), a molecular biologist at Cold Spring Harbor Laboratory, who led the team that develop the method for converting cancer cells into healthy cells. “And research like this is the soil from which new drugs are born.” As these findings are confirmed, it may be that clinical laboratories and anatomic pathologists will be needed to identify the specific cancer cells in patients once treatment is developed. (Photo copyright: Cold Spring Harbor Laboratory.)
According to an article in the Chinese Journal of Cancer on the National Library of Medicine website, “Differentiation therapy is based on the concept that a neoplasm is a differentiation disorder [aka, differentiation syndrome] or a dedifferentiation disease. In response to the induction of differentiation, tumor cells can revert to normal or nearly normal cells, thereby altering their malignant phenotype and ultimately alleviating the tumor burden or curing the malignant disease without damaging normal cells.”
Vakoc and his team first pursued differentiation therapy to treat Ewing sarcoma, a pediatric cancer that forms in soft tissues or in bone. In January 2023, GEN reported that the researchers had discovered that “Ewing sarcoma could potentially be stopped by developing a drug that blocks the protein known as ETV6.”
“This protein is present in all cells. But when you perturb the protein, most normal cells don’t care,” Vakoc told GEN. “The process by which the sarcoma forms turns this ETV6 molecule—this relatively innocuous, harmless protein that isn’t doing very much—into something that’s now controlling a life-death decision of the tumor cell.”
The researchers discovered that when ETV6 was blocked in lab-grown Ewing sarcoma cells, the cells became normal, healthy cells. “The sarcoma cell reverts back into being a normal cell again,” they told GEN. “The shape of the cell changes. The behavior of the cells changes. A lot of the cells will arrest their growth. It’s really an explosive effect.”
The scientists then turned their attention on Rhabdomyosarcoma to see if they could elicit a similar response.
“In this study, we developed a high-throughput genetic screening method to identify genes that cause rhabdomyosarcoma cells to differentiate into normal muscle. We used this platform to discover the protein NF-Y as an important molecule that contributes to rhabdomyosarcoma biology. CRISPR-based genetic targeting of NF-Y converts rhabdomyosarcoma cells into differentiated muscle, and we reveal the mechanism by which this occurs,” they wrote in PNAS.
“Scientists have successfully induced rhabdomyosarcoma cells to transform into normal, healthy muscle cells. It’s a breakthrough that could see the development of new therapies for the cruel disease, and it could lead to similar breakthroughs for other types of human cancers,” ScienceAlert reported.
“The cells literally turn into muscle,” Vakoc told ScienceAlert. “The tumor loses all cancer attributes. They’re switching from a cell that just wants to make more of itself to cells devoted to contraction. Because all its energy and resources are now devoted to contraction, it can’t go back to this multiplying state,” he added.
Promising New Therapies for Multiple Cancers in Children
Differentiation therapy as a treatment option gained popularity when “scientists noticed that leukemia cells are not fully mature, similar to undifferentiated stem cells that haven’t yet fully developed into a specific cell type. Differentiation therapy forces those cells to continue their development and differentiate into specific mature cell types,” ScienceAlert noted.
Vakoc and his team had previously “effectively reversed the mutation of the cancer cells that emerge in Ewing sarcoma.” It was those promising results from differentiation therapy that inspired the team to push further and attempt success with rhabdomyosarcoma.
Their results are “a key step in the development of differentiation therapy for rhabdomyosarcoma and could accelerate the timeline for which such treatments are expected,” ScienceAlert commented.
Developing New Therapies for Deadly Cancers
Vakoc and his team are considering differentiation therapy’s potential effectiveness for other types of cancer as well. They note that “their technique, now demonstrated on two different types of sarcoma, could be applicable to other sarcomas and cancer types since it gives scientists the tools needed to find how to cause cancer cells to differentiate,” ScienceAlert reported.
“Since many forms of human sarcoma exhibit a defect in cell differentiation, the methodology described here might have broad relevance for the investigation of these tumors,” the researchers wrote in PNAS.
Clinical laboratories and anatomic pathologist play a critical role in identifying many types of cancers. And though any treatment that comes from the Cold Spring Harbor Laboratory research is years away, it illustrates how new insights into the basic dynamics of cancer cells is helping researchers develop effective therapies for attacking those cancers.
Scientists believe useful new clinical laboratory assays could be developed by better understanding the huge number of ‘poorly researched’ genes and the proteins they build
Researchers have added a new “-ome” to the long list of -omes. The new -ome is the “unknome.” This is significant for clinical laboratory managers because it is part of an investigative effort to better understand the substantial number of genes, and the proteins they build, that have been understudied and of which little is known about their full function.
The Unknome Database includes “thousands of understudied proteins encoded by genes in the human genome, whose existence is known but whose functions are mostly not,” according to a news release.
The database, which is available to the public and which can be customized by the user, “ranks proteins based on how little is known about them,” the PLOS Biology paper notes.
It should be of interest to pathologists and clinical laboratory scientists. The fruit of this research may identify additional biomarkers useful in diagnosis and for guiding decisions on how to treat patients.
“These uncharacterized genes have not deserved their neglect,” said Sean Munro, PhD (above), MRC Laboratory of Molecular Biology in Cambridge, England, in a press release. “Our database provides a powerful, versatile and efficient platform to identify and select important genes of unknown function for analysis, thereby accelerating the closure of the gap in biological knowledge that the unknome represents.” Clinical laboratory scientists may find the Unknome Database intriguing and useful. (Photo copyright: Royal Society.)
Risk of Ignoring Understudied Proteins
Proteomics (the study of proteins) is a rapidly advancing area of clinical laboratory testing. As genetic scientists learn more about proteins and their functions, diagnostics companies use that information to develop new assays. But did you know that researchers tend to focus on only a small fraction of the total number of protein-coding DNA sequences contained in the human genome?
The study of proteomics is primarily interested in the part of the genome that “contains instructions for building proteins … [which] are essential for development, growth, and reproduction across the entire body,” according to Scientific American. These are all protein-coding genes.
Proteomics estimates that there are more than two million proteins in the human body, which are coded for 20,000 to 25,000 genes, according to All the Science.
To build their database, the MRC researchers ranked the “unknome” proteins by how little is known about their functions in cellular processes. When they tested the database, they found some of these less-researched proteins important to biological functions such as development and stress resistance.
“The role of thousands of human proteins remains unclear and yet research tends to focus on those that are already well understood,” said Sean Munro, PhD, MRC Laboratory of Molecular Biology in Cambridge, England, in the news release. “To help address this we created an Unknome database that ranks proteins based on how little is known about them, and then performed functional screens on a selection of these mystery proteins to demonstrate how ignorance can drive biological discovery.”
In the paper, they acknowledged the human genome encodes about 20,000 proteins, and that the application of transcriptomics and proteomics has “confirmed that most of these new proteins are expressed, and the function of many of them has been identified.
“However,” the authors added, “despite over 20 years of extensive effort, there are also many others that still have no known function.”
They also recognized limited resources for research and that a preference for “relative safety” and “well-established fields” are likely holding back discoveries.
The researchers note “significant” risks to continually ignoring unexplored proteins, which may have roles in cell processes, serve as targets for therapies, and be associated with diseases as well as being “eminently druggable,” Genetic Engineering News reported.
Setting up the Unknome Database
To develop the Unknome Database, the researchers first turned to what has already come to fruition. They gave each protein in the human genome a “knownness” score based on review of existing information about “function, conservation across species, subcellular localization, and other factors,” Interesting Engineering reported.
It turns out, 3,000 groups of proteins (805 with a human protein) scored zero, “showing there’s still much to learn within the human genome,” Science News stated, adding that the Unknome Database catalogues more than 13,000 protein groups and nearly two million proteins.
The researchers then tested the database by using it to determine what could be learned about 260 “mystery” genes in humans that are also present in Drosophila (small fruit flies).
“We used the Unknome Database to select 260 genes that appeared both highly conserved and particularly poorly understood, and then applied functional assays in whole animals that would be impractical at genome-wide scale,” the researchers wrote in PLOS Biology.
“We initially selected all genes that had a knownness score of ≤1.0 and are conserved in both humans and flies, as well as being present in at least 80% of available metazoan genome sequences. … After testing for viability, the nonessential genes were then screened with a panel of quantitative assays designed to reveal potential roles in a wide range of biological functions,” they added.
“Our screen in whole organisms reveals that, despite several decades of extensive genetic screens in Drosophila, there are many genes with essential roles that have eluded characterization,” the researchers conclude.
Clinical Laboratory Testing Using the Unknome Database
Future use of the Unknome Database may involve CRISPR technology to explore functions of unknown genes, according to the PLOS Biology paper.
Munro told Science News the research team may work with other research efforts aimed at understanding “mysterious proteins,” such as the Understudied Proteins Initiative.
The Unknome Database’s ability to be customized by others means researchers can create their own “knownness” scores as it applies to their studies. Thus, the database could be a resource in studies of treatments or medications to fight diseases, Chemistry World noted.
According to a statement prepared for Healthcare Dive by SomaLogic, a Boulder, Colorado-based protein biomarker company, diagnostic tests that measure proteins can be applied to diseases and conditions such as:
“The 27-protein model has potential as a ‘universal’ surrogate end point for cardiovascular risk,” the researchers wrote in Science Translational Medicine.
Proteomics definitely has its place in clinical laboratory testing. The development of MRC-LMB’s Unknome Database will help researchers’ increase their knowledge about the functions of more proteins which should in turn lead to new diagnostic assays for labs.
Silicon Valley startup is using gene sequencing to identify in the bloodstream free-floating genetic material shed by tumors
There has been plenty of excitement about the new diagnostic technologies designed to identify circulating tumor cells in blood samples. Now, a well-funded Silicon Valley startup has developed a blood test that it says holds promise for detecting early-stage lung and other cancers.
Though experimental, the screening test—which uses gene sequencing to identify in the bloodstream cancer-signaling genetic material shed by tumors—would be a boon for clinical laboratories and health networks. It also could play a role in advancing precision medicine treatments and drug therapies.
“There is an unmet need globally for early-detection tests for lung cancer that can be easily implemented by healthcare systems,” lead study author Geoffrey Oxnard, MD (above), said in the Dana-Farber news release. “These are promising early results and the next steps are to further optimize the assays and validate the results in a larger group of people.” (Photo copyright: Dana-Farber Cancer Institute.)
According to the news release, researchers in this initial analysis explored the ability of three different prototype sequencing assays, each with 98% specificity, to detect lung cancer in blood samples:
“The initial results showed that all three assays could detect lung cancer with a low rate of false positives (in which a test indicates a person has cancer when there is no cancer),” the Dana-Farber news release noted.
Identifying Disease Risk Before Symptoms Appear
Screening tests help identify individuals who are not displaying disease symptoms but may be at high risk for developing a disease. GRAIL’s goal is to develop a test with a specificity of 99% or higher. This means no more than one out of 100 people would receive a false-positive.
Otis Brawley, MD, Chief Medical and Scientific Officer at the American Cancer Society, points out that specificity is important when developing a population-based screening test that ultimately would be given to large portions of the general public based on age, medical history, or other factors.
“I am much more concerned about specificity than sensitivity [true positive rate], and [GRAIL] exhibited extremely high specificity,” Brawley told Forbes. “You don’t want a lot of false alarms.”
Some cancer experts have a wait-and-see reaction to GRAIL’s initial results, due in part to the small sample size included in the sub-study. Benjamin Davies, MD, Associate Professor of Urology at the University of Pittsburgh School of Medicine, and an expert on prostate cancer screening, told Forbes the early data was “compelling,” but the number of patients in the study was too small to generate excitement.
Oxnard, however, believes the initial results validate the promise of GRAIL’s blood screening test project.
“I was a skeptic two years ago,” Oxnard, a GRAIL consultant, told Forbes. “I think these data need to put a lot of the skepticism to rest. It can be done. This is proof you can find cancer in the blood, you can find advanced cancer, therefore this has legs. This has a real future. It’s going to be many steps down the line, but this deserves further investigation and should move forward.”
Researchers next plan to verify the initial results in an independent group of 1,000 CCGA participants as part of the same sub-study. They then will attempt to optimize the assays before validating them in a larger data set from CCGA, the Dana-Farber news release explained.
Illumina, a sequencing-technology developer, formed GRAIL in 2016, with participating investments from Bill Gates, Bezos Expeditions and Sutter Hill Ventures. Since then, GRAIL has attracted other high-flying investors, including Amazon, Merck, Johnson and Johnson, and Bristol-Myers Squibb.
Forbes notes that as of 2018 GRAIL has raised $1.6 billion in venture capital and has a $3.2 billion valuation, according to private market data firm Pitchbook. Last year, GRAIL merged with Hong Kong-based Cirina Ltd., a privately held company also focused on the early detection of cancer.
While GRAIL’s projects hold promise, anatomic pathologists and clinical laboratories may be wise to temper their enthusiasm until more research is done.
“We all would like to dream that someday you’d be able to diagnose cancer with a blood test,” Eric Topol, MD, Executive Vice President and Professor of Molecular Medicine at Scripps Research, told Forbes. Topol says he’s “encouraged” by GRAIL’s methodical approach, but warns: “We’re at the earliest stage of that.”
Their study, published last month in Nature Genetics, found that a genome analysis called polygenic risk scoring can identify individuals with a high risk of developing one of five potentially deadly diseases:
Polygenic Scoring Predicts Risk of Disease Among General Population
To date, most genetic testing has been “single gene,” focusing on rare mutations in specific genes such as those causing sickle cell disease or cystic fibrosis. This latest research indicates that polygenic predictors could be used to discover heightened risk factors in a much larger portion of the general population, enabling early interventions to prevent disease before other warning signs appear. The ultimate goal of precision medicine.
“We’ve known for long time that there are people out there at high risk for disease based just on their overall genetic variation,” senior author Sekar Kathiresan, MD, co-Director of the Medical and Population Genetics Program at the Broad Institute, and Director, Center for Genomic Medicine at Massachusetts General Hospital, said in a Broad Institute news release. “Now, we’re able to measure that risk using genomic data in a meaningful way. From a public health perspective, we need to identify these higher-risk segments of the population, so we can provide appropriate care.”
“What I foresee is in five years, each person will know this risk number—this ‘polygenic risk score’—similar to the way each person knows his or her cholesterol,” Sekar Kathiresan, MD (above), Co-Director of the Medical and Population Genetics Program at the Broad Institute, and Director, Center for Genomic Medicine at Massachusetts General Hospital, told the Associated Press (AP). He went on to say a high-risk score could lead to people taking other steps to lower their overall risk for specific diseases, while a low-risk score “doesn’t give you a free pass” since an unhealthy lifestyle can lead to disease as well. (Photo copyright: Massachusetts General Hospital.)
The researchers conducted the study using data from more than 400,000 individuals in the United Kingdom Biobank. They created a risk score for coronary artery disease by looking for 6.6 million single-letter genetic changes that are more prevalent in people who have had early heart attacks. Of the individuals in the UK Biobank dataset, 8% were more than three times as likely to develop the disease compared to everyone else, based on their genetic variation.
In absolute terms, only 0.8% of individuals with the very lowest polygenic risk scores had coronary artery disease, compared to 11% for people with the highest scores, the Broad Institute news release stated.
“The results should be eye-opening for cardiologists,” Charles C. Hong, MD, PhD, Director of Cardiovascular Research at the University of Maryland School of Medicine, told the AP. “The only disappointment is that this score applies only to those with European ancestry, so I wonder if similar scores are in the works for the large majority of the world population that is not white.”
In its news release, the Broad Institute noted the need for additional studies to “optimize the algorithms for other ethnic groups.”
The Broad Institute’s results suggest, however, that as many as 25 million people in the United States may be at more than triple the normal risk for coronary artery disease. And millions more may be at similar elevated risk for the other conditions, based on genetic variations alone.
Reanalyzing Data from DNA Testing Companies
The researchers are building a website that would enable users to receive a low-cost polygenic risk score—such as calculating inherited risk score for many common diseases—by reanalyzing data users previously receive from DNA testing companies such as 23andMe.
Kathiresan told Forbes his goal is for the 17 million people who have used genotyping services to submit their data to the web portal he is building. He told the magazine he’s hoping “people will be able to get their polygenic scores for about as much as the cost of a cholesterol test.”
Some Experts Not Impressed with Broad Institute Study
In an article in GEN that noted polygenic risk scores were receiving “the type of attention reserved for groundbreaking science,” Torkamani said the recent news is “not particularly” a big leap forward in the field of polygenic risk prediction. He described the results as “not a methodological advance or even an unexpected result,” noting his own group had generated similar data for type 2 diabetes in their analysis of the UK dataset.
Nevertheless, Kathiresan is hopeful the study will advance disease treatment and prevention. “Ultimately, this is a new type of genetic risk factor,” he said in the news release. “We envision polygenic risk scores as a way to identify people at high or low risk for a disease, perhaps as early as birth, and then use that information to target interventions—either lifestyle modifications or treatments—to prevent disease.”
This latest research indicates healthcare providers could soon be incorporating polygenic risking scoring into routine clinical care. Not only would doing so mean another step forward in the advancement of precision medicine, but clinical laboratories and pathology groups also would have new tools to help diagnose disease and guide treatment decisions.
Authorities named prenatal DNA tests in particular as an area of concern in genetic testing. This may surprise pathologists and clinical laboratory professionals, who have regularly read about the substantial investments major Chinese companies have made in the field of gene sequencing. (more…)