Breast cancer is a heterogeneous disease exhibiting diverse biological characteristics and clinical responses. Gene expression profiling has defined genetic signatures corresponding to at least five distinct molecular subtypes of breast cancer including an aggressive form known as triple-negative breast cancer (TNBC). TNBCs are typically high grade (poorly differentiated) and rapidly progressive, with a higher risk of relapse and lower survival than other subtypes of the disease. Additionally, for unknown reasons, TNBCs are often diagnosed in younger women and women of African-American descent. Although TNBC represents a relative small percentage of all breast cancers (~20%), it is associated with a disproportionate number of deaths. By definition, TNBCs fail to express three molecules shown to promote many breast cancers: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Current clinical approaches for breast cancer include agents that target these three molecules; endocrine therapies and the monoclonal antibody targeting HER2, Trastuzumab. Because TNBC is defined as absence of these targets, conventional cytotoxic chemotherapies are currently the mainstay of systemic treatment for these patients. However, conventional systemic treatments are limited by poor therapeutic response, high toxicity, and the development of resistance. Thus, there is a pressing need for both new therapeutic approaches, and mechanistic understandings, of TNBC. Our studies directly address both of these needs.
We have developed AMPI-109, a novel drug with the characteristic of specifically killing TNBC cells. The long-term goals of our studies are to understand the molecular mechanisms which provide specificity of AMPI-109 to TNBC cells and to establish the efficacy of AMPI-109 as a therapeutic agent For TNBC.
To elucidate the mechanism of action for AMPI-109 in TNBC, and identify novel alterations specific to TNBC, we conducted a genome-wide functional shRNA screen and identified the oncogenic phosphatase PRL-3 as a mediator of AMPI-109 action. PRL-3 has emerged as an important oncogenic mediator in a number of cancer types and is best known for its role in promoting metastasis. PRL-3 has also been shown to promote a variety of pro-tumorigenic functions including cellular proliferation, angiogenesis and cell cycle progression. Importantly, we have shown through histological evaluation of human breast cancers that PRL-3 is significantly associated with the TNBC subtype and correlates positively with regional and distant metastases. Thus a major focus of our research is to understand the role of PRL-3 in TNBC and how we might target PRL-3 in therapeutic strategies using AMPI-109.
These studies also have the added significance of providing a fundamental understanding of cancer cell targeting in general. The striking observation that AMPI-109 has no effect on untransformed cells suggests a critical “cancer-specific” mode of this drug’s action. Our research will lay the ground work of our understanding of this unique mechanism of action. Finally, these studies are also expected to provide the necessary pre-clinical knowledge on the use of AMPI-109 that will allow us to move AMPI-109 into clinical trials for TNBC patients and potentially, other cancer types.
Email Address:jim.lambert@cuanschutz.edu
Primary Phone:303-724-3472
Research I South
12801 East 17th Avenue
Aurora, CO 80045
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