This is the first of a three-part series on revenue cycle management for molecular testing laboratories and pathology practices, produced in collaboration with XiFin, Inc.
Setting Your Organization Up for Success: Maximizing Revenue for Molecular Diagnostics and Pathology Testing Starts Well Before Billing
What progressive revenue cycle management technology reveals about revenue levers, test clearances, and strategic planning for molecular and pathology testing.
CFOs and other leaders of molecular testing laboratories and pathology groups need to raise their awareness of the most vulnerable aspects of revenue. To this end, this article outlines three specific areas of potential revenue cycle management (RCM) improvement so molecular diagnostic and pathology organizations can better identify and adapt to localized market dynamics and individual patient needs.
“Many people look at RCM as just billing or getting a clean billing process, but laboratory testing is getting more complex; consequently, reimbursement is getting more complicated, and continually changing payer policies are also making it more challenging for labs to keep up. It is important for business executives, revenue cycle leaders, and CFOs to look more broadly at the revenue cycle,” explained Clarisa Blattner, XiFin Senior Director of Revenue and Payor Optimization. XiFin recommends lab and pathology leaders consider revenue cycle within the broader context of the patient journey, which generally includes, among other things, three key revenue-impacting patient engagement stages.
The first of the three stages, patient access and financial clearance, begins when patient demographics and insurance information are captured. Following demographics and insurance details is a determination of benefits coverage and verification of eligibility. Financial information on any required copay and deductibles are determined, and pre-payment is collected. Finally, the patient receives a financial responsibility estimate for any out-of-pocket expenses.
In stage 2, clinical/medical clearance requires ordering physician engagement to address medical necessity questions and obtain supporting documentation. Clinical assessment and diagnostic testing are conducted. The encounter document is completed. Results are shared via secure, seamless, connected communication between the ordering physician’s office, the lab of the diagnostic provider, and the patient. Finally, the claim is submitted for reimbursement with all relevant supporting documentation.
The third stage is when payer management activities are essential to maximizing reimbursement by ensuring claim submissions include prior authorizations, clinical documentation, proprietary payer forms and comply with payer policies and requirements. Through this stage, patient engagement ensures all the correct data is in place, and insurance information or coverage hasn’t changed or is appropriately updated. Anticipating payer responses and subsequent actions is critical to collecting the full amount payers are responsible for to minimize patient financial impact. Once all payer activities are exhausted, the patient must be sent their statement for the remaining balance in their preferred communication method (paper, text, email, portal, etc.). Additionally, payment collection is accelerated when a diagnostic provider makes it easy and convenient to make payments, manage payment plans, and change payment methods.
These three stages in the patient journey encompass important revenue levers that cannot be overlooked. They are foundational to automating the financial performance engine needed for molecular diagnostics and pathology practices, Blattner continued. Whereas specialty diagnostics are rapidly coming to market and localized with varying reach, availability, and insurance coverage assurance, activating specific “clearance” functions or “engagement” opportunities within these levers will be key to smooth claims processing, timely filing, and optimizing all payment avenues.
Blattner stresses that when not built into automatic administrative functions, these three types of stages (i.e., patient access, physician engagement, and payer management) will slow or indefinitely stall payment for molecular diagnostics and pathology providers.
Market Expansion and Shift in at-Home Testing Stresses Traditional Administrative Approaches
Novel diagnostics are being introduced in record numbers as physicians and diagnostic business leaders seek to address and fulfill unmet diagnostic and medical needs to support better health outcomes. Along with these new medical breakthroughs comes the demand for traditional administrative approaches to reinvent themselves – including RCM. This major operational shift and frequent payer policy changes with advanced diagnostics have strained traditional administrative practices. According to Blattner, when executives realize that manual processes and inadequate electronic billing functions have reached a breaking point, specialized automation is the natural next step. The items corresponding to the highest value revenue cycle activities may sound surprising within the three revenue levers—patient access, medical clearance, and payer management.
Patient Access, Engagement, and Financial Clearance
“Making it easy for physicians to order molecular diagnostics and pathology tests is so important for success in today’s market,” Blattner continued. Ordering physicians and lab teams must have accurate and timely information regarding a patient’s ‘financial clearance’ (the likelihood a test will be covered, what the patient is likely to be charged out-of-pocket, and whether prior authorization is required). Patient portals and multi-channel communications are important parts of effective RCM functionality that facilitate patient access and financial clearance.
“It used to be that a patient went to the lab, and a phlebotomist saw the patient, but now more tests involve specimen collection at home. A kit is distributed at the physician’s office or ordered online and shipped to the patient,” Blattner said. “There is more follow-through needed to make sure not only did the test get done, but did it get returned, because while there are upfront costs to serve the patient, the lab doesn’t get paid until the test is completed, returned, processed and the diagnosis is determined for the claim to be processed. That is an evolution as these tests leave the laboratory or the business and enter the home environment.”
Patient access and engagement tools provide various benefits, including offering a cost-effective alternative to traditional customer service calls and supporting patients’ communication preferences. Effective physician access and engagement programs and technology help diagnostic providers offer self-service tools that enable patients to securely log in, anytime, to:
View statements
Make credit card payments
Set up payment plans (using lab-specified rules and parameters)
Establish paperless billing
View patient responsibility estimates
View test results
Another critical aspect of patient financial clearance for diagnostic testing is the ability to provide patients with an accurate estimation of their out-of-pocket costs associated with a test. Practical patient communication tools enable ordering physicians’ staff members to assist patients in preparing for out-of-pocket expenses, which increases test completion rates and has been proven to reduce write-offs.
To accurately assess a patient’s financial responsibility, the estimation tool must consider relevant provider and plan specific pricing and test or procedure information, as well as provide access to real-time eligibility data. A proper estimation of a patient’s out-of-pocket expenses is also predicated on receiving complete and accurate information from the payer. Examining payer behavior can uncover responses that create inaccurate patient responsibility estimates.
Physician engagement programs help diagnostic providers integrate communication and data exchange more deeply with ordering physicians and complete clinical clearance. Clinical clearance involves things like medical necessity, familial history, and social determinants of health. Robust RCM also requires diagnostic providers, laboratories, and pathology practices to be able to seamlessly communicate with patients to ensure that samples, devices, or readings are collected and returned to the diagnostic provider so that services/tests can be completed.
Effective physician engagement and clinical clearance increase ordering volume, maximize clean claims and automate denials and appeals management. Physician engagement technology, including electronic communication tools such as portals, helps physicians and their teams streamline the online correction of missing information and errors. This improves satisfaction, expedites reimbursement, and provides cost savings. With effective physician engagement programs and technology tools, physicians and their staff can more effectively:
Perform order entry
Access clinical decision support
Examine statements at the line-item level
View test information and pricing
Correct billing errors upfront to expedite reimbursement
Provide patients with an estimate of their out-of-pocket cost
Payer Management
Molecular diagnostic and genetic tests are famously complex and present many unique operational and financial challenges for laboratories. Payer policies and behavior are constantly changing, and labs (and their billing partners) must stay abreast of changes to avoid lengthy delays that denials and subsequent appeals can cause. Intelligent automation of prior authorizations, insurance discovery, and benefits determination are especially important for these tests.
Unfortunately, it is common for diagnostic providers to only learn about a change in reimbursement after the month-end close. These changes manifest in billing as:
New denials
Changes in denial rate
Changes in reimbursement rate
Change in time to payment
Failure to quickly recognize and adapt workflows to payer reimbursement changes can result in costly appeals and write-offs. XiFin recommends that providers adopt a proactive strategy to identify changes in reimbursement earlier. It is essential to understand the impacts and risks of price discrepancies and changes in pricing to patients. Staying abreast of policy changes for Medicare and commercial payers enables molecular diagnostic laboratories and pathology groups to proactively employ front-end billing system edits to avoid denials.
Keys to Success
For molecular diagnostic providers and pathology groups to maximize reimbursement, CFOs, and revenue cycle leaders must take a broader view of RCM. The RCM process starts well before billing and runs parallel to the patient journey in many respects. This means that effective RCM technology and tools also stretch beyond the billing system to incorporate seamless communication between systems and parties throughout the patient journey.
Adaptive RCM approaches require automation, intelligence, and real-time communication for the three key revenue-impacting stages discussed in this article: patient access, medical clearance, and payer management. This involves seamless integration with various tools that enable insurance discovery, patent demographic and eligibility verifications, patient financial responsibility estimation, and reporting and analytics that allow early identification of and response to changes in payer behavior.
Molecular diagnostic labs and pathology practices must have tools and technology to align with payers on evidence requirements, including clinical utility evidence, current billing policies, and preferred coding approaches. They must have seamless connectivity to ordering physicians to order tests and ensure the completeness of medical necessity and medical record documentation.
Finally, XiFin recommends that diagnostic organizations use analytics to enable early insight into changes in payer behavior, address root causes, and be able to adjust to changes in ordering patterns and client data quality. Be sure to consider an RCM platform that has embedded artificial intelligence (AI) to drive efficient automation of workflow adaptation to payer changes and future-proof your RCM investment.
Financial executives seeking to maximize market access and capitalize on growth opportunities in key markets will want to explore how successfully their administrative teams are navigating the unique revenue cycle landscape specific to molecular testing and pathology.
Part 2 of this three-part series is coming soon. Watch for updates here at DarkDaily.
As doctors become more familiar with using biomarkers to monitor Crohn’s disease, clinical laboratories may play a greater role in that process
New evidence-based guidelines from the American Gastroenterological Association (AGA) that call for using specific biomarkers to help manage Crohn’s disease (CD) may decrease the number of invasive procedures patients must undergo and increase the role clinical laboratories play in monitoring the disease.
The new AGA guidelines “recommend using the C-reactive protein (CRP) biomarker in blood and the fecal calprotectin (FCP) biomarker in stool to measure inflammation levels and assess whether Crohn’s disease is in remission or active,” Medical News Today reported.
Crohn’s disease is a chronic inflammatory bowel disease (IBD) that causes inflammation in the digestive tract, primarily in the small and large intestine. The cause of the disease is unknown, but genetics may play a role.
Typically, CD patients must undergo repeated colonoscopies to monitor the disease’s progression or remission. This has long been standard practice. Now, however, “AGA recommends the use of biomarkers in addition to colonoscopy and imaging studies,” according to an AGA news release. This hints at a greater role for clinical laboratories in helping physicians manage patients with Crohn’s Disease.
“Patients’ symptoms do not always match endoscopic findings, so biomarkers are a useful tool to understand and monitor the status of inflammation and guide decision making in patients with Crohn’s disease,” said gastroenterologist Siddharth Singh, MD, Assistant Professor of Medicine at UC San Diego Health and a co-author of the new AGA guidelines.
The AGA’s new guidelines demonstrate how medical science is generating new insights about how multiple biomarkers can be associated for diagnosis/management of a disease in ways that change the standard of care, particularly if it can reduce invasive procedures for the patient by the use of less invasive methods (such as a venous blood draw instead of a colonoscopy).
“Based on this guideline, biomarkers are no longer considered experimental and should be an integral part of inflammatory bowel disease care,” Ashwin Ananthakrishnan MD (above), a gastroenterologist at Massachusetts General Hospital and co-author of the guidelines, told Medical News Today. Under the new AGA guidelines, clinical laboratories will play a greater role in helping patients monitor their disease. (Photo copyright: Massachusetts General Hospital.)
Patient’s Needs Determine Biomarker vs Endoscopy Monitoring
AGA’s new guidelines could give patients a more comfortable, cost-effective, and possibly more efficient treatment plan to manage their Crohn’s disease. That’s even true if a patient’s Crohn’s disease is in remission.
With these new guidelines, Crohn’s disease patients in remission would only need their biomarkers to be checked every six to 12 months. Patients with active symptoms would need their biomarkers checked roughly every two to four months.
Biomarker testing can be seen as a useful addition to Crohn’s disease care rather than a full replacement of other forms of care. For example, the new AGA guidelines do not fully omit imaging studies and colonoscopies from treatment. Rather, they are recommended in treatment plans based on the patient’s needs.
In their Gastroenterology paper, the AGA authors wrote, “A biomarker-based monitoring strategy involves routine assessment of symptoms and noninvasive biomarkers of inflammation in patients with CD in symptomatic remission to inform ongoing management. In this situation, normalization of biomarkers is an adequate treatment target—asymptomatic patients with normal biomarkers would continue current management without endoscopy, whereas those with elevated biomarkers would undergo endoscopy.”
Fecal Matter Biomarkers
In speaking with Medical News Today on the benefits of using fecal biomarkers to assess a patient’s disease maintenance, gastroenterologist Jesse Stondell, MD, an Associate Clinical Professor at UC Davis Health, said, “If we start a patient on therapy, they’re not responding appropriately, they’re still having a lot of symptoms, we can check that fecal calprotectin test and get a very quick sense of if things are working or not.
“If the calprotectin is normal, it could be reassuring that there may be other reasons for their symptoms, and that the medicine’s working. But if they have symptoms, and a calprotectin is elevated, that’s a signal that we have to worry the medicine is not working. And that we need to change therapy in that patient,” he added.
“This is a win for Crohn’s disease patients,” Ashwin Ananthakrishnan, MD, a gastroenterologist at Massachusetts General Hospital and co-author of the AGA’s new guidelines, told Medical News Today. “Biomarkers are usually easier to obtain, less invasive, more cost-effective than frequent colonoscopies, and can be assessed more frequently for tighter disease control and better long-term outcomes in Crohn’s disease.”
Clinical laboratories should expect these guidelines to increase demand for the processing of blood or fecal matter biomarker testing. As Crohn’s disease monitoring becomes more dependent on biomarker testing, clinical labs will play a critical role in that process.
Newly-defined Cardiovascular-Kidney-Metabolic Syndrome (CKM) means physicians will be in close collaboration with clinical laboratories to make accurate diagnoses
In a presidential advisory, the AHA defines a newly described systemic health disorder called Cardiovascular-Kidney-Metabolic Syndrome (CKM). The syndrome “is a systemic disorder characterized by pathophysiological interactions among metabolic risk factors, CKD (chronic kidney disease), and the cardiovascular system leading to multi-organ failure and a high rate of adverse cardiovascular outcomes.”
A CKM diagnosis, which is meant to identify patients who are at high risk of dying from heart disease, is based on a combination of risk factors, including:
weight problems,
issues with blood pressure, cholesterol, and/or blood sugar,
reduced kidney function.
CKM is a new term and doctors will be ordering medical laboratory tests associated with diagnosing patients with multiple symptoms to see if they match this diagnosis. Thus, clinical laboratory managers and pathologists will want to follow the adoption/implementation of this new recommendation.
“The advisory addresses the connections among these conditions with a particular focus on identifying people at early stages of CKM syndrome,” said Chiadi Ndumele, MD, PhD (above), Associate Professor of Medicine at Johns Hopkins University and one of the authors of the AHA paper, in a news release. “Screening for kidney and metabolic disease will help us start protective therapies earlier to most effectively prevent heart disease and best manage existing heart disease.” Clinical laboratories will play a key role in those screenings and in diagnosis of the new syndrome. (Photo copyright: Johns Hopkins University.)
Stages of CKM Syndrome
In its presidential advisory, the AHA wrote, “Cardiovascular-Kidney-Metabolic (CKM) syndrome is defined as a health disorder attributable to connections among obesity, diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD), including heart failure, atrial fibrillation, coronary heart disease, stroke, and peripheral artery disease. CKM syndrome includes those at risk for CVD and those with existing CVD.”
The five stages of CKM syndrome, which the AHA provided to give a framework for patients to work towards regression of the syndrome, are:
Stage 0: No CKM risk factors. Individuals should be screened every three to five years for blood pressure, cholesterol, and blood sugar levels, and for maintaining a healthy body weight.
Stage 1: Excess body fat and/or an unhealthy distribution of body fat, such as abdominal obesity, and/or impaired glucose tolerance or prediabetes. Patients have risk factors such as weight problems or prediabetes and are encouraged to make healthy lifestyle changes and try to lose at least 5% of their body weight.
Stage 2: Metabolic risk factors and kidney disease. Includes people who already have Type 2 diabetes, high blood pressure, high triglyceride levels, and/or kidney disease. Medications that target kidney function, lower blood sugar, and which help with weight loss should be considered at this stage to prevent diseases of the heart and blood vessels or kidney failure.
Stage 3: Early cardiovascular disease without symptoms in people with metabolic risk factors or kidney disease or those at high predicted risk for cardiovascular disease. People show signs of disease in their arteries, or have heart function issues, or may have already had a stroke or heart attack or have kidney or heart failure. Medication may also be needed at this stage.
Stage 4: Symptomatic cardiovascular disease in people with excess body fat, metabolic risk factors or kidney disease. In this stage, people are categorized as with or without having kidney failure. May also have already had a heart attack, stroke or heart failure, or cardiovascular conditions such as peripheral artery disease or atrial fibrillation.
“We now have several therapies that prevent both worsening kidney disease and heart disease,” said Chiadi Ndumele, MD, PhD, Associate Professor of Medicine at Johns Hopkins University and one of the authors of the Circulation paper, in a news release. “The advisory provides guidance for healthcare professionals about how and when to use those therapies, and for the medical community and general public about the best ways to prevent and manage CKM syndrome.”
According to an AHA 2023 Statistical Update, one in three adults in the US have three or more risk factors that contribute to cardiovascular disease, metabolic disorders, or kidney disease. While CKM affects nearly every major organ in the body, it has the biggest impact on the cardiovascular system where it can affect the blood vessels, heart muscle function, the rate of fatty buildup in the arteries, electrical impulses in the heart and more.
“There is a need for fundamental changes in how we educate healthcare professionals and the public, how we organize care and how we reimburse care related to CKM syndrome,” Ndumele noted. “Key partnerships among stakeholders are needed to improve access to therapies, to support new care models, and to make it easier for people from diverse communities and circumstances to live healthier lifestyles and to achieve ideal cardiovascular health.”
New AHA Risk Calculator
In November, the AHA announced PREVENT (Predicting risk of cardiovascular disease EVENTs), a tool that doctors can use to assess a person’s risk for heart attack, stroke, and heart failure. The new risk calculator, which incorporates CKM, allows physicians to evaluate younger people as well, and examine their long-term risks for cardiovascular issues.
Doctors can use PREVENT to assess people ages 30 to 79 and predict risk for heart attack, stroke, or heart failure over 10 to 30 years.
“Longer-term estimates are important because short-term or 10-year risk in most young adults is still going to be low. We wanted to think more broadly and apply a life-course perspective,” Khan said. “Providing information on 30-year risk may reveal earlier opportunities for intervention and prevention efforts in younger people.”
According to CDC data, about 695,000 people died of heart disease in the US in 2021. That equates to one in every five deaths. Clinical pathologists will need to understand the AHA recommendations and how doctors will be ordering clinical laboratory tests to determine if a patient has CKM. Then, labs will play a role in helping doctors monitor patients to optimize health and prevent acute episodes that put patients in the hospital.
If validated, study findings may result in new biomarkers for clinical laboratory cholesterol tests and for diagnosing dementia
Researchers continue to find new associations between biomarkers commonly tested by clinical laboratories and certain health conditions and diseases. One recent example comes from research conducted by the University of California San Francisco. The UCSF study connected cholesterol biomarkers generally used for managing cardiovascular disease with an increased risk for dementia as well.
The researchers found that both high and low levels of high-density lipoprotein (HDL)—often referred to as “good” cholesterol—was associated with dementia in older adults, according to a news release from the American Academy of Neurology (AAN).
UCSF’s large, longitudinal study incorporated data from 184,367 people in the Kaiser Permanente Northern California health plan. How the findings may alter cholesterol biomarker use in future diagnostics has not been determined.
“The elevation in dementia risk with both high and low levels of HDL cholesterol was unexpected, but these increases are small, and their clinical significance is uncertain,” said epidemiologist Maria Glymour, ScD (above), study author and Professor of Epidemiology and Biostatistics at UCSF School of Medicine, in a news release. This is another example of how researchers are associating common biomarkers tested regularly by clinical laboratories with additional health conditions and disease states. (Photo copyright: University of California San Francisco.)
HDL Levels Link to Dementia Risk
The UCSF researchers used cholesterol measurements and health behavior questions as they tracked Kaiser Permanente Northern California health plan members who were at least 55 years old between 2002 and 2007, and who did not have dementia at the time of the study’s launch.
The researchers then followed up with the study participants through December 2020 to find out if they had developed dementia, Medical News Today reported.
“Previous studies on this topic have been inconclusive, and this study is especially informative because of the large number of participants and long follow-up,” said epidemiologist Maria Glymour, ScD, study author and Professor of Epidemiology and Biostatistics at UCSF School of Medicine, in the AAN news release. “This information allowed us to study the links with dementia across the range of cholesterol levels and achieve precise estimates even for people with cholesterol levels that are quite high or quite low.”
According to HealthDay, UCSF’s study findings included the following:
More than 25,000 people developed dementia over about nine years. They were divided into five groups.
53.7 milligrams per deciliter (mg/dL) was the average HDL cholesterol level, amid an optimal range of above 40 mg/dL for men and above 50 mg/dL for women.
A 15% rate of dementia was found in participants with HDL of 65 mg/dL or above.
A 7% rate of dementia was found in participants with HDL of 11 mg/dL to 41 mg/dL.
“We found a U-shaped relationship between HDL and dementia risk, such that people with either lower or higher HDL had a slightly elevated risk of dementia,” Erin Ferguson, PhD student of Epidemiology at UCSF, the study’s lead study author, told Medical News Today.
What about LDL?
The UCSF researchers found no correlation between low-density lipoprotein (LDL)—often referred to as “bad” cholesterol”—and increased risk for dementia. But the risk did increase slightly when use of statin lipid-lowering medications were included in the analysis.
“Higher LDL was not associated with dementia risk overall, but statin use qualitatively modified the association. Higher LDL was associated with a slightly greater risk of Alzheimer’s disease-related dementia for statin users,” the researchers wrote in Neurology.
“We found no association between LDL cholesterol and dementia risk in the overall study cohort. Our results add to evidence that HDL cholesterol has similarly complex associations with dementia as with heart disease and cancer,” Glymour noted in the AAN news release.
Australian Study also Links High HDL to Dementia
A separate study from Monash University in Melbourne, Victoria, Australia, found that “abnormally high levels” of HDL was also associated with increased risk for dementia, according to a Monash news release.
The Monash study—which was part of the ASPREE (ASPpirin in Reducing Events in the Elderly) trial of people taking daily aspirin—involved 16,703 Australians and 2,411 Americans during the years 2010 to 2014. The researchers found:
850 participants had developed dementia over about six years.
A 27% increased risk of dementia among people with HDL above 80 mg/dL and a 42% higher dementia risk for people 75 years and older with high HDL levels.
These findings, Newsweek pointed out, do not necessarily mean that high levels of HDL cause dementia.
“There might be additional factors that affect both these findings, such as a genetic link that we are currently unaware of,” Andrew Doig, PhD, Professor, Division of Neuroscience at University of Manchester, told Newsweek. Doig was not involved in the in the Monash University research.
Follow-up research could explore the possibility of diagnosing dementia earlier using blood tests and new biomarkers, Newsweek noted.
Cholesterol Lab Test Results of Value to Clinical Labs
If further studies validate new biomarkers for testing and diagnosis, a medical laboratory’s longitudinal record of cholesterol test results over many years may be useful in identifying people with an increased risk for dementia.
Clinical pathologists and laboratory managers will want to stay tuned as additional study insights and findings are validated and published. Existing laboratory testing reference ranges may need to be revised as well.
As well, the findings of this UCSF research demonstrate that, in this age of information, there will be plenty of opportunities for clinical lab scientists and pathologists to take their labs’ patient data and combine it with other sets of data. Digital tools like artificial intelligence (AI) and machine learning would then be used to assess that large pool of data and produce clinically actionable insights. In turn, that positions labs to add more value and be paid for that value.
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.)
Differentiation Therapy
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.
