Background: Triple-negative breast cancer (TNBC) characterized by estrogen and progesterone receptor and HER-2-negativity is a particularly aggressive tumor with currently no effective targeted therapies. Our previous findings demonstrated that Hsp90 inhibition by the purine-scaffold inhibitor PU-H71 is a promising therapeutic approach in this tumor type. In TNBC cells, a multitude of malignancy driving proteins, including EGFR, HER3, Akt, PDK1, Bcl-xL and Raf-1, were in a complex with Hsp90 and were preferentially targeted for degradation by PU-H71 (Abstract 5637, AACR-Annual Meeting 2008/2009). In TNBC xenografts, PU-H71 exhibited potent and durable anti-tumor activity inducing complete responses without toxicity to the host. PU-H71 also inhibited the invasiveness of TNBC cells through a mechanism involving downregulation and inhibition of several pro-metastatic proteins such as NF-kB, p-Akt, ERK2, TYK2 and PKC, suggesting a potential effect of PU-H71 on TNBC metastasis.

Study design: In order to determine whether in vivo PU-H71 also inhibits TNBC metastasis, we analyzed the effect of the Hsp90 inhibitor on lung colonization and metastastic body formation in immunocompromised mice. A lung tropic MDA-MB231 derivative expressing luciferase was used to establish the experimental models of metastasis. Animals were treated with 75mg/kg PU-H71 three times/week and lung metastases were monitored periodically by bioluminiscence imaging (IVIS system).

Results: At completion of treatment both bioluminescent imaging and histological analyses demonstrated significant reduction of the metastastatic burden in mice treated with PU-H71 compared to the vehicle treated group. Importantly, flow cytometry analysis demonstrated that circulating hematopoietic precursors related to metastatic spread were reduced after treatment with PU-H71 and several hematopoietic cell types recruited to metastatic sites such as CD11b+/Gr1+ were reduced after the treatment. In addition, analysis of metastatic lungs demonstrated that CD24low/CD44+ cells were attracted to metastatic lung in MDA-MB231 bearing mice and strongly reduced after PU-H71 treatment.

Conclusion: These data demonstrate that in addition to inhibition of primary tumors, PU-H71 leads to potent impairment of lung metastasis in an in vivo model of TNBC, supporting the use of PU-H71 for clinical trials involving patients with advanced and metastatic disease.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5766.

©2010 American Association for Cancer Research
2010