ACTA2

In collaboration with leading cancer centers, research results to be presented from seven studies across a breadth of tumor types and genomic alterations demonstrating Caris' impact on precision medicine IRVING, Texas, Oct. 17, 2023 /PRNewswire/ -- Caris Life Sciences®(Caris), the leading next-generation AI TechBio company and precision medicine pioneer that is actively developing and delivering innovative solutions to revolutionize healthcare and improve the human condition using molecular science and AI, today announced that the company and collaborators within the Caris Precision Oncology Alliance™ (POA) will collectively present seven studies across a breadth of tumor types at the European Society for Medical Oncology (ESMO) Congress 2023 in Madrid, Spain from October 20-24, 2023 (Booth #513). The findings demonstrate the power of Caris' comprehensive clinico-genomic database that enable novel insights into cancer that could have profound effects on a patient's diagnosis, prognosis, care plan and response to treatment. Continue Reading "The research being presented at this year's ESMO Congress is a testament to Caris' continued commitment to data-driven molecular innovation and large-scale collaboration to answer some of the pressing questions in precision oncology today," said Chadi Nabhan, M.D., MBA, FACP, Chairman of the Caris POA. "The findings of these studies illustrate the power of comprehensive molecular profiling to identify underlying tumor biology setting the stage for therapeutics that improve patient outcomes. Alongside our POA partners, we are pioneering new approaches to help deliver the right treatments to the right patients at the right time." Research results to be presented demonstrate Caris Life Sciences' impact on precision medicine Tweet this "More than ever before, our comprehensive molecular profiling coupled with rich clinical data is enabling Caris to help clinicians make the best treatment choices, researchers to discover novel cancer biology, and the biopharmaceutical industry to develop the next breakthrough medicines," said George W. Sledge, Jr., M.D., Executive Vice President and Chief Medical Officer of Caris. "Data presented at this year's ESMO Congress highlight not only our efforts to achieve these goals but also the value of Caris' comprehensive approach to molecular profiling, built on our extensive data, to better understand the biological hallmarks of cancers and ultimately improve outcomes for all cancer patients." Data to be presented by Caris and the POA include the results of a molecular analysis of more than 278,000 tumors that indicate potential new therapeutic opportunities in gastrointestinal cancers. Other notable topics explored in these abstracts include a real-world data analysis of gene expression and outcomes in breast cancer, exploration of the tumor-immune microenvironment in lung cancer, and genomic and immune profiling of patients with a rare and aggressive form of eye cancer: Therapeutic opportunities for Porcupine inhibition in Gastrointestinal cancer (Abstract Number: 222P) October 21, 2023 An Analysis of Proviral Insertion Site of Moloney Murine Leukemia Virus 1 Kinase Expression (PIM1) and Clinical Outcomes in Advanced Breast Cancer (ABC) (Abstract Number: 494P) October 21, 2023 Multi-omics evaluation of TFE3-fusions and potential association with immuno-metabolic vulnerabilities in alveolar soft part sarcoma (ASPS) and translocation-positive renal cell carcinoma (tRCC) (Abstract Number: 2281P) October 21, 2023 Landscape of Delta-like-ligand 3 (DLL3) expression across neuroendocrine neoplasms (NENs) (Abstract Number: 1188P) October 22, 2023 Chemokine expression in uveal melanoma and association with tumor genetics and response to immunotherapy (Abstract Number: 1132P) October 22, 2023 STAT3, ACTA2, and SPARC stromal markers predict response to Gemcitabine/Cisplatin/Nab-paclitaxel (GCN) in patients with advanced pancreatic adenocarcinoma (aPDAC) (Abstract Number: 1645P) October 23, 2023 Tumor-immune microenvironment analysis of de novo and acquired KRAS-mutated non-small cell lung cancer (Abstract Number: 1399P) October 23, 2023 Abstract summaries of this research will be available onsite at Caris' booth #513. The full abstracts are available through the official ESMO website. The POA includes 89 cancer centers, academic institutions, research consortia and healthcare systems. These institutions have early access to the extensive database and artificial intelligence platform within Caris to establish evidence-based standards for cancer profiling and molecular testing in oncology. By leveraging the comprehensive genomic, transcriptomic and proteomic profiling available through Caris molecular profiling, Caris seeks to provide this network with the ability to prioritize therapeutic options and determine which clinical trial opportunities may benefit their patients. POA members are also able to integrate with a growing portfolio of biomarker-directed trials sponsored by biopharma. Additionally, POA member institutions have access to the most comprehensive clinico-genomic database in the industry, which includes matched molecular and clinical outcomes data from hundreds of thousands of cancer patients, covering over 1 million data points per patient. About Caris Life Sciences Caris Life Sciences® (Caris) is the leading next-generation AI TechBio company and precision medicine pioneer that is actively developing and delivering innovative solutions to revolutionize healthcare and improve the human condition using molecular science and AI. Through comprehensive molecular profiling (Whole Exome and Whole Transcriptome Sequencing) and the application of advanced AI and machine learning algorithms, Caris has created the large-scale, clinico-genomic database and computing capability needed to analyze and unravel the molecular complexity of disease. This convergence of sequencing power, big data and AI technologies provides an unmatched platform to deliver the next-generation of precision medicine tools for early detection, diagnosis, monitoring, therapy selection and drug development. Headquartered in Irving, Texas, Caris has offices in Phoenix, New York, Tokyo, Japan and Basel, Switzerland. Caris or its distributor partners provide services in the U.S., Europe, Asia and other international markets. To learn more, please visit CarisLifeSciences.com. Caris Life Sciences Media Contact: Lisa Burgner [email protected] 214.294.5606 SOURCE Caris Life Sciences

A novel molecular pathway to explain how a mutation in the gene ACTA2 can cause individuals in their 30s -- with normal cholesterol levels and no other risk factors -- to develop coronary artery disease has now been identified,. A novel molecular pathway to explain how a mutation in the gene ACTA2 can cause individuals in their 30s -- with normal cholesterol levels and no other risk factors -- to develop coronary artery disease has been identified, according to researchers with UTHealth Houston. The study was published in the European Heart Journal. "The gene ACTA2 codes a specific protein that has nothing to do with cholesterol," said Dianna Milewicz, MD, PhD, senior author of the study and professor and director of the Division of Medical Genetics at McGovern Medical School at UTHealth Houston. "It was a surprise to find that people with the gene mutation had too much atherosclerosis at a young age and with no risk factors." A 2009 study led by Milewicz found that a number of mutations in ACTA2 predispose humans to develop early onset (30s or younger) coronary artery disease. Atherosclerosis is a buildup of fats, cholesterol, and other substances in and on the artery walls. It can develop over time and most people don't know they have it until they suffer a heart attack or stroke. Traditional risk factors for developing atherosclerosis include high cholesterol, high blood pressure, diabetes, smoking, obesity, lack of exercise, and consuming a high-fat diet. ACTA2 is typically found in the smooth muscle cells, which line the arteries and allow the arteries to contract to control blood pressure and flow. Milewicz and her team found that protein coded by this gene is not folded correctly because of the mutation, and it triggers stress in the smooth muscle cell, which then forces the cell to make more cholesterol internally, regardless of the levels of cholesterol in the blood, driving atherosclerotic plaque formation. "This finding is unique in that we found a completely new pathway to atherosclerosis. It explains why for years we have known statins protect people from heart attacks, even those people whose blood cholesterol levels are normal. In the people with ACTA2 mutations, the statins block the cholesterol made by the stressed smooth muscle cells," said Milewicz, the President George Bush Chair in Cardiovascular Medicine with McGovern Medical School. "In our study, the mutant protein made by the ACTA2 mutation caused the cells in the artery wall to be stressed, but there are many other factors that can stress cells. We are now working on the risk factors for coronary artery disease, like hypertension, that would also stress the cells and activate this novel pathway for coronary artery disease." One of the results of stress in smooth muscle cells associated with atherosclerosis is the deposition of calcium in the arteries. "Cardiac calcium imaging in individuals with ACTA2 mutations could be a useful early diagnostic tool to monitor the development of the early atherosclerosis in these people. This would allow physicians to decide at what age to start these patients on statins," Milewicz said. Using a genetically engineered mouse that contains a particular ACTA2 mutation and feeding the mice a diet rich in cholesterol, the researchers induced atherosclerosis and found that these mice have much more atherosclerosis than similarly treated mice normal mice. The study also found that the increased atherosclerosis could be reversed by treating the mice with pravastatin, a member of the statin group of drugs commonly prescribed to lower blood cholesterol. The researchers confirmed that same molecular pathway is activated in smooth muscles cells isolated from a human patient with an ACTA2 mutation. Statins prevent coronary artery disease by lowering the levels of cholesterol in the blood. At the same time, more than half of heart attacks occur in apparently healthy men and women with average or low levels of plasma LDL-cholesterol. Statins also reduce heart attack events in people with normal cholesterol levels. This work was supported by the National Heart, Lung, and Blood Institute (RO1 HL146583); an America Heart Association Merit Award, NIH T32GM120011; Marfan Foundation McKusick Fellowship Award; and American Heart Association Grant 20CDA35310689. Lipid pro was performed at the Mouse Metabolism and Phenotypic Core at Baylor College of Medicine, funded by NIH RO1DK114356 and UM1HG006348. Single cell RNA sequencing was performed at the Single Cell Genomics Core at Baylor College of Medicine, funded by National Institutes of Health shared instrument grants S10OD023469, S10OD025240 and P30EY002520. Additional UTHealth Houston authors include Kaveeta Kaw, MD, PhD; Abhijnan Chattopadhyay, PhD; Pujun Guan, MM; Jiyuan Chen, PhD; Suravi Majumder, PhD; Xue-yan Duan, PhD, and Callie S. Kwartler, PhD. Other authors include Shuangtao Ma, MD, MSc, with Michigan State University College of Human Medicine (a former postdoctoral fellow at UTHealth Houston) and Chen Zhang, MD, with Baylor College of Medicine.

Using whole genome sequencing, researchers identified a single variant in a microRNA gene, MIR145-5p, as the source of multisystemic smooth muscle dysfunction syndrome, which had gone undiagnosed in a child for years. A team of investigators from Massachusetts General Hospital (MGH), a founding member of Mass General Brigham (MGB) and Mass General for Children (MGfC) has identified -- for the first time -- the mutation in a single non-coding gene of a young patient responsible for the extremely rare disease known as multisystemic smooth muscle dysfunction syndrome (MSMDS), which causes profound cerebrovascular, gastrointestinal and urologic impairment. For the child's family, the discovery helped unravel the mystery of a condition that had afflicted their son since birth and will now enable physicians to initiate treatment to lessen the risk of future strokes. The team's findings were reported in The Journal of Clinical Investigation. "Thousands of other families live with the burden of children with undiagnosed diseases whose lives could be significantly changed with the help of the latest research and technologies to shed light on what are often hereditary disorders," says senior author Patricia Musolino, MD, PhD, a critical care and vascular neurologist at MGH and a globally recognized authority in MSMDS. "The child we evaluated had been to five other hospitals before Mass General, which is part of the Harvard Clinical Site of the Undiagnosed Diseases Network(UDN) study, funded by the National Institutes of Health. Without that specialized team of experts under one roof, it would have been impossible to arrive at the diagnosis we did for this child." Past research has shown a mutation in the coding gene ACTA2 to be commonly associated with multisystemic smooth muscle dysfunction syndrome, which prevents smooth muscle throughout the body from contracting and working properly. In the case of the young MGH patient, the disease was characterized by multiple strokes beginning at age three, along with severe bowel, bladder and feeding issues. Standard genetic testing did not detect a mutation in the ACTA2 gene as the source of the problem. MGH's Undiagnosed Diseases Network team was the first to put all the clinical pieces together. Co-authors David Sweetser, MD, PhD, and Lauren Briere, MS, CGC, narrowed the search to a single nucleotide variant in the gene MIR145, a microRNA gene. The team followed up with a detailed molecular analysis which confirmed that the variant affects the expression of several cytoskeletal proteins and smooth muscle cell function. The genetic breakthrough represents only the sixth recorded monogenetic disorder (resulting from the dysfunction of a single gene) attributed to the microRNA (miRNA) class of genes. "Despite major advances in genetic testing that now allow us to routinely sequence the entire genome, large numbers of patients with suspected genetic disorders still remain undiagnosed," notes Sweetser. "One reason for this might be that practically all genetic testing performed today focuses on protein coding genes. The UDN has allowed us to delve much deeper, beyond standard clinical testing. "The finding of disease-causing mutations in regulatory non-protein encoding genes, such as this microRNA, opens up a new frontier in our search for answers that can impact patient care." "As it turns out, the patient's MIR145 variant actually causes the same cellular changes that result from the well-described MSMDS-causing ACTA2 variants," says Briere. "That finding meant we were able to identify for the first time a second gene that interacts with ACTA2 to influence smooth muscle behavior," adds co-author Mark Lindsay, MD, PhD, an MGfC cardiologist. "More important, though, is the impact it may have on the MGH patient, whose condition had baffled clinicians for so long," adds Lindsay. "The hopeful message from this case is that advanced genetic research can change the course of a disease not just for one family, but potentially for others faced with the same debilitating condition," says Musolino. "But that will only happen if the Undiagnosed Diseases Network, which Mass General is fortunate enough to be part of, is able to significantly expand its research through NIH funding." Musolino is co-director of Pediatric Stroke and Cerebrovascular Service, MGfC, and assistant professor of Neurology at Harvard Medical School (HMS). Lindsay is assistant professor of Medicine, HMS. Lead author Christian Lacks Lino Cardenas, PhD, is an instructor in Medicine at the Cardiovascular Research Center, Mass General Research Institute. Co-lead author Briere is a genetic counselor at MGH, working on the UDN study. Sweetser is a medical geneticist, lead principal investigator of the UDN at MGH, and chief of Medical Genetics and Metabolism at MGH and MGfC The study was funded by the National Institutes of Health through the Undiagnosed Diseases Network and the Caitlin and Rich Hill Family Fund for Undiagnosed Diseases at MGH.