Abstract B109: Novel orally bioavailable triple-negative breast cancer drug candidates that prevent the development of cancer associated fibroblasts in the tumor stroma
Authors: Fung Leah , Chan Kyle W.H. , Sullivan Robert W. , Ottilie Sabine , Swindlehurst Cathy A. 
Published: May 2015

Abstract
One in 8 women in the US will develop breast cancer during her lifetime. Breast cancer is the second most commonly diagnosed form of cancer and the second leading cause of cancer deaths in women. The main cause of breast cancer death is metastasis. Although the survival rate is 99% for localized disease, it is only 23% for distant stage disease. Changes in the tumor stroma create an environment that provides support for tumor growth, progression, invasion and metastasis. The most prominent cell type in the tumor stroma is an activated form of fibroblasts, known as cancer (or carcinoma) associated fibroblast (CAF). In breast cancer, as much as 80% of stromal fibroblasts acquire the CAF phenotype.
Triple negative (estrogen receptor, progesterone receptor, and HER2 negative) breast cancer (TNBC) has a low detection rate by mammography, and TNBC tumors generally have a higher mean size and grade at diagnosis than other forms of breast cancer. TNBC can be particularly aggressive with a high rate of recurrence and metastasis and a less favorable prognosis than other subtypes (64% vs. 81%, respectively). Unlike other forms of breast cancer (Tamoxifen for ER+ tumors, Herceptin for tumors with HER2/Neu), no targeted therapy exists for TNBC.
We have previously described small molecule inhibitors of translation initiation with safety and efficacy in animal models for the treatment of TNBC. One of these compounds, NM891, showed a durable response after treatment cessation even though plasma and tumor tissue concentrations were negligible. Recent data indicate that this may be a result of NM891 acting on the stroma that supports the growth and progression of the tumor. In preliminary studies, NM891 and NM922 (a related analog) were shown to prevent the TGF-β dependent activation of fibroblasts using alpha smooth muscle actin (α-SMA) as a biomarker of CAF. Studies to determine the effect of NM891 and NM922 on pathways (such as TGF-β) that drive the development of CAF are ongoing.
In addition, both NM891 and NM922 have recently been demonstrated to be orally bioavailable (20.5% and 19.6%, respectively, after oral gavage compared to i.v. administration in mice) with reasonable serum half-lives (1.5 and 2.4 hours, respectively), making them attractive not only for initial treatment, but also as part of a maintenance regimen. Future studies include the development of formulations to further enhance oral bioavailability and serum half-life as well as determination of optimum dosing range and schedule in support of an IND.
NM891 and NM922 are promising orally bioavailable clinical candidates that preferentially kill tumor cell and also prevent the transition of stimulated fibroblasts to the CAF phenotype, thus potentially decreasing recurrence and metastasis and increasing survival rates in TNBC.
Citation Format: Leah Fung, Kyle W.H. Chan, Robert W. Sullivan, Sabine Ottilie, Cathy A. Swindlehurst. Novel orally bioavailable triple-negative breast cancer drug candidates that prevent the development of cancer associated fibroblasts in the tumor stroma. [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 B109.