Marsha A. Moses, PhD

2012-2013 BCRF Project:
(made possible by generous support from Clinique)
Laboratory of the late Judah Folkman, MD

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 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 Dr. Moses's research 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 ultra-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. Their work during the past funding period has focused on two of these potential early breast tumor regulators. Dr. Moses has now shown that, in addition to their previous studies in zebrafish, one of these proteins, called ZNF24, is also capable of suppressing angiogenesis and subsequent human breast tumor growth in a laboratory model by inhibiting the stimulation of angiogenesis. They have also now identified the mechanism by which it exerts this effect. This is a completely novel finding that provides the important opportunity to target ZNF24 as a potential breast cancer therapeutic. Dr. Moses's team has also begun to study a second novel regulator of breast cancer growth and metastasis, which they recently found, can induce new blood vessel formation in early human breast tumors as well as primary tumor growth and metastasis.

Mid-year Progress: The goal of Dr. Moses's research is to identify, validate and target these genes and their proteins with the aim of treating early breast cancer lesions before they become harmful. During the last six months, they have published two new studies in which BCRF support was acknowledged. In the first of these studies, Dr. Moses's team demonstrated that ZNF24 represses VEGF transcription through direct binding to an 11 bp fragment of the VEGF proximal promoter. Moreover, they showed for the first time that this transcription factor can function as a negative regulator of tumor growth by inhibiting tumor angiogenesis in vivo. During this last funding period, not only was their study accepted for publication, the team was thrilled to learn that it would be the cover feature of the journal Blood.

Dr. Moses's group was also the first to demonstrate that lipocalin 2 (Lcn2) regulates breast cancer angiogenesis. They showed that this protein is a potent stimulator of angiogenesis in vitro and in vivo and suggested a novel mechanism through which Lcn2 may promote breast tumor progression. This study was submitted for publication during this last funding period and appeared in the Journal of the Federation of American Societies for Experimental Biology.

Bio:
Marsha A. Moses, PhD 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 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. A prolific inventor, she holds approximately 70 patents, issued and pending, serves on a number of advisory boards and is a scientific founder of Predictive Biosciences, Inc., a molecular diagnostics company.

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.