PD08-02: Targeting BCL-2 Expressing Breast Tumors with BH3-Mimetics – A New Class of Drugs in Breast Cancer?
Authors: Lindeman GJ , Oakes SR , Vaillant F , Lim E , Lee L , Breslin K , Feleppa F , Deb S , Ritchie ME , Takano E , Ward T , Fox SB , Generali D , Smyth GK , Strasser A , Huang DCS , Visvader JE 
Published: June 2012

Abstract
Background: Impairment of apoptosis is a hallmark of cancer and can result in resistance to chemotherapy. Tumor resistance to apoptosis is frequently acquired through deregulated expression of BCL-2 family members or inactivation of the p53 tumor suppressor pathway. Over-expression of the pro-survival protein BCL-2 is common in breast cancer (where it is readily detected by immunostaining), and has been shown to be an important prognostic marker. A potential role for BCL-2 as a therapeutic target in breast cancer, however, has not been explored. Recently, small molecules termed ‘BH3-mimetics’ have been developed that mimic the action of pro-apoptotic BH3-only proteins. These bind and neutralize pro-survival proteins including BCL-2. Here we have derived a panel of primary breast tumor xenografts (that include basal-like breast tumors) to study the efficacy of the BH3-mimetic ABT-737 combined with docetaxel in targeting BCL-2-positive breast cancer.
Methods and Results: We first studied the expression of BCL-2, pro-survival family members BCL-XL and MCL-1, and the pro-apoptotic protein BIM in tissue microarrays of 197 primary breast tumors, which were subtyped on the basis of ER, PR, HER2, CK5/6 and EGFR expression. BCL-2 was overexpressed in luminal (83.3%), HER2−positive (50.0%), basal-like (18.5%) and ‘marker-null’ (41.4%) breast cancers. BCL-2-positive tumors generally co-expressed BCL-XL (96.2%), MCL-1 (94.7%) and BIM (93.5%). To determine whether the BH3-mimetic ABT-737 (which neutralizes BCL-2, BCL-XL and BCL-W) was effective in targeting BCL-2-expressing breast tumors, we generated a panel of 28 primary breast tumor xenografts in immunocompromised NOG mice. Five xenograft lines (838T, 24T, 315T, 13T and 806T) were selected for further analysis. Four were basal-like, and one (315T) was a luminal B tumor, as determined by gene profiling. Mice bearing tumor xenografts were treated with ABT-737 (50 mg/kg i.p. d1-10), docetaxel (10 mg/kg i.p. d1) or a combination in q21d cycles. Tumor response and overall survival were significantly improved by combination therapy, but only for tumors that expressed elevated levels of BCL-2. Treatment with ABT-737 alone was ineffective, suggesting that ABT-737 sensitized tumors to docetaxel. Combination therapy was accompanied by a marked increase in apoptosis and dissociation of BIM from BCL-2, indicating that a perturbation of BIM complexes may contribute to the activation of the apoptotic cascade. Notably, ABT-737 appeared effective in targeting BCL-2-expressing basal-like tumor xenografts (838T and 24T) harboring p53 mutations.
Discussion: Primary breast tumor xenograft models that recapitulate the phenotype of the primary tumor have been developed as useful ‘proof-of-principle', pre-clinical models. Here we provide the first in vivo evidence that BH3-mimetics can be used to sensitize primary BCL-2-expressing breast tumors to taxane chemotherapy. Our results suggest that elevated BCL-2 expression constitutes a predictive response marker in breast cancer. These findings provide a rationale for the development of clinical protocols using the oral analogue ABT-263 (navitoclax) as an adjunct to taxane chemotherapy in BCL-2-expressing basal-like and luminal breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD08-02.