CAD

Researchers have discovered a key mechanism used by Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), to induce cancer. The research points to effective new treatment options for KSHV-associated cancers, including Kaposi's sarcoma, primary effusion lymphoma, and HHV8-associated multicentric Castleman disease. Cleveland Clinic researchers have discovered a key mechanism used by Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), to induce cancer. The research points to effective new treatment options for KSHV-associated cancers, including Kaposi's sarcoma, primary effusion lymphoma, and HHV8-associated multicentric Castleman disease. "Our findings have significant implications: viruses cause between 10% to 20% of cancers worldwide, a number that is constantly increasing as new discoveries are made. Treating virus-induced cancers with standard cancer therapies can help shrink tumors that are already there, but it doesn't fix the underlying problem of the virus," said Jun Zhao, Ph.D., of Cleveland Clinic Florida Research & Innovation Center. "Understanding how pathogens transform a healthy cell into a cancer cell uncovers exploitable vulnerabilities and allows us to make and repurpose existing drugs that can effectively treat virus-associated malignancies." The Nature Communicationsstudy, led by Dr. Zhao, reveals that KSHV manipulates two human enzymes called CDK6 and CAD to reshape the way human cells produce new nucleotides -- the building blocks of DNA and RNA -- and process glucose. The changes to how infected cells grow and how KSHV persists put cells at a much higher risk of forming tumors and play a crucial role in causing cancer. The team showed the virus activates a specific pathway driving cell metabolism and proliferation. Inhibiting this process with existing FDA-approved breast cancer drugs reduced KSHV replication, blocked lymphoma progression and shrunk existing tumors in preclinical models. Like other herpesviruses, KSHV often has no symptoms initially and remains in the body after primary infection. The virus stays dormant, suppressed by the immune system. However, KSHV can reactivate when immunity is weakened -- as in older people, those with HIV/AIDS, and transplant recipients. In these high-risk groups, the now active virus can trigger aggressive cancers. KSHV-induced cancers are fast-acting, aggressive and difficult to treat. An estimated 10% of people in North America and Northern Europe have KSHV, but this ranges throughout the globe. More than 50% of individuals in parts of Northen Africa are estimated to have the virus. Experts estimate these rates are higher, as KSHV often goes undiagnosed because of lack of symptoms. These findings have implications that reach past KSHV; researchers can apply knowledge about KSHV to other cancer-associated viruses that might use the same process to cause cancer. To understand the cells' metabolic processes to uncover the virus's vulnerabilities, Dr. Zhao collaborated with Michaela Gack, Ph.D., Scientific Director of the Florida Research & Innovation Center. Rapidly replicating cancer cells reprogram metabolism to fuel growth. Meanwhile, most viruses cannot produce energy or necessary molecules on their own, so they rely on human cells to do the work for them. The team found that the virus takes over the host protein CDK6 and CAD, causing the infected cells to produce extra metabolites, which allows faster replication of the virus and an uncontrolled proliferation of the cells. The research team treated pre-clinical models with a CDK6-blocking drug, Palbociclib, an FDA-approved breast cancer medication, as well as a compound targeting CAD. They saw significant decreases in tumor size and increases in cancer survival rates: most tumors virtually disappeared after about a month of treatment, and remaining tumors shrank around 80%. Survival increased to 100% for selected lymphoma cell lines. Dr. Zhao and his team are working to better understand the connections among KSHV, CDK6/CAD pathway, and cancer formation. With the knowledge they obtain, they plan to implement and refine their experimental drug combinations for clinical trials. "Cellular metabolism could be hijacked by both viruses and cancers for pathogenesis," said Dr. Zhao. "By investigating these metabolic rewiring mechanisms, we aim to find the Achilles' heel of cancer-causing viruses and non-viral cancers. I'm excited to see what the future of this work holds."

Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers led by investigators from Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, in collaboration with the Broad Institute of MIT and Harvard and Stanford Medicine, combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. In a study published in Nature, the researchers applied this technique to endothelial cells, which line blood vessels. The team found that a key biological mechanism involved in a rare vascular disease may influence CAD risk. "Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process," said corresponding author Rajat Gupta, MD, of the Divisions of Genetics and Cardiovascular Medicine at Brigham and Women's Hospital. "We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function." The mapping technique developed by the researchers is called the Variant-to-Gene-to-Program (V2G2P) approach. First, in collaboration with researchers at Stanford Medicine, the researchers matched CAD loci previously identified through genome-wide association studies to genes impacted by these genetic variants. Then, they used CRISPRi-Perturb-seq, a technology developed at the Broad Institute of MIT and Harvard, to "delete" thousands of CAD-associated genes, one at a time, and to examine how each deletion impacted the expression of all the other genes in that cell. In total, the researchers sequenced 215,000 endothelial cells to determine how 2,300 "deletions" influenced expression of 20,000 other genes in each cell. With applied machine learning algorithms, they were able to identify the biological mechanisms that consistently appeared to be related to CAD-associated variants. In particular, the researchers found that 43 of 306 of the CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway. CCM is a rare, devasting vascular disease that impacts the brain, but the researchers hypothesized that smaller, subtler mutations in the genes involved in CCM may contribute to CAD risk by affecting vascular inflammation, thrombosis, and the structural integrity of the endothelium. Moreover, the researchers highlighted a previously unrecognized role for the TLNRD1 gene in regulating the CCM pathway alongside other known CCM regulators and hypothesized that TLNRD1 may be involved in both CAD, a common disease, and CCM, a rare one. Going forward, the researchers hope to study patients with endothelial CAD-associated variants as well as CCM patients to determine whether there are distinct opportunities for treating these populations. For the latter, the researchers are interested in determining whether further investigation into TLNRD1 can lead to better forms of genetic testing and risk stratification. This study focused on endothelial cells, which line blood vessels and are increasingly understood to influence CAD risk. It examined endothelial mechanisms unrelated to lipid metabolism (a known driver of CAD risk with effective therapies, like statins) in hopes of uncovering other mechanisms driving CAD risk for which therapies may yet be developed. "Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using," Gupta said. "We are also focused on this study's implications for CCM patients. It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease, CCM. Perhaps now we can better describe the risk factors and pathways that drive it." Beyond CAD and CCM, the researchers emphasize that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell-type relevant to that disease can be genetically modified in the lab. "It was remarkable that this unbiased, systematic approach? -- in which we deleted all candidate CAD genes in a single experiment? -- pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered," said co-corresponding author Jesse Engreitz, PhD, assistant professor of genetics at Stanford Medicine.