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. For other studies, they 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. The team has fully characterized these samples, assembled a large comprehensive database, and initiated analysis of DAXX and biomarkers.

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 neoadjuvant therapy. Their results will determine the potential for DAXX and other biomarkers to predict response to endocrine therapy for ER-positive breast cancer and/or chemotherapy for 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 plan to screen existing DAXX-inducing agents for their ability to prevent drug resistance and tumor relapse in laboratory models. Building on their findings, they will also develop new therapies that can target BCSCs, keep DAXX levels high, prevent resistance, and ultimately cure more cancers.