Cleveland Clinic Cancer Center unites more than 450 highly skilled physicians, researchers, nurses and technicians to care for thousands of patients each year. Programs with multi-specialty teams working together to drive innovation through research, provide options and maximize rapid access for our patients. Cleveland Clinic Cancer Center unites clinicians and researchers in Taussig Cancer Institute and in Cleveland Clinic’s 26 other clinical and surgical institutes, as well as cancer specialists at our regional hospitals, health centers and at Cleveland Clinic Florida.
Dr. Alok Khorana, a co-PI of the Cleveland Clinic program, developed the Khorana score in 20018. Since its introduction, the Khorana Score has helped clinicians worldwide calculate the risk of venous thromboembolism for an individual cancer patient. He has recently led an international study focused on the use of direct oral anticoagulants to prevent blood clots in patients with cancer initiating chemotherapy.
The Khorana Score uses readily available clinical information including the type of cancer, the complete blood count and the patient’s body mass index. Part of its advantage lies in its ease of use.
Dr. Keith McCrae, the other co-PI of the Cleveland Clinic program, is a hematologist with expertise in thrombosis and vascular biology. Dr. Khorana, McCrae and their collaborators are currently studying whether it is possible to identify new biomarkers that add precision to the previously-developed Khorana score, thus allowing prophylactic anticoagulation to be better targeted to cancer patients at highest risk for the development of blood clots.
The Cleveland Clinic group is also studying epigenetics biomarkers of thrombosis in cancer patients, including small circulating RNAs
Keith McCrae, M.D.
Alok Khorana, M.D.
Jane Freedman, M.D.
Specific Aims of the Cleveland Clinic Program
Venous thromboembolism (VTE) is an important cause of morbidity and mortality in patients with cancer. Approximately 20% of patients with cancer develop, and 10% die, from VTE. However, the risk of VTE in cancer is highly variable. Identifying high-risk patients is important to optimize benefit from thromboprophylaxis, but solitary risk factors have not proven to be useful VTE predictors. A clinical scoring system developed by one of the PIs of this application (“Khorana score”) combines five clinical variables to segregate patients into high, intermediate, or low risk groups, and is the most widely used system for predicting VTE in cancer. The risk of VTE in the low-risk group is < 1%, however only 18% of patients in the high-risk group develop VTE; thus, the positive predictive value is low. Moreover, most patients fall into an intermediate-risk group for which improved risk prediction is needed. Several hemostatic biomarkers, including circulating tissue factor (TF), D-dimer, and P-selectin have been assessed for their ability to predict VTE, but found to have limited utility. New and innovative biomarkers are therefore urgently needed.
In this program, we propose a two-phase study to define novel biomarkers of cancer-associated VTE. We first propose a discovery phase to identify novel candidate biomarkers. This encompasses Aim 1, which examines biomarkers of contact and complement activation, and Aim 2, which examines circulating plasma/exosome microRNA profiles. Emerging data has linked the contact activation system (CAS), which consists of FXII, prekallikrein and kininogen and leads to activation of FXI and the intrinsic coagulation pathway, to pathologic thrombosis; however, the role of the CAS in cancer-associated thrombosis (CAT) has not been studied. Our compelling preliminary data indicates the importance of this system, and we have developed an array of novel assays of CAS activity.
Aim 1, We will prospectively assess the predictive value of these assays in three large cohorts of patients with pancreas, lung, and colorectal cancers. Complement is also activated by the CAS, is linked to thrombosis in hematologic disorders, and our preliminary studies demonstrate that C3a and C5a are associated with outcomes in pancreatic cancer; thus, we will further evaluate these biomarkers as well.
Aim 2, We will explore another emerging area of biomarker research- circulating microRNA (miRNA). We hypothesize that plasma from cancer patients at greatest risk of VTE contains increased levels of specific miRNAs, or unique miRNA profiles, and our preliminary studies have identified six plasma miRNAs associated with VTE in cancer.
Aim 3, In the second, validation phase of our proposal, will validate candidate biomarkers discovered in Aims 1 and 2 using plasma samples from an independent 700 patient cohort of cancer patients obtained from 3 large, multinational studies. We will incorporate this data into a new VTE prediction model using risk modeling strategies. Our proposed studies are highly responsive to RFAHL-18-021, and will lead to novel biomarkers and improved risk stratification strategies to predict and prevent VTE in cancer.
Specific Aims of the University of Massachusetts Medical School Program
UMass Medical School is home to some of the world’s preeminent researchers who are working together to seek, identify and develop solutions to a variety of diseases. Founded in 1962, it is consistently ranked by U.S. News and World Report as one of the leading medical schools in the country. The School of Medicine is committed to training students with an emphasis in the primary care specialties. UMMS is a world-class research institution which has produced many noteworthy advances in both clinical and basic research.
The major research initiatives in Dr. Freedman’s laboratory emphasize the regulation of pathways contributing to atherothrombotic disease and how these factors contribute to acute coronary syndromes. Dr. Freedman’s lab is focused on two research programs; the first is a basic science laboratory that examines the role of immunity, infection, and inflammation on atherothrombotic disease. The second facility uses high-throughput, nano-chip, proteomic and RNAseq technologies to study gene and protein expression providing translational data for a wide range of projects and has measured gene expression in thousands of clinical and biological samples for dozens of studies.
The National Heart, Lung and Blood Institute (NHLBI), part of the National Institutes of Health, awarded a $4.7 million grant to Cleveland Clinic to study the prevention of life-threatening, cancer-associated blood clots. This funding will support a Cleveland
The study will incorporate data from more than 5,000 patients with colorectal, lung and pancreatic cancer enrolled in clinical trials enrolled at various research centers. Researchers will use this robust biobank to identify coagulation-related and genetic biomarkers associated with abnormal blood clotting. They will build on research that suggests that activation of a specific blood-clotting pathway may contribute to
The team ultimately plans to synthesize this data to develop a comprehensive risk calculator by incorporating the identified biomarkers and statistical modeling. The online risk assessment tool would be available for clinical use. The new grant builds upon important work initiated through Cleveland Clinic’s Center of Excellence in Cancer Thrombosis Research, which focuses on novel approached