Director of the Vascular Biology Program
Boston Children's Hospital
Julia Dyckman Andrus Professor of Surgery
Harvard Medical School
In order for a small breast tumor to establish itself, grow and metastasize, it must recruit its own blood vessels via the process called angiogenesis. In the absence of this blood supply, a tumor will remain dormant, existing as a tiny lesion of only a few millimeters in diameter, often clinically undetected and doing no harm—essentially “cancer without disease.” This state is recapitulated during metastasis at distant sites in the body as well. However, under the influence of certain genes and the proteins they encode, this dormant tumor can escape the dormant state to become an active, growing one.
Dr. Moses’s goal is to identify, validate and target these genes and their proteins with the aim of treating these early breast cancer lesions before they become harmful. Her team is also working to identify non-invasive breast cancer biomarkers that appear at this early stage of tumor development with the goal of developing these markers into early breast cancer diagnostics. They have identified a number of very interesting genes that are either upregulated or downregulated as these tiny dormant tumors become active. During the last funding period, Dr. Moses has reported that one of the proteins encoded by these differentially expressed genes, called ZNF24, can potently inhibit the new vasculature induced by human breast cancer cells in vivo. Moreover, the researchers have shown that it works by suppressing a powerful blood vessel stimulator and that it does so by binding to the promoter of this angiogenic stimulator. They have now initiated studies to determine whether the manipulation of ZNF24 can block the escape from tumor dormancy in laboratory models. They have also identified the binding site on the promoter of the target stimulator and have used it as a “molecular decoy” to block the suppression of blood vessel development. This decoy may have therapeutic value in instances where the promotion of angiogenesis would be required. Interestingly, they have recently discovered that, under certain physiological conditions, ZNF24 itself may be a direct regulator of capillary endothelial cell migration and invasion as well. Dr. Moses’s team is currently working to understand the mechanism by which ZNF24 is exerting this effect under these conditions as well as to determine the potentially novel downstream targets of ZNF24.
In order for a small breast tumor to establish itself, grow and metastasize, it must recruit its own blood vessels via the process called angiogenesis. In the absence of this blood supply, a tumor will remain dormant. This state is recapitulated in metastasis at distant sites in the body as well. However, under the influence of certain genes and the proteins they encode, this dormant tumor can escape the dormant state to become an active, growing one. The goal of the Moses team is to identify, validate and target these genes and their proteins with the aim of treating these early breast cancer lesions before they become harmful. They have previously identified one of these genes, a novel regulator of the escape from breast tumor dormancy, called ZNF24. They have also reported the mechanism by which this regulator controls the production of vascular endothelial growth factor (VEGF), a key regulator of the new vessel growth that is required for human tumors to grow and progress. During the last funding period, they have shown that ZNF24 may be playing an essential role in modulating the angiogenic potential of capillary endothelial cells by directly regulating their growth and ability to migrate. They have also made significant progress in studying the relationship between dietary cholesterol, new capillary growth and breast cancer in tightly-controlled laboratory models. They have shown that a major biological effect of hypercholesterolemia on breast tumors is increased new capillary growth. In addition, the researchers have found that this regulation of angiogenesis in breast cancer may be more complex than that of prostate and other cancers and appears to require different regulators of new capillary growth. Since their prior progress report, they have developed a novel potential mechanism of cholesterol-mediated breast tumor development and progression based on these findings and they will be validating this proposed mechanism in future studies.
Dr. Marsha A. Moses is the Julia Dyckman Andrus Professor at Harvard Medical School and the Director of the Vascular Biology Program at Children's Hospital Boston. She received a doctorate in Biochemistry from Boston University and completed a National Institutes of Health postdoctoral fellowship at Children's Hospital Boston/Harvard Medical School and Massachusetts Institute of Technology (MIT). Dr. Moses is the recipient of a number of awards and honors and was elected to the Institute of Medicine of the National Academies of the United States in 2008 and to the National Academy of Inventors in 2013. A prolific inventor, she holds approximately 75 patents, issued and pending.
The Moses Laboratory has had a long-standing interest in identifying and characterizing the biochemical and molecular mechanisms underlying the regulation of angiogenesis during tumor progression, from the angiogenic switch through metastasis. In the course of these studies, Dr. Moses and her group have discovered a number of angiogenesis inhibitors that are undergoing pre-clinical development. Significant efforts are now underway in the lab to identify the genes and proteins that are responsible for the ""angiogenic switch."" This critical checkpoint, during which time a tiny benign, avascular tumor acquires the vascular phenotype, is a prerequisite for subsequent tumor growth and progression. The Moses Lab has recently identified and validated a number of genes which are differentially expressed during the angiogenic switch and is currently developing molecular and biochemical interventions to prevent the switch from occurring by targeting some of these genes.
Dr. Moses is also a pioneer in the field of ""biomarker medicine."" Some years ago, she established a proteomics initiative in her laboratory that has now led to the discovery and validation of a panel of non-invasive cancer biomarkers that predict disease status and stage in cancer patients. These sensitive and specific markers have the potential to be used to monitor disease progression and therapeutic efficacy of cancer drugs. A number of these urine tests are currently commercially available.