Jenny Chang, MD

2009-2010 BCRF Project:
Chemotherapy treatments are often effective at first in controlling breast cancer. Yet, many women relapse and, sadly, die from their disease, even if they had originally responded to treatment. In the U.S, more than 40,000 women this year alone will relapse, and standard therapies today can only palliate and prolong lives but cannot eradicate the disease.

There is increasing evidence that standard treatments like chemotherapy just kill the dividing "daughter" (progenitor) cells, without killing the cancer stem cell that neither divides rapidly nor dies. This is especially relevant for young women, as they have "aggressive" cancers, and although current therapies can stop the rapidly dividing daughter progenitor cancer cells, women still relapse because the chemotherapy has not affected or killed the therapy-resistant cancer stem cells that have the ability, when activated, to give rise to many daughter cells of high proliferative potential.

By analogy with the propensity of dandelion roots to regenerate weeds, re-growth of tumors from this intrinsically resistant subpopulation 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 and colleagues have shown that chemotherapy reduces the overall size of the tumor, but spares this rare sub-population of cells, which therefore increases proportionately as the bulk of the tumor decreases. They have also shown that these CD44+/CD24-/low cells are capable of forming cancers (called mammospheres) in culture medium, and can form new cancers in immuno-compromised laboratory models. Their data suggest that chemotherapy is not effective in killing these CD44+/CD24-/low cells that have the 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 such dataset to date, that certain pathways like the Notch, EGFR/PI3K, and Hedgehog pathways, may be important in cancer stem cells. In keeping with these findings, the researchers conducted a clinical trial with lapatinib, an EGFR/HER2 inhibitor, that showed for the first time, that "cancer stem cells" could be targeted, with a decrease in both CD44+/CD24-/low and mammospheres. These exciting results have been reported in the Journal of National Cancer Institute.

In addition, another manuscript entitled "Residual tumors display mesenchymal as well as tumor initiating features," has been accepted by Proceedings of the National Academy of Sciences. In this publication, Dr. Change and team have shown that cancer stem cells express mesenchymal markers, and thus may escape and invade into surrounding tissue. Hopefully, by targeting these resistant cells scientists might be better able to improve current treatments for women with breast cancer.

The Baylor team havs created novel STAT 3 inhibitors, and thus, propose a series of experiments to study if adding these STAT 3 inhibitors to conventional chemotherapy improves patient outcome. These combinations of cancer stem cell inhibitors and standard therapies may eradicate residual disease and thereby help even women with metastatic disease, whose outlook is poor.

Beginning first with preclinical models, using mammospheres and human breast cancers grown in immunocompromised laboratory models, they will determine which of the STAT3 inhibitors will be the most effective when combined with chemotherapy. In the future, they aim to start clinical studies adding a novel STAT3 inhibitor to chemotherapy. Knowing the biology of cancer stem cells is the first and most critical step in finding therapies that might prevent cancer from relapsing, and thereby help women with breast cancer, even those with metastatic disease.

Mid-Year Progress Report:
Dr. Chang's team has preliminary data in preclinical models, using mammospheres and human breast cancers grown in immunocompromised laboratory models, showing that STAT3 inhibition is most effective when combined with chemotherapy. In the future, they aim to start clinical studies of adding novel STAT3 inhibitor to chemotherapy. Knowing the biology of cancer stem cells is the first and most critical step in finding therapies that might prevent cancer from relapsing, and thereby help women with breast cancer, even those with metastatic disease.

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.