Xiang (Shawn) Zhang, PhD

2012-2013 BCRF Project:
Over 90% of cancer-related deaths are caused by metastases rather than the primary tumor. For most patients with breast cancer, primary tumors are removed soon after diagnosis, while metastases are detected, sometimes years or even decades later. During this protracted latency, disseminated tumor cells are likely to exist as undetectable microscopic metastases (or micrometastases) in distant organs.

Adjuvant therapies, such as endocrine treatment (also called anti-estrogen therapies) on estrogen receptor positive tumors, may eradicate some latent tumor cells. However, many patients with breast cancer still relapse despite the treatment. This occurrence suggests that a substantial proportion of micrometastases is resistant and remains viable for years to decades. Biological mechanisms underpinning therapeutic resistance and strategies to overcome it have been central to cancer research. Yet, very little is known about the biology of these micrometastases, which are the intended targets of adjuvant therapy, escape the effects of these treatments as single or small clumps of cells in distant organs.

Accordingly, Dr. Zhang's long-term research goals are two-fold: first, to elucidate biological mechanisms underpinning the persistence of micrometastases, and second to identify therapeutic strategies for the eradication of latent cancer cells. Bone is the organ most frequently involved by metastases of estrogen receptor positive breast cancers, especially those with long latency. In the upcoming year, Dr. Zhang aims to investigate mechanisms underlying the resistance of these micrometastases to standard hormonal therapies (estrogen deprivation and tamoxifen treatment) in bone itself.

Mid-year Progress: Dr. Zhang's overarching objective is to discover molecular mechanisms and therapeutic strategies that can lead to the eradication of slowly-growing or dormant cancer cells in the bone marrow of breast cancer patients. These cells are usually resistant to traditional adjuvant therapies. Thus, how to overcome the resistance is an imperative question and is the focus of this project.

During this grant period, Dr. Zhang has fulfilled the following tasks. First, he and colleagues have established two estrogen receptor-positive (ER+) breast cancer cell models that, when introduced to the bone marrow, exhibit indolent growth and/or dormancy behavior. These models provide promising systems for the researchers to further investigate resistance to anti-hormonal therapies. Second, Dr. Zhang has found that the indolence/dormancy of these cancer cells remain for weeks after the host bone is extracted, fragmented, and kept in culture dishes. This finding raises intriguing possibility of a "tissue-in-culture" system, which can be used not only as a surrogate of laboratory model experiments, but also as a new platform for medium-throughput screenings of effective drugs.