TY - JOUR
T1 - Folate hydrolase-1 (FOLH1) is a novel target for antibody-based brachytherapy in Merkel cell carcinoma
AU - Ramirez-Fort, M. K.
AU - Meier-Schiesser, B.
AU - Lachance, K.
AU - Mahase, S. S.
AU - Church, C. D.
AU - Niaz, M. J.
AU - Liu, H.
AU - Navarro, V.
AU - Nikolopoulou, A.
AU - Kazakov, D. V.
AU - Contassot, E.
AU - Nguyen, D. P.
AU - Sach, J.
AU - Hadravsky, L.
AU - Sheng, Y.
AU - Tagawa, S. T.
AU - Wu, X.
AU - Lange, C. S.
AU - French, L. E.
AU - Nghiem, P. T.
AU - Bander, N. H.
N1 - Funding Information:
The authors acknowledge and thank Mr. Jonathan Moy and Ms. Jessica Vississchio for their assistance in data collection as visiting students in Dr. Neil Bander's Urology Oncology laboratory at Weill Cornell Medicine. The authors express their gratitude to Drs. Anthony Nicastri, Jianying Zeng and Edward Heilman of the departments of Pathology and Permatology at the SUNY Downstate Health Sciences University for their histopathological evaluation, critical revision and technical support. The data presented in this manuscript were generated during Dr. Marigdalia Ramirez-Fort's Holman Research Pathway in Radiation Oncology under mentorship of Drs. Christopher Lange, Lars French and Neil Bander. This research was funded in part through the NIH/NCI Cancer Center Support Grant (P30 CA015704); and the National Cancer Institute (K24 CA139052), the Kelsey Dickson Team Science Courage Research Team Award Prostate Cancer Foundation (PCF, award #15CHAS04) and the University of Washington MCC Patient Gift Fund to Dr. Paul Nghiem.
Funding Information:
The authors acknowledge and thank Mr. Jonathan Moy and Ms. Jessica Vississchio for their assistance in data collection as visiting students in Dr. Neil Bander's Urology Oncology laboratory at Weill Cornell Medicine. The authors express their gratitude to Drs. Anthony Nicastri, Jianying Zeng and Edward Heilman of the departments of Pathology and Permatology at the SUNY Downstate Health Sciences University for their histopathological evaluation, critical revision and technical support. The data presented in this manuscript were generated during Dr. Marigdalia Ramirez‐Fort's Holman Research Pathway in Radiation Oncology under mentorship of Drs. Christopher Lange, Lars French and Neil Bander. This research was funded in part through the NIH/NCI Cancer Center Support Grant (P30 CA015704); and the National Cancer Institute (K24 CA139052), the Kelsey Dickson Team Science Courage Research Team Award Prostate Cancer Foundation (PCF, award #15CHAS04) and the University of Washington MCC Patient Gift Fund to Dr. Paul Nghiem.
Publisher Copyright:
© 2020 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.
PY - 2021/3
Y1 - 2021/3
N2 - Backgrounds: Folate Hydrolase-1 (FOLH1; PSMA) is a type II transmembrane protein, luminally expressed by solid tumour neo-vasculature. Monoclonal antibody (mAb), J591, is a vehicle for mAb-based brachytherapy in FOLH1+ cancers. Brachytherapy is a form of radiotherapy that involves placing a radioactive material a short distance from the target tissue (e.g., on the skin or internally); brachytherapy is commonly accomplished with the use of catheters, needles, metal seeds and antibody or small peptide conjugates. Herein, FOLH1 expression in primary (p) and metastatic (m) Merkel cell carcinoma (MCC) is characterized to determine its targeting potential for J591-brachytherapy. Materials & Methods: Paraffin sections from pMCC and mMCC were evaluated by immunohistochemistry for FOLH1. Monte Carlo simulation was performed using the physical properties of conjugated radioisotope lutetium-177. Kaplan–Meier survival curves were calculated based on patient outcome data and FOLH1 expression. Results: Eighty-one MCC tumours were evaluated. 67% (54/81) of all cases, 77% (24/31) pMCC and 60% (30/50) mMCC tumours were FOLH1+. Monte Carlo simulation showed highly localized ionizing tracks of electrons emitted from the targeted neo-vessel. 42% (34/81) of patients with FOLH1+/− MCC had available survival data for analysis. No significant differences in our limited data set were detected based on FOLH1 status (p = 0.4718; p = 0.6470), staining intensity score (p = 0.6966; p = 0.9841) or by grouping staining intensity scores (− and + vs. ++, +++, +++) (p = 0.8022; p = 0.8496) for MCC-specific survival or recurrence free survival, respectively. Conclusions: We report the first evidence of prevalent FOLH1 expression within MCC-associated neo-vessels, in 60-77% of patients in a large MCC cohort. Given this data, and the need for alternatives to immune therapies it is appropriate to explore the safety and efficacy of FOLH1-targeted brachytherapy for MCC. What's already known about this topic?. We report the first evidence of prevalent folate hydrolase-1 (FOLH1; also known as prostate-specific membrane antigen) expression within MCC-associated neovessels. What does this study add?. Herein, FOLH1 expression in Merkel cell carcinoma neovasculature is validated, and the therapeutic mechanism of specific, systemic targeting of disseminated disease with antibody-based brachytherapy, is defined.
AB - Backgrounds: Folate Hydrolase-1 (FOLH1; PSMA) is a type II transmembrane protein, luminally expressed by solid tumour neo-vasculature. Monoclonal antibody (mAb), J591, is a vehicle for mAb-based brachytherapy in FOLH1+ cancers. Brachytherapy is a form of radiotherapy that involves placing a radioactive material a short distance from the target tissue (e.g., on the skin or internally); brachytherapy is commonly accomplished with the use of catheters, needles, metal seeds and antibody or small peptide conjugates. Herein, FOLH1 expression in primary (p) and metastatic (m) Merkel cell carcinoma (MCC) is characterized to determine its targeting potential for J591-brachytherapy. Materials & Methods: Paraffin sections from pMCC and mMCC were evaluated by immunohistochemistry for FOLH1. Monte Carlo simulation was performed using the physical properties of conjugated radioisotope lutetium-177. Kaplan–Meier survival curves were calculated based on patient outcome data and FOLH1 expression. Results: Eighty-one MCC tumours were evaluated. 67% (54/81) of all cases, 77% (24/31) pMCC and 60% (30/50) mMCC tumours were FOLH1+. Monte Carlo simulation showed highly localized ionizing tracks of electrons emitted from the targeted neo-vessel. 42% (34/81) of patients with FOLH1+/− MCC had available survival data for analysis. No significant differences in our limited data set were detected based on FOLH1 status (p = 0.4718; p = 0.6470), staining intensity score (p = 0.6966; p = 0.9841) or by grouping staining intensity scores (− and + vs. ++, +++, +++) (p = 0.8022; p = 0.8496) for MCC-specific survival or recurrence free survival, respectively. Conclusions: We report the first evidence of prevalent FOLH1 expression within MCC-associated neo-vessels, in 60-77% of patients in a large MCC cohort. Given this data, and the need for alternatives to immune therapies it is appropriate to explore the safety and efficacy of FOLH1-targeted brachytherapy for MCC. What's already known about this topic?. We report the first evidence of prevalent folate hydrolase-1 (FOLH1; also known as prostate-specific membrane antigen) expression within MCC-associated neovessels. What does this study add?. Herein, FOLH1 expression in Merkel cell carcinoma neovasculature is validated, and the therapeutic mechanism of specific, systemic targeting of disseminated disease with antibody-based brachytherapy, is defined.
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U2 - 10.1002/ski2.9
DO - 10.1002/ski2.9
M3 - Article
AN - SCOPUS:85142846229
SN - 2690-442X
VL - 1
JO - Skin Health and Disease
JF - Skin Health and Disease
IS - 1
M1 - e9
ER -