Clodia Osipo, PhD

Developing strategies to block the survival of dormant breast cancer stem cells in order to improve patient outcomes.

Impact

Development of resistance to endocrine therapy (tamoxifen and/or aromatase inhibitors) for estrogen receptor (ER)-positive breast cancer or to chemotherapy for triple-negative breast cancer (TNBC) remains a clinical challenge. Breast cancer stem cells (BCSCs) are the tumor cells most likely to survive anti-cancer therapies and cause breast cancer recurrence many years later. Drs. Osipo and Albain are focused on defining the mechanisms involved in BCSC survival that may be targeted to prevent treatment resistance. With BCRF support, they have identified key pathways involved in the resistance of BCSCs to cancer treatment and demonstrated that a gene called DAXX is a potent inhibitor of BCSCs. They have shown that high amounts of the DAXX gene correlate with a reduction in the number of BCSCs and a better response to endocrine therapy, standard chemotherapy, and PARP inhibitor treatment in ER-positive and TNBC cells. Further work has the potential to inform the development of new strategies to reduce drug resistance in ER-positive and TNBC.

Progress Thus Far

Drs. Osipo and Albain have shown that increasing DAXX levels in breast cancer cells effectively kills all breast cancer cells including BCSCs. In addition, they found high levels of the DAXX gene in ER-positive breast cancer cells inhibited endocrine therapy resistance and DAXX status also predicted sensitivity to chemotherapy, DNA damage response, and PARP inhibition in TNBC cells. They have collected breast cancer biopsies before and after pre-surgical (neoadjuvant) endocrine therapy or chemotherapy to determine how the levels of DAXX and other cancer stem cell biomarkers are affected by neoadjuvant therapies. In their most recent work, the team discovered that DAXX controls the activity of the estrogen receptor itself—meaning that how much DAXX is present in a cell directly affects how well the ER functions. They also identified a second protein, KMT2D, that promotes resistance to anti-HER2 therapy by causing cancer stem cells to cluster together, which helps these cells survive treatment. High-throughput screening of nearly 4,000 FDA-approved drugs is now underway to identify new agents capable of eliminating therapy-resistant cancer stem cells.

What’s next

Using the large national tumor biorepository they have developed, Drs. Osipo and Albain are correlating the status of DAXX and other BCSC biomarkers with response to therapies. Their results will determine which biomarkers are reliable predictors of response to endocrine therapy in ER–positive breast cancer or chemotherapy in TNBC. Ongoing research aims to understand how DAXX mediates the growth of breast tumors by keeping levels of stem cell genes low while increasing those genes required for response to therapy. They will continue to screen existing DAXX-inducing agents for their utility in preventing drug resistance and tumor relapse. They hope that their findings will enable the development of new therapies that can target BCSCs, keep DAXX levels high, prevent resistance, and ultimately cure more cancers.