Jenny Chang, MD

Every year, close to 40,000 women in the US alone will suffer a breast cancer relapse, and most of these will die of their disease. The cancer stem cell hypothesis fundamentally alters the way that we look at cancer recurrence and how to prevent it. With access to uniquely suited human breast cancer tissues before and after endocrine treatment, Dr. Chang and her team are poised to answer the critical question of the relationship between cancer stem cells, treatment resistance, and relapse in breast cancer patients.

Urgent treatment is needed for women with estrogen receptor-negative (ER-) and HER2/neu-negative (HER2-) breast cancers, as the only present option is chemotherapy, which is toxic and associated with side effects like hair loss, nausea and vomiting. Advances in the understanding of the pathways that maintain cancer cell growth have led to the development of targeted drug therapies. Indeed, targeted drugs like Gleevec, Herceptin, and Tarceva that are effective yet have few side effects have greatly changed the treatment of leukemia, breast, and lung cancer. However, no such molecularly targeted agents have been found for the treatment of ER-/HER2- breast cancer. Dr. Chang plans to extend on earlier work on looking for effective yet safe treatments for estrogen receptor-negative (ER-) and HER2/neu-negative (HER2-) breast cancers.

Mid-Year Progress Report:
There is increasing evidence that standard treatments like chemotherapy just kill the dividing "daughter" (progenitor) cells, without killing the cancer stem cell that does not divide or die. This is especially relevant for young women, as they have "aggressive" cancers that divide, and although current therapies can stop the dividing daughter progenitor cancer cells, women still relapse because the chemotherapy has not affected or killed the therapy-resistant cancer stem cells, with the ability, when activated, to give rise to many daughter cells of high proliferative potential.

Analogous with the propensity of dandelion roots to regenerate weeds, regrowth of tumors from this intrinsically resistant sub-population has been termed "the dandelion hypothesis". This hypothesis provides a unified explanation for the success and failures of cytotoxic chemotherapy - namely, although the majority of cells in the original tumor may be killed, the most important target, a small population of therapy resistant cancer cells possessing the capacity to form new cancers is spared.

Recently, a small sub population of breast cancer stem cells, labeled as CD44+/CD24-/low, was isolated. Dr. Chang has shown that chemotherapy reduces the overall size of the tumor, but spares this rare subpopulation of cells, labeled as CD44+/CD24-/low, which increases proportionately as the bulk of the tumor decreases. Her team has also shown that these CD44+/CD24-/low cells are capable of forming cancers in culture medium (called mammospheres), and new cancers in immunocompromised models. Their data suggests that chemotherapy is not effective in killing these cells CD44+/CD24-/low cells, with ability to form new cancers.

By isolating these CD44+/CD24-/low cells and using high-throughput genomic profiling, the researchers have determined, in the largest data set to date, that certain pathways like the Notch, EGFR/PI3K, and Hedgehog pathways, may be important in cancer stem cells. They propose to translate their findings by finding new treatments for patients. They propose to study if the combination of inhibitors of these stem cell pathways with conventional chemotherapy would be able to improve patient outcome. These combinations of cancer stem cell inhibitors and standard therapies may lead to the eradication of residual disease and thereby help even women with metastatic disease whose outlook is poor.

Bio:
Dr. Chang is the Chief of Breast Medical Oncology in Ben Taub General Hospital and an Associate Professor in the Breast Center, Baylor College of Medicine, Houston, Texas. Ben Taub General Hospital is an under-served inner city hospital where the lack of screening services has resulted in 60% of patients presenting with locally advanced and metastatic disease which is generally incurable. Dr. Chang has used the clinical situation of locally advanced breast cancer, in which patients are traditionally treated with pre-operative chemotherapy, to assess the use of such markers in predicting treatment response.

Dr. Chang's BCRF research is focused on the use of cDNA array technology, which allows the expression of thousands of genes to be studied simultaneously, to comprehensively seek patterns of gene expression in breast tumors that are associated with sensitivity or resistance to specific chemotherapies. The goal of her research is to identify novel pathways responsible for therapeutic resistance and cancer stem cell self-renewal in human breast cancer biopsies, and to rapidly translate these findings into clinical trials with inhibitors of cancer stem cell self-renewal.