Abstract 3731: A novel heat shock protein 90-targeted photosensitizer (HS-201) enables enhanced tumor-specific photodynamic therapy of inflammatory breast cancers
Authors: Kensuke Kaneko, Takuya Osada, Philip F. Hughes, Timothy A. Haystead, Michael A. Morse, Herbert K. Lyerly
Journal: Cancer Research (2019)

Abstract Background: Photodynamic therapy (PDT) is an effective local anti-cancer modality applied for the treatment of early stage disease and palliation of advanced disease, and could be used in managing inflammatory breast cancer (IBC). Although PDT can be focused by limiting the area of near infrared (nIR) light exposure, normal tissue injury due to the photosensitizer (PS) uptake by non-tumor tissues remains a barrier to broader applicability. We reported that selective delivery of a compound to malignant cells by exploiting their heat shock protein 90 (Hsp90) activity could be used for imaging breast cancers. This work was extended by the development of an Hsp90 targeted PS (HS201), in which a well characterized PS, verteporfin (VP), has been chemically tethered to a small molecule Hsp90 inhibitor and assessed the tumor-specificity and antitumor efficacy of HS201-based PDT (HS201-PDT). Methods &amp; Results: HS201 was taken up by human breast cancer cell lines, including IBC in vitro more readily than VP, resulting in increased tumor killing in vitro after exposure to a laser with a 690 nm wavelength. The in vivo selectively of HS201 uptake in tumor tissue was confirmed in both human breast cancer xenograft models and spontaneous tumors from HER2-transgenic mice. HS201 accumulation in the tumor was dramatically enhanced after the first laser exposure due to the feed forward increase in Hsp90 expression in the treated tumor cells, and thus a repeated laser exposure was conducted to enhance antitumor effects. This strategy enhanced antitumor effects, as MDA-MB-231 tumors implanted into SCID-beige mice responded to HS201-PDT but not to VP-PDT. Human xenograft breast cancer cell lines, including the IBC cell lines SUM149 and KPL-4, as well as non-IBC cell line BT474M1 and the patient-derived breast cancer xenograft HCI-013, were also tested in SCID-beige mice and demonstrated significantly suppressed tumor growth by HS201-PDT. Conclusions: HS201 showed selective uptake and longer retention by tumor cells, including IBC, especially when the tumors were exposed to local laser treatment. Due to the advantage of this feed-forward control of HS201 distribution, HS201-PDT demonstrated superior anti-tumor effects compared to VP-PDT against various human breast cancer xenografts in mice. These results suggest that HS201-PDT may be used in managing IBC, and may have an important role in anti-cancer therapy. Citation Format: Kensuke Kaneko, Takuya Osada, Philip F. Hughes, Timothy A. Haystead, Michael A. Morse, Herbert K. Lyerly. A novel heat shock protein 90-targeted photosensitizer (HS-201) enables enhanced tumor-specific photodynamic therapy of inflammatory breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3731.