Abstract 4527: Oral multi-pathway inhibitors for the treatment of triple negative breast cancer
Authors: Swindlehurst Cathy A. , Chan Kyle W. H. , Fung Leah , Sullivan Robert W. , Ottilie Sabine , Slepenkov Sergey V. , Huang Shile , Rhoads Robert E. 
Published: May 2015

Abstract
Triple negative breast cancer (TNBC: estrogen and progesterone receptor and Her2/Neu negative) is a high grade malignancy that is more aggressive with a higher rate of drug resistance, recurrence, metastasis, and death than other breast cancer subtypes. No targeted therapies exist, and women with TNBC have limited therapeutic options. There is clearly a need for new, more effective therapies for TNBC.
We have previously demonstrated that two different classes of translation initiation inhibitors (represented by NM043 and NM922) are safe and effective in animal models of TNBC. Recent studies show that both classes of compounds have activities in the mTORC1 and mTORC2 pathways. In particular, NM043 inhibited phosphorylation of p70 S6 kinase at Thr389, phosphorylation of 4E-BP1 at Ser65, phosphorylation of Akt at Ser473, and phosphorylation of PI3 kinase at Tyr458. Phosphorylation of all of these proteins was similarly inhibited by NM922 but at higher concentrations than for NM043. Phosphorylation of PTEN was inhibited by NM043 but not NM922. Current research is aimed at identifying the tyrosine kinase-linked receptor pathway(s) and/or target(s) affected by NM043 and NM922 that result in inhibition of phosphorylation of PI3K.
In addition to being effective in animal models of TNBC, NM922 (but not NM043) was shown to retain its anti-tumor effect after treatment withdrawal. Further, NM922 (but not NM043) was shown to prevent the TGF-β dependent activation of fibroblasts. These data indicate that in addition to anti-proliferative effects on the tumor itself, NM922 may act on the tumor stroma that supports the growth and development of the tumor, thus potentially decreasing recurrence and metastasis. Although there are several possible pathways by which TGF-β promotes fibroblast differentiation (including PI3K), the most likely additional pathway that NM922 affects is the Smad pathway.
NM922 has good oral bioavailability and is at least as effective at treating TNBC when administered orally as when administered i.p. This, combined with its dual activities on both the primary tumor and the tumor stroma makes it a very attractive clinical candidate for reducing recurrence and metastasis and increasing survival rates in TNBC. NM922 has a novel mechanism of action and should be valuable both as a stand-alone therapy and in conjunction with other therapeutic agents. The fact that it is orally active makes it attractive not only as part of the initial treatment, but also as part of a maintenance regimen.
Scale-up and formulation studies are currently underway. Future efforts will be focused on GLP toxicology and studies to determine dosing range, route, and schedule in support of an IND to advance these drugs into Phase I/II clinical trials.
(Supported by grant 2R44CA14456 from the NCI and R01GM20818 from the NIH).
Citation Format: Cathy A. Swindlehurst, Kyle W. H. Chan, Leah Fung, Robert W. Sullivan, Sabine Ottilie, Sergey V. Slepenkov, Shile Huang, Robert E. Rhoads. Oral multi-pathway inhibitors for the treatment of triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4527. doi:10.1158/1538-7445.AM2014-4527