Abstract 3830: Novel small molecule translation inhibitors with safety and efficacy in triple negative breast cancer (TNBC) animal models

Abstract

Abstract Although the overall survival rate for early stage breast cancer is high, triple negative breast cancers are particularly aggressive and are more likely to recur than other breast cancer subtypes, resulting in a significantly increased risk of death. Eukaryotic mRNAs possess a capped 5′-end that is required for initiation of protein synthesis known as cap-dependent translation, which in normal cells is tightly controlled. Deregulation of translation initiation can lead to uncontrolled growth, a hallmark of cancer cells. Eukaryotic initiation factor 4E (eIF4E) is a critical component of the machinery that carries out cap-dependent translation in the cell and a strong determinant for the rate of translational initiation. Greater than 60% of triple negative breast tumors have high levels of eIF4E, and elevated levels of eIF4E have been shown to correlate with higher rates of recurrence and increased risk of death. We have recently developed two new classes of translation initiation inhibitors using in vitro and cellular assays of protein translation and cancer cell proliferation. These inhibitors are novel drug-like molecules with molecular weights < 500, micromolar IC50s in TNBC cells lines, desirable PK properties, and no significant toxicity. A xenograft study (MDA-MB-231 s.c. in nude mice) was performed on lead compounds NM043 and NM891 and compared to vehicle control and paclitaxel. Daily i.p. injections were initiated when mean tumor volumes reached 100 mm3 (Day 0). Mean tumor volumes at Day 31 were as follows; vehicle: 898 ±260 mm3, paclitaxel: 493± 123 mm3, NM043: 394 ± 143 mm3, and NM891: 276± 119 mm3. Analysis of AUC indicated that there were significant differences between the vehicle control group and groups treated with NM043 (p=0.003) and NM891 (p=0.001), but not paclitaxel. The groups treated with NM043 and NM891 were subdivided into 2 groups on Day 32. For the next 10 days, one group continued to receive treatment while the other did not. Statistically significant differences were noted between the vehicle control group and all treatment groups (including the drug withdrawal groups) on Day 42. Although tumor growth resumed quickly after NM043 treatment was withdrawn, tumor growth did not resume within 10 days of the withdrawal of NM891. On day 45, mice treated with NM891 were sacrificed and detectable levels of NM891 were found in both plasma and tumor samples from the mice that discontinued treatment on Day 31, indicating that less frequent dosing of NM891 will likely be an option. NM043 and NM891 are promising clinical candidates and represent potential first in class small molecule therapeutics aimed at reducing recurrence and increasing survival rates for TNBC. 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. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3830. doi:1538-7445.AM2012-3830