Rachel Schiff, PhD

2009-2010 BCRF Project:
Co-Investigator: C. Kent Osborne, MD, Baylor College of Medicine, Houston

Currently approved targeted treatments against the HER2 membrane receptor protein in aggressive HER2+ breast cancers include the monoclonal antibody trastuzumab (Herceptin), and the orally active small molecule inhibitor lapatinib (Tykerb). While these therapies are very effective in some patients, many HER2+ tumors have or will develop resistance resulting in tumor progression and eventual patient death. Drs. Schiff and Osborne have developed multiple HER2+ resistant models and have demonstrated that different mechanisms are responsible for tumor resistance to trastuzumab (T), lapatinib (L), or the combined therapy of T+L. Investigating new therapeutic approaches to overcome or prevent resistance to HER2-targeted therapy is the goal of this proposal, with a particular focus on the role of the PI3K pathway and strategies to inhibit it.

Mid-Year Progress Report:
Therapeutic strategies that specifically target breast tumor cells without affecting normal cells have been proven very effective, but success in the clinic has varied and drug resistance remains a challenge. Both the HER2 cell-surface receptor protein, which is overexpressed in 25% of breast cancers and is associated with an aggressive tumor phenotype, and the estrogen receptor (ER), a nuclear protein that is present in 70% of breast cancers, have been shown to play an essential role in the biology of breast cancer. Not surprisingly, then, targeting these pathways, using antiHER2 agents such as the monoclonal antibody trastuzumab (Herceptin) or hormonal (endocrine) therapies to target ER, provides the most effective therapies in appropriately selected patients. Still, many HER2+ and ER+ tumors have or will develop resistance to these targeted therapies, resulting in tumor recurrence and eventually patients' death.

Drs. Schiff and Osborne have previously shown that intimate interaction between the ER and the HER2 pathway is a major contributor for resistance to therapies against both pathways. Investigating new therapeutic approaches to overcome or prevent resistance to endocrine and antiHER2 therapies and translating them to the clinic is the goal of this proposal, with a particular focus on the role of the PI3K pathway and strategies to inhibit it. Towards this project, Drs. Osborne and Schiff and their team of collaborators have developed and characterized multiple HER2+ and ER+ responsive and resistant models and have already identified different mechanisms that are responsible for tumor resistance to the various therapies. They have further developed molecular signature of the PI3K pathway and have shown in multiple datasets of clinical breast cancers that this PI3K signature is associated with a more aggressive and less hormonally responsive subtype of ER+ breast cancers (so called luminal B), as well as with many HER2+ tumors. Initial therapeutic studies using a specific PI3K inhibitor in various relevant experimental models are thus far promising and suggest that targeting PI3K might reverse resistant growth and restore sensitivity to both antiHER2 and endocrine therapies.

Bio: