Associate Professor, Department of Pathology
Member, Breast Cancer Basic Science Program
Member, Cancer Immunology Research Program
Loyola University Chicago
Estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer is the most common subtype in women diagnosed with early stage breast cancer. Endocrine therapy (tamoxifen or aromatase inhibitors, AIs) after definitive surgery has resulted in significantly decreased mortality from breast cancer. However, there are many breast cancers that are either resistant to endocrine therapy right at the start or become resistant duringtreatment. Oncologists currently have no good strategies to overcome this resistance. Cancer stem cells drive the growth of breast cancers and these cells, unlike the rest of the breast tumor, are resistant to standard treatments. Notch signaling (a complex of many genes) is a key “driver” of stem cell survival and growth, and this pathway is intimately related to estrogen signaling pathways. A novel class of drugs called gamma secretase inhibitors (GSIs) inhibit Notch activation and genes subsequently targeted by Notch, which in turn inhibit survival of cancer stem cells, leading to cancer cell death. In laboratory models, combining endocrine therapy with a GSI resulted in significantly better tumor shrinkage. As a first test of this exciting discovery in humans, Drs. Albain and Osipo completed a “biomarker modulation” trial of adding a GSI to endocrine therapy for a short period before surgery. The women donated biopsy material at three time points to allow the investigators to conduct experiments on which genes are increased and/or decreased by the GSI to prove that the Notch pathway is shut down. At the end of this project, Drs. Albain and Osipo aim to identify a “Notch/stem cell gene signature” and propose its use in definitive clinical trials designed to test that Notch inhibitors such as GSIs in combination with standard endocrine therapy might provide more cures for women with estrogen receptor-positive breast cancer.
Drs. Albain and Osipo report exciting results from the first 3 months of this project. They identified 14 genes that are impacted significantly by the gamma secretase inhibitors (GSI), in other words are either turned on or turned off by the GSI. The 3 genes that are turned on promote the death of cancer cells. The 11 genes that are turned off include genes that regulate Notch signaling, cancer stem cells, and growth, plus new genes and pathways. A bioinformatician is currently working on defining how Notch signaling regulates these multiple genes and pathways. This will complete Aim 1, so the researchers are on track with their timeline. In February they will progress to work on Aim 2, to identify a “Notch/stem cell gene signature”. This signature will be used in definitive clinical trials with endocrine therapy and GSIs to hopefully result in more cures of women with ER positive breast cancer.
Dr. Clodia Osipo received her doctorate in Molecular and Cellular Biochemistry from Loyola University Chicago. She did her postdoctoral fellowship at the Robert H. Lurie Comprehensive Cancer Center of the Feinberg School of Medicine at Northwestern University. Dr. V. Craig Jordan, the principal developer of adjuvant tamoxifen therapy for estrogen receptor positive breast cancer, was her mentor. Dr. Osipo’s research under Dr. Jordan focused on investigating the role of HER2/neu, the second member of the epidermal growth factor receptor family, in breast tumors that had acquired resistance to tamoxifen in vivo. During this time, Dr. Osipo has published numerous articles, reviews, and book chapters on tamoxifen and other selective estrogen receptor modulators and downregulators.
Dr. Osipo joined Loyola’s breast cancer program as an Assistant Professor in 2005. She is currently an Associate Professor in the Department of Pathology and a member of the Breast Cancer Basic Science Program and the Cancer Immunology Research Program.