Kathryn B. Horwitz, PhD
University of Colorado Denver
2013-2014 BCRF Project:
(The Play for P.I.N.K. Award)
If you want to know how something works, break it down into its component parts then reassemble it. The most common form of breast cancer – called luminal – grows in response to women’s hormones and is treated by hormone blockade. This assumes that all of the cancer’s cells need hormones to grow. But cell-by-cell analysis of luminal cancers finds no such uniformity. In some tumors, 90% of the cells may need hormones. But in others, 50%, 20% or even fewer cells do so. Yet remarkably, cancers are treated with hormone blockade if only 1% of the cells need hormones. Dr. Horwitz’s lab asks: what about the other cells in those cancers? Don’t we have to understand them, where they come from and how to treat them? Dr. Horwitz’s group has identified four luminal cancer-cell populations. Only one of the four is the classic hormone-dependent cell. The researchers intend to break down luminal cancer into four component cell parts, learn how to treat each component, then reassemble the tumor and prescribe rational treatment strategies.
With last year’s BCRF support, Dr. Horwitz’s team learned how to purify two of the four cell types. The first is the true “luminal” cell that requires hormones to grow. The second, called “luminobasal,” does not need hormones. Dr. Horwitz purified both, screened luminobasal cells for sensitivity to 89 non-hormone drugs already approved for oncology use, and found at least one class of drugs that strongly suppresses them.
Dr. Horwitz’s studies will show whether one luminal breast cancer cell type can morph into others. If so, suppressing it may be vitally important. In any case, the idea that all cancerous cells in a tumor need to be treated seems logical on its face. If combination therapies using already-approved cancer drugs work in the luminal cancer models, they will represent “proof of principle” for immediate Phase I/II trials.
When a woman is told she has breast cancer the news is devastating. Imagine how she would feel if she were told she had three breast cancers? Unfortunately, the latter is often closer to the truth than one might think. A simple analysis of any breast cancer will show that it is composed of several different cancer-cell types. Usually only one of these cells – not necessarily the major one – is targeted for treatment. What about the other cells in her cancer? We know little about them and definitely don’t know how to treat them. Dr. Horwitz argues that if a breast cancer is a mixture of several malignant cells, all of them need to be treated. This seems to make good sense.
Her laboratory studies the most common form of breast cancers called “Luminal”. These cancers have receptors for estrogens (ER) and progesterone (PR) and are treated with endocrine therapies like Tamoxifen. Their analysis of multiple Luminal breast cancers shows that they can contain as many as four cancer cell types. The first is the expected pure ER+ or PR+ cell. The second and third cells are ER– and PR– and would be Tamoxifen-resistant. The fourth cell is rare and has mixed features of Luminal and non-Luminal breast cancers. At present we have no idea how to treat cell type number 2, 3 or 4.
The goal of Dr. Horwitz’s project is to isolate and purify all four cell types, explain the role of each within Luminal cancers, and test each individually for its sensitivity to dozens of drugs currently approved for human use. They will then artificially reconstruct mixed-cell tumors and test them for sensitivity to combination therapies designed to target each cell in the tumor. Because the drugs being tested are already approved for oncology use, the findings should be immediately ready for clinical confirmation.
Dr. Horwitz is a graduate of Barnard College, received a Master's degree from New York University, and a Doctoral degree from the University of Texas, Southwestern Medical School in Dallas. She then joined the Department of Medicine faculty at the University of Colorado's School of Medicine, where she was rapidly promoted to Professor. She has received many awards and recognitions for her work. The University of Colorado has recognized her extensive service to the University, and to the local, national and international community of scientists and patients, by naming her a "Distinguished Professor" of the University, an accolade reserved for only a handful of professors on the four university campuses. In addition, Dr. Horwitz received the 2010 Fred Conrad Koch Award, The Endocrine Society's highest award.