Michael Andreeff, MD, PhD

2012-2013 BCRF Project:
Breast cancer stem cells, which are but a fraction of cells present in primary tumors, are metastatic, drug resistant, and able to cause secondary tumors. Because of their importance as therapeutic targets, efforts to distinguish these cells from the other tumor cells have recently intensified.

Isolating breast cancer stem cells for study remains a challenge, as well as identifying specific antigens, substance produced by tumor cells, for use as potential drug targets. However, recent studies reveal that breast cancer stem cells seem to contain a high level of the CD44 glycoprotein but low levels of the CD24 glycoprotein. Dr. Andreeff's team identified GD2 as a novel marker of breast cancer stem cells. Their recent data suggest that GD2 is exclusively expressed in breast cancer cell lines and primary tumor of patients. Cells with GD2 seem to possess higher tumor forming ability than those breast cancer cells without.

In addition, gene expression analysis revealed that an enzyme responsible for synthesis of GD2, called GD3 synthase (GD3S), is highly expressed in cells with GD2 compared to those without. Also, preliminary laboratory studies showed that the inhibition of GD3S by Triptolide reduced GD2 expression, reduced tumor growth and increased survival. However, the mechanism by which levels of GD3 or GD3S contribute to stem cell function of breast cancer cells is not known.

The objective of Dr. Andreeff's project is to describe the role of GD2 in stem cell function of breast cancer cells and identify chemical agents that could inhibit GD3S. Based on their preliminary data, Dr. Andreeff's team hypothesizes that the inhibition of GD2 expression or GD2 mediated signaling mechanisms in breast cancer cells results in new therapeutic tools against breast cancer therapy. The functional data they have developed supports the notion of GD2 as a marker specific for BCSC and GD3 synthase as a target, will allow the researchers to identify signaling pathways that regulate GD2+ breast cancer stem cell function and develop chemical inhibitors to target GD3 synthase enzyme activity. Dr. Andreeff's team anticipates that these studies will lead to the isolation of a pure population of breast cancer initiating cells, development of strategies that target these cells and the design of new treatment for breast cancer metastases.

Mid-year Progress: Breast cancer stem cells reside in primary tumors, are resistant to treatment, metastasize, and cause secondary tumors. Dr. Andreeff reports that he and his team analyzed GD2+ cells from human breast cancer cell lines with an antibody microarray platform comprising 850 validated antibodies. Pathway analysis of differentially expressed/phopshorylated proteins derived from this array revealed that signaling pathways that comprise proteins including STAT-3, NFκB, MAPK were found to be active in GD2-positive (GD2+), compared to GD2-negative cells. Building on their previous efforts, Dr. Andreeff's team continues to target GD2+ cells, where they are exploring whether specific targeted white blood cells (also called T-cells) can eliminate GD2+ breast cancer stem cells. Utilizing GD2-specific CAR-T-cells, they observed 80+/-10% reduction of GD2+ cells. Currently, they are in the process of testing various commercially available NFκB inhibitors to inhibit GD2 expression and induce cell death in GD2+ BCSCs and target GD2+ tumors using GD2-specific CAR-T-cells in laboratory experiments.

Bio:
Michael Andreeff, MD, PhD received his medical degree and doctorate from the University of Heidelberg, Germany, and additional training and faculty appointments at the Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, NY, in the Departments of Pathology and Leukemia. Dr. Andreeff has been a pioneer in flow cytometry since 1971, when he established the first flow cytometry laboratory at the University of Heidelberg and organized the first European conference on flow cytometry. In 1977 he joined Memorial Sloan-Kettering Cancer Center in New York, NY, became head of the Leukemia Cell Biology and Hematopathology flow cytometry laboratory, organized the first Clinical Cytometry Conference in 1986 and the first Molecular Cytogenetics Conference in 1990. He is professor of medicine and holds the Paul and Mary Haas Chair in Genetics at MDACC. He has received uninterrupted NCI funding for over 30 years, serves as PI of the P01 grant entitled "The Therapy of AML" participates as PI in MDACC Leukemia, Lymphoma, Ovarian and Breast Cancer SPORE grants, the CML P01 and additional R21 and R01 grants. He has published over 450 peer-reviewed papers, 5 books and 75 book chapters Dr Andreeff's group has worked extensively on drug resistance in hematopoietic malignancies and breast cancer and developed or co-developed several new therapeutic agents including the novel triterpenoids CDDO and CDDO-Me and Bcl-2-, XIAP-, surviving-, MEK- and HDM2- inhibitors. Over the last decade, his group has made major contributions to the understanding of micro-environment-mediated drug resistance and developed strategies to exploit the underlying mechanisms for the treatment of hematopoietic and epithelial malignancies. His group reported the role of bone marrow-derived multipotent mesenchymal stromal cells (MSC) In tumor stroma formation and developed therapeutic strategies based on this discovery.