Abstract IA07: Breast tumor grafts as preclinical models for anti-metastasis therapy

Abstract

Abstract Metastasis is the major cause of death from breast cancer. The goal of adjuvant therapy, including systemic chemotherapy and targeted therapies such as hormone modulating therapies and trastuzumab (Herceptin), is to prevent any disseminated tumor cells from growing into overt metastases. While adjuvant therapy clearly provides benefit, it is estimated that 150,000-200,000 people are living with metastatic breast cancer (MBC) today; most of these cases are due to metastatic relapse after treatment. Many people live for years following diagnosis of metastatic relapse, but MBC remains incurable, and nearly always progresses, so approximately 40,000 people succumb to this disease each year in the U.S. New therapies to prevent metastatic outgrowth and to treat established metastases are urgently needed. There are multiple challenges to developing new therapies to prevent or treat metastasis, including our lack of understanding of (1) how disseminated tumor cells remain “dormant” for long periods of time and the processes required for these cells emerge as overt metastases; (2) why established metastases are so resistant to existing therapies; and (3) whether there are unique features of established metastases, including their microenvironment, that might be exploited for therapy. A major barrier to overcoming these challenges has been lack of models in which to address these questions experimentally. Genetically engineered mouse models have been indispensable for important studies of tumor initiation and progression, but generally do not display the metastatic spectrum of human tumors. Xenograft models based on injection of established human breast cancer cell lines into immune-deficient mice allow study of human tumors in vivo; however, these tumors do not exhibit high levels of spontaneous metastasis from the primary tumor (perhaps due to long term culturing) and must be conducted in the presence of an incomplete immune system. Experimental metastasis models, in which these cell lines are injected via a direct route to a metastatic site, overcomes the first issue but it is unlikely that injection of a bolus of metastatic cancer cells accurately models tumor shedding/dissemination, dormancy at the metastatic site, or the relatively rare event of successful colonization and metastatic outgrowth that occurs in patients. Patient-derived tumor grafts (also referred to as patient-derived xenografts; PDX) are derived by implanting tumor cells or fragments directly from patients into immune-deficient mice. We previously established a bank of breast cancer PDX models, which display remarkable fidelity to the original tumor, including retention of molecular and histopathological features and, importantly, spontaneous metastasis to clinically relevant sites. We report here that chemotherapy sensitivity and resistance in PDX models closely parallels therapeutic response in patients. We have also determined that the Ron receptor tyrosine kinase pathway is a major driver of breast tumor progression and metastasis, functioning through multiple mechanisms in both tumor and host cells. Our data indicates that Ron inhibitors can prevent tumor growth and metastatic outgrowth of orthotopic breast tumors using both conventional and PDX models – even in highly chemoresistant models of established MBC. These data suggest potential for Ron inhibitors for prevention and treatment of MBC. Citation Format: Alana L. Welm. Breast tumor grafts as preclinical models for anti-metastasis therapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA07.