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Gail M Seigel, Pia Mendoza, Eszter Szalai, Dhaval K Shah, Hans E Grossniklaus; HER2 immunoreactivity and drug targeting in human retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1777. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Retinoblastoma (RB) is an ocular malignancy of early childhood. Although there has been success in treating RB through enucleation, recent emphasis has been on vision-preserving chemotherapy treatments that spare the eye and preserve visual function, but may not kill chemoresistant cells. There is a need for targeted RB therapies that can address chemoresistance and provide a wider therapeutic index. One potential therapeutic target for RB is HER2, (ERBB2), a member of the epidermal growth factor family that is expressed in RB cell lines and tumors, as we have shown previously. In this study, we conducted a larger scale examination of 28 human RB tumors to address the following hypotheses: 1) HER2 is preferentially expressed in high grade, invasive tumors and 2) HER2 is sufficiently expressed in RB tumors to warrant further development of HER2-targeted RB therapies.
Twenty-eight paraffin sections of RB tumors (Groups B-D; TNM Stages pT1-pT4) were examined by HER2 immunohistochemistry, along with isotype negative controls. Fluorescence intensities in specific regions of the tumors (eg. central tumor, leading edge, vitreous seeds) were quantitated by ImageJ analysis and analyzed by Prism Software for statistical significance. Fluorescence results and clinical parameters (Group, TNM status) were correlated for each tumor.
Fourteen of the 28 human RB samples show HER2 staining intensity at least two standard deviations above the mean of the negative control. Specific tumor regions were statistically more fluorescent than the negative control (p values ranging from 0.0001 to 0.042). Of the eight RB tumors with the brightest regions of fluorescence, five were staged pT3b and seven were in Group D or E, considered high grade tumors in our cohort. Only one of these tumors was not (yet) invasive. Half of the pT3b grade were HER2-high (5/10), compared to the combined lower grades of pT1-pT2a (2/10).
Our results suggest that HER2 is expressed at significant levels in at least half of our RB cohort, with higher levels of immunoreactivity in higher grade tumors. This information will be important for personalized medicine decisions as we develop HER2-targeted therapies for RB. In turn, this may lead to innovative and targeted drug treatment options designed to spare the eye, preserve vision and improve quality of life for RB patients.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
HER2 immunoreactivity in RB
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