Marsha A. Moses, PhD

2009-2010 BCRF Project:
(made possible by generous support from Clinique)
Laboratory of the late Judah Folkman, MD

Dr. Moses and her colleagues in the Vascular Biology Program at Children's Hospital, headed by Dr. Judah Folkman until his death in January 2008, will carry on research he began. During the past year, they have continued studies focused on the identification and clinical exploitation of the mechanisms regulating tumor dormancy in breast cancer.

1. One of their continuing goals is to determine how BRCA1 may directly or indirectly interact with p53 to regulate breast cancer angiogenesis. Their studies have investigated the cross-talk between the breast cancer susceptibility gene BRCA-1 and the tumor suppressor p53 to determine whether dysregulation of endogenous angiogenesis inhibitors as a consequence of BRCA-1 loss of function was mediated through p53. Their recent data suggest that BRCA-1's regulation of endogenous angiogenesis inhibitors is independent of p53.

2. Their recent studies on the role of HSP27 in angiogenesis and tumor growth have demonstrated that the reversal of the angiogenic phenotype in human breast cancer to a non-lethal, dormant, microscopic disease can be achieved by targeting HSP27. The researchers are currently conducting transcriptional profiling studies to pursue the regulators that are functioning at the transcriptional level to regulate the angiogenic switch mediated by HSP27.

3. In studies focused on the identification and validation of non-invasive biomarkers for breast cancer, they have identified approximately 60 proteins that are unique to healthy, age-matched control urine samples, approximately 40 proteins that are uniquely found in the samples from patients with LCIS and approximately 60 proteins that are present only in urine from patients diagnosed with metastatic breast cancer. These proteins may represent a biomarker fingerprint that may be unique to breast cancer status and stage. Using a bioinformatics approach, they have now prioritized the proteins within each cohort and are currently validating these mass spectrometry results.

In the coming year, the scientists will continue their studies to: (i) Determine whether knock-down of BRCA-1 expression directly effects TSP-1 levels. (i) Determine the mechanism(s) by which the downregulation of HSP27 may suppress the angiogenic switch in breast cancer. (ii) Discover non-invasive breast cancer biomarkers of early breast cancer and validate their importance as potential biomarkers of early breast cancer, its progression and its recurrence.

Mid-Year Progress Report:
Angiogenesis is the process of new capillary formation from pre-existing blood vessels. It is required for tumor growth and progression. Dr. Moses's work focuses on identifying and characterizing the mechanisms underlying one of the earliest events in breast cancer progression, the angiogenic switch. The angiogenic switch is that stage in a tumor's growth at which it acquires a blood supply that, in turn, provides that tumor with a critical survival advantage. It has been demonstrated that tumors remain dormant, tiny and harmless, in the absence of angiogenesis and that the acquisition of this new vasculature signals the end of the dormancy period. Dr. Moses and colleagues have developed a number of novel laboratory models that recapitulate the switch to the angiogenic phenotype in human breast cancer and are utilizing these models to identify the genes and proteins that regulate the angiogenic switch. They are working to determine how these genes and proteins function and are developing ways to manipulate them in order to maintain tumor dormancy. They are also using these in vivo models to identify and validate urinary biomarkers that can detect the switch from dormancy to an actively growing cancer with the goal of developing non-invasive urine tests for early breast cancer.

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 being tested in clinical trials, both locally and nationally.