US Pharm. 2023;48(2):37-42.
Genetic Code Change Drives Common Lung Cancer Type
Researchers at New York University (NYU) Langone Health’s Perlmutter Cancer Center have identified a gene that drives development of the second most common type of lung carcinoma, offering greater insight into how the disease might be treated.
There is currently no approved, targeted, first-line therapy for lung squamous carcinoma (LUSC), a cancer that forms in cell layers lining the organ that is responsible for 20% to 30% of lung carcinoma deaths. A new study published in Cancer Cell, however, found that deleting a gene called KMT2D caused normal (basal) lung cells grown in complex cultures called organoids to transform into LUSC cells.
According to the study authors, KMT2D regulates the activity of genes that enable the building of protein tyrosine phosphatases, enzymes that restrain the cell-growth–encouraging signals sent through another enzyme set called receptor tyrosine kinases (RTKs). Two RTKs, called EGFR and ERBB2, are known to take part in the abnormal activation of the RTK-RAS signaling pathway in which a molecular switch gets “stuck in the on mode,” causing cells to continually multiply as part of cancer.
“Our study identifies KMT2D as a pivotal contributor to the development of lung squamous cancers and offers vital clues about how to target KMT2D-deficient LUSC,” said co-corresponding author Kwok-Kin Wong, MD, PhD, director of the Division of Hematology and Medical Oncology at NYU Langone Health. “The same genetic changes that cause the gene to contribute to cancer also create tumors that are very sensitive to existing drugs that target a related pathway.”
The new study confirms prior evidence that the KMT2D gene encodes a protein (a histone methyltransferase) that determines the degree to which the tyrosine phosphatase genes can be accessed by the cellular machinery trying to read them.
Given the better understanding of LUSC mechanisms resulting from the new study, the research team chose to test in study mice a combination of two drugs: SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib. ERBB is made more active by KMT2D signaling flaws, and the enzyme SHP turns up the RTK-RAS pathway, much like EGFR and ERBB2, which are rendered more active by the lack of KMT2D. The team reasoned that experimental drugs designed to inhibit SHP might also counter the effect of KMT2D deficiency when used alongside the ERBB inhibitor.
They found that the combination slowed lung tumor growth in mice with LUSC that had been engineered to lack KMT2D as well as in tumors in mice derived from the human LUSC tumors with KMT2D mutations.
“Multiple SHP2 inhibitors are currently testing in clinical trials, and afatinib is already available,” said co-corresponding author Hua Zhang, MD, PhD, formerly an instructor in the Department of Medicine at NYU Langone Health and now an assistant professor in the Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh School of Medicine, and UPMC Hillman Cancer Center. “Our findings warrant the design of clinical trials that test these therapies in KMT2D-deficient patients with LUSC.”
Revealing Genes’ Role in Obesity Treatment Response
Collaborative research between the University of Galway in Ireland and Brunel University London in the United Kingdom discovered that patients with severe and complicated obesity respond differently to a dietary weight-loss program based on their genes.
The GERONIMO project studied patients attending the obesity clinic at Galway University Hospital who were undergoing an intensive, short-term program of medically supervised dietary restriction to attempt to reverse some of the medical problems with severe obesity.
During the research, scientists analyzed small variations in hundreds of genes that are known to be associated with obesity. By combining information from these measured gene variations, a “genetic risk score” was calculated for six obesity-related traits.
Francis Finucane, senior lecturer in the School of Medicine at University of Galway and consultant endocrinologist at Galway University Hospitals, who led the clinical study, said, “Mechanistic studies like these, which help us to understand why some people respond better than others to the same intervention, are really important in providing more personalized and effective treatments for people with obesity.
“We know that in general, heritability and genetics play a huge role in influencing body weight and the risk of obesity-related complications like diabetes, but finding the genes that account for this risk has been a challenge.”
Alex Blakemore, professor of Human Genomics at Brunel University London, said, “No one chooses their genes, so, as a society, we need to recognize that when it comes to maintaining a healthy weight, the challenge is greater for some people than for others. This study reveals just a small part of the picture of how our genes can help or hinder us in reaching our health goals.”
The GERONIMO project involved 93 patients who were monitored while taking part in a meal-replacement program. Their average body mass index at the start of the study was 52 kg m-2, which means that they weighed more than twice their maximum “healthy weight.”
The participants lost an average of 16% of their body weight, or 21 kg, after 24 weeks. The research found that that the “waist hip ratio” genetic risk score, which measures an individual’s genetic tendency to hold on to central or abdominal fat, was associated with less weight loss after the intervention.
Regarding next stages in the research, Dr. Finucane said, “This work is exciting and important because it is the first Irish study to demonstrate a genetic effect on the response to a treatment for obesity.
“The genetic effects we found here were subtle, but we think it would be good to explore this further, in larger studies and with different obesity treatments, such as drug therapy or ‘metabolic surgery.’”
Predicting Placenta Accreta Through Blood Panels
Of the nearly 4 million births each year in the United States, roughly 50,000 are marked by life-threatening complications, and up to 900 result in maternal death during delivery. One major, often life-threatening complication is placenta accreta spectrum (PAS), which poses a threat to both the mother and the baby. Currently, PAS cases are identified by ultrasound, MRI, and predictive confounding conditions, but these methods leave between 33% and 50% of PAS cases undetected prior to delivery.
Investigators from Brigham and Women’s Hospital (Brigham) in Boston, Massachusetts, embarked on a study to create a targeted test for predicting PAS during pregnancy, better preparing patients and practitioners for the delivery day. By studying circulating microparticle (CMP) protein panels in pregnant women, the team identified five unique CMP proteins that can predict PAS as early as the second trimester of pregnancy. Their results are published in Scientific Reports.
“PAS is a significant contributor to maternal morbidity and mortality worldwide,” said corresponding author Hope Yu, MD, a maternal-fetal medicine physician in the Department of Obstetrics and Gynecology at Brigham. “Before our study, up to half of these cases weren’t able to be detected before delivery. Our study aims to improve that detection rate using a blood test and to eventually improve health outcomes worldwide.”
Placenta accreta, a condition where the placenta attaches excessively into the uterine wall, gets its “spectrum” designation because of varying degrees of placental penetration into the body that can occur. In some cases, the placenta attaches to the uterine muscle; in more severe cases, the placenta attaches through the uterine wall and to other organs, like the bladder. There are two major complications for PAS patients: abnormal placenta delivery after birth and heavy bleeding. Identification of PAS cases prior to delivery can help reduce and prepare for such complications.
To identify PAS early, the Brigham team looked to proteins associated with CMPs. CMPs are tiny, extracellular vesicles that cells use to communicate with one another and have been studied extensively in other disciplines since they provide a glimpse into cell crosstalk. The team set out to study CMPs at the maternal-fetal interface, with the goals of pinpointing a clinically useful PAS biomarker and investigating CMP mechanisms of PAS pathogenesis. The team’s primary goal was to construct a blood panel to identify PAS pregnancies.
The team conducted a nested case-control study with 35 PAS patients and 70 control patients who all were retroactively diagnosed after delivery. CMP proteins were isolated and identified from patient plasma sampled during the second and third trimesters of pregnancy. In samples collected from patients who were 26 weeks pregnant, five CMP proteins distinguished PAS patients from control patients; at 35 weeks pregnant, four CMP proteins distinguished PAS patients from control patients. Additionally, in the second trimester iron homeostasis and erythropoietin signaling were overrepresented—a trend that revealed abnormal immune function in the third trimester.
The study successfully identified five second-trimester CMP protein PAS indicators and four third-trimester CMP protein PAS indicators, enabling safe predication of PAS well before delivery. The authors note that more research and clinical trials will be needed to further test the applicability of the protein panel. Next steps include widening the patient sample size and creating a standardized commercial test.
“It is so important to identify these cases prior to delivery,” said Dr. Yu. “If we can identify a PAS case during pregnancy, the patient can then make a potentially life-saving choice to deliver in a tertiary delivery center with specialized providers. Having an experienced, multidisciplinary team by your side during a PAS birth can make an enormous difference when it comes to mortality and morbidity outcomes.”
“This is another step toward proactive, personalized prenatal care,” added Thomas McElrath, MD, PhD, senior author and also a Maternal-Fetal Medicine physician in the Department of Obstetrics and Gynecology at Brigham. “Right now, prenatal care too often assumes that every person has the same risks of complications during pregnancy. To be able to personalize and make each patient’s care profile particular to their needs is the ultimate goal.”
AMD a Risk Factor for COVID-19 Infection, Severe Disease
Recent evidence has emerged to suggest that age-related macular degeneration (AMD) is a clinical risk factor for increased risk for infection and mortality. AMD has been reported to confer higher risk of severe complications of SARS-CoV-2 infection, including respiratory failure and death (25%), a risk that is higher than type 2 diabetes (21%) and obesity (1%).
Considering these observations, researchers from Boston University (BU) Chobanian & Avedisian School of Medicine hypothesized that AMD and COVID-19 share common genetic risk factors and designed and executed a study that identified a novel association of the two diseases with variants in the PDGFB gene. This gene encodes a platelet-derived growth factor (PDGF), which has a role in the formation of new blood vessels and is involved in the abnormal blood vessel changes that occur in AMD. The scientists also found that more severe COVID-19 outcomes were associated with AMD, likely arising from genetic predisposition to dysfunction involving complement proteins, as well as with a higher level of PDGF in blood serum.
“Our findings add to the body of evidence for the increased risk of infection and mortality from COVID-19 among AMD patients. Our analysis lends credence to previously reported clinical studies that found those with AMD have a higher risk for COVID-19 infection and severe disease, and that this increased risk may have a genetic basis,” explained co-corresponding author Lindsay A. Farrer, PhD, chief of biomedical genetics.
The BU research team conducted a genome-wide search for variants that are jointly associated with AMD and each of three COVID-19 outcomes (infection rate, critical illness, and hospitalization) using large genetic datasets that contained tens of thousands of individuals. These datasets were previously assembled and studied separately for genetic factors contributing to the risk of AMD and for each of the COVID-19 disease outcomes. Subsequently, the researchers analyzed publicly available data from patients with AMD or COVID-19 and control groups to assess the association of variants in PDGFB with the gene activity. Finally, they employed an analytical technique that allowed them to investigate causal relationships between PDGFB gene variants, PDGFB concentration in blood, AMD, and COVID-19 outcomes.
According to the researchers, these findings suggest that lowering PDGFB gene activity and serum PDGF concentration may reduce the severity of COVID-19, particularly among older people. “Therapeutic strategies combining anti–vascular endothelial growth factor (VEGF) therapy (a current treatment for AMD that limits blood vessel growth in the eye that can harm vision) with antagonists (drugs that bind to receptors) for blocking PDGF signaling have been considered even more effective than the single VEGF treatment and are currently under investigation in clinical trials,” added co-corresponding author Manju L. Subramanian, MD, associate professor of ophthalmology.
The researchers believe this discovery of shared genetic risk factors will require a larger sample size for critical illness and hospitalizations to better understand the shared pathology and risk factors that contribute to worsening clinical outcomes in both disease states. The findings appeared online in the Journal of Clinical Medicine.
Study Attributes Late-Onset Ataxia to Genetic Cause
A study published in The New England Journal of Medicine reports the identification of a previously unknown genetic cause of a late-onset cerebellar ataxia (LOCA), a discovery that may improve diagnosis and open new treatment avenues for this progressive condition.
LOCA are a heterogenous group of neurodegenerative diseases that manifest in adulthood with unsteadiness. One to three in 100,000 people worldwide will develop a LOCA. Until recently, most patients with LOCA had remained without a genetic diagnosis.
An international team led by Bernard Brais, a neurologist and researcher at The Neuro (Montreal Neurological Institute-Hospital) of McGill University, and Stephan Züchner of the University of Miami’s Miller School of Medicine, in collaboration with neurologists from the universities of Montreal and Sherbrooke, studied 66 Quebec patients from different families who had LOCA for which an underlying genetic cause had not yet been found. Using the most advanced genetic technologies, the team found that 40 (61%) of the patients carried the same novel disease-causing variant in the gene FGF14, making it the most common genetic cause of LOCA in Quebec. They found that a small stretch of repetitive DNA underwent a large size increase in patients, a phenomenon known as repeat expansion.
To confirm their initial findings, the team reached out to international collaborators in Tübingen, Germany; Perth, Australia; London, United Kingdom; and Bengaluru, India. They found that 10% to 18% of LOCA patients in these independent cohorts also carried the same FGF14 error. These results confirmed that a repeat expansion in FGF14 is one of the most common genetic cause of LOCA described to date.
Going beyond gene discovery, the team also studied brains from deceased patients and neurons derived from patients and found that the error causes decreased expression of the gene and its protein.
Patients with an FGF14-related LOCA experience unsteadiness (ataxia) usually beginning in their fifties. The disease may start with short episodes of ataxia that can be precipitated by exercise and alcohol intake. The coordination problems become permanent, on average around age 59 years. The disease usually progresses slowly and affects walking, speech, and hand coordination. With time, it often requires walking aids. The condition is most often transmitted from an affected parent, although it can appear in families with no previous history of ataxia.
The FGF14 GAA repeated sequence of the mutation raises much interest, since it is identical to the one causing Friedreich ataxia in the FXN gene, the most common cause of autosomal recessive ataxia worldwide. Because of this similarity, it is possible that some of the new treatments under development for Friedreich ataxia may be used to treat patients with an expansion in FGF14.
This study also suggests that patients may benefit from the drug aminopyridine that is already marketed for other neurological conditions. This is especially promising since some patients with an expansion in FGF14 have responded well to this treatment.
“This opens the door to a clinical trial of this drug in these patients,” said Dr. Brais. “It’s great news for patients in Canada and worldwide. It also makes genetic testing possible so people and families can arrive at the end of their long diagnostic journey.”
Finnish Study Finds Hundreds of Novel Genes
Results from the FinnGen research study, published recently in Nature, include previously unknown genetic risk factors for many debilitating diseases, potentially facilitating the development of new therapies. The FinnGen flagship study describes results based on 224,737 Finnish biobank participants. After performing comprehensive genetic analyses for more than 1,900 diseases, the researchers identify almost 2,500 genomic regions that are linked with at least one of these diseases.
“Even with less than half of the recruited 500,000 participants analyzed at this stage, this snapshot of results describes a wealth of important genetic discoveries emerging from FinnGen, including novel risk and protective variants for both common and rare diseases,” said FinnGen Scientific Director Aarno Palotie from the Institute for Molecular Medicine Finland (FIMM), University of Helsinki.
The study authors compare the FinnGen results with earlier genetic findings for 15 previously well-studied common diseases, such as type 2 diabetes, asthma, and Alzheimer’s disease. In addition to verifying the validity of register data, the researchers show that identification of novel risk variants in FinnGen is possible with a much smaller number of patients compared with the largest published disease-specific genetic studies.
“The Finnish health registers, containing health and medication data throughout an individual’s lifetime, allowed us to rapidly and accurately identify disease cases. This accurate phenotyping, coupled with Finnish population history, is a very powerful combination for novel genetic discoveries in a wide variety of diseases,” said Mitja Kurki, the first author of the study from the Broad Institute of MIT and Harvard and the University of Helsinki.
Among these variants, the researchers highlight 29 that are located in genes not previously linked to any disease. One example is a variant in a gene called TNRC18 that predisposes to inflammatory bowel disease and other inflammatory conditions. Other examples include variants increasing the risk of hypothyroidism, hearing loss, or endometriosis and variants that offer protection from arthrosis, glaucoma, or heart disease.
“These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through variants that are rather rare but have a strong biological impact,” said Mark Daly, director of FIMM at the University of Helsinki.
A limitation of the study is that it was retrospective and observational and does not prove cause and effect. It only suggests an association. The study also did not include people taking the MS drugs siponimod, cladribine, ocrelizumab, ofatumumab, or rituximab.
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