Abstract A198: Identification and preclinical testing of novel targeted therapies for human triple-negative breast cancer.

Abstract

Abstract Basal-like triple negative breast cancer (BTNBC) is characterized by the absence of estrogen receptor, progesterone receptor, and Her2 expression, and represents an estimated 15% of all human breast cancers. This subtype is highly prevalent in African American women (35%) and is associated with distant metastasis and poor prognosis. As there are currently no targeted therapies for this subtype of breast cancer, our research focuses on the development of improved therapies to increase patient survival. We have previously shown that primary mammary tumors from the C3(1)/SV40-TAg genetically engineered mouse (GEM) model express a critical proliferation/ DNA repair/ cell cycle gene signature (TAg signature) that is shared with human BTNBC. SV40-TAg functionally inactivates p53 and pRb, two critical tumor suppressor genes whose functions are lost in most human BTNBC. We hypothesize that targeting dysregulated genes and biological networks present in the TAg signature will lead to the identification of novel targets and potential combination therapies. To test this idea we developed a custom siRNA library screen to inhibit the expression of individual genes represented in the TAg signature using human MDA-MB-231 BTNBC cells. Additionally, we performed a synthetic lethal screen in which TAg signature genes were knocked down in MDA-MB-231 cells using pooled siRNAs in combination with either UCN-01 or gemcitabine, small molecule inhibitors of CHK1 and RRM1/2 respectively. It was found that the knockdown of BMI-1, EZH2, GeneA, GeneB, or GeneC significantly decreased cell proliferation with the addition of UCN-01 or gemcitabine. A second synthetic lethal screen was performed in which the above genes were knocked down using four deconvoluted siRNAs per gene with the addition of gemcitabine, UCN-01, or AZD7762 (a more specific CHK1 inhibitor). Synergistic activity was shown between the siRNA knockdown of these genes and UCN-01 and AZD7762 compared to siRNA alone. To determine whether the knockdown of these genes alters sensitivity to gemcitabine or CHK1 inhibitors, the EC50 values of these drugs are currently being evaluated in stable knockdown MDA-MB-231 cell lines expressing shRNA to the selected genes. Our results suggest that using GEM models to help identify new targets may be useful in the development of novel therapeutics for BTNBC in combination with available CHK1 inhibitors and/or gemcitabine. These studies will enhance our understanding of BTNBC and allow us to identify innovative combination therapies to treat this challenging form of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A198.