January's Jackpot

Featured Advocate
Dr. Vera Donnenberg

Vera is a very active member of the advocacy network. Dr. Donnenberg is an extraordinary woman and devoted scientist, who is changing the way the medical community thinks about breast cancer therapy. We are very grateful she agreed to tell us about her work.

Five years ago we initiated a series of investigations on the nature of therapy resistance in breast cancer. Recent discoveries in the field of regenerative medicine suggested to us that a small fraction of breast cancer cells could protect themselves from chemotherapy using the same mechanisms by which normal tissue stem cells protect themselves. Together with my husband Albert, an expert in regenerative medicine and analysis of living cells, we resolved to redirect our research toward this very important but previously unsolvable problem, the solution to which suddenly appeared within reach. Like so many others, our lives have been touched personally by breast cancer, adding a level of urgency to our work. Our approach, which relies on freshly removed tumors, required us to develop close ties with our clinical colleagues, and to interact directly with the patients who volunteer the use of their tissues. From the first, we have concentrated on the problem that pharmacologists call therapeutic index. A drug or regimen with high therapeutic index is one that is lethal to the tumor, but has relatively low or at least tolerable toxicity to the patient as a whole. Our hypothesis, that the most therapy resistant breast cancer cells share protective mechanisms with normal tissue stem cells (cells that maintain and repair our vital organs), has focused our research on two important questions:

1) What do the therapy resistant cells look like? Breast cancer cells are heterogeneous. In our search for a unique "profile" of the type of cell responsible for therapy resistance, dormancy and recurrence we have discovered not one, but a "family" of markers to identify such cells. This finding points out the difficulty in targeting one particular molecule in the hope of eliminating every tumorigenic cell type.

Analogous to normal tissue stem cells, a fraction of tumor cells are protected from therapy by cellular pumps even before encountering anti-cancer drugs. We have shown that a proportion of metastatic breast cancer cells that are dormant (not actively growing) at the time that we find them, express proteins normally associated with healthy tissue stem cells in combination with multiple drug resistance transporters (cellular pumps) that have presumably allowed them to survive anti-cancer treatment. To complicate the difficulty of therapeutic index, we must consider the fact that tumorigenic cancer cells have merely to survive and reactivate in order to perpetuate the cancer, whereas vital organ functions cannot be compromised for long without lethal consequences.

2) How can we preferentially target therapy resistant cancer cells without also targeting the normal tissue stem cells so vitally important for tissue repair? This question has caused us to focus on targeting embryonic signaling pathways that are exploited by cancer cells and which appear to control drug resistance and other protective mechanisms. These pathways may not be critical for the activity of normal adult tissue stem cells, providing a potential therapeutic wedge. We have initiated a collaboration with Novartis Oncology and an internationally known developmental biologist, Dr. Philip Beachy, to study the effect of pharmacologic inhibition of the hedgehog signaling, an embryonic pathway which appears to control self-protection in cancer cells. There are several newly developed compounds now entering phase I studies, and it is our goal to study their effects in breast cancer. We also have active collaborations directed at targeting therapy resistant breast cancer cells with vaccines, and in understanding whether tissue regeneration after reconstructive surgery modifies the behavior of dormant breast cancer cells.

Lastly, I would like to express my gratitude to the patients which volunteered their tissue for our research studies knowing that their participation would not directly benefit them; every member of our laboratory deeply appreciates this.