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Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues.

ABSTRACT: Purpose: This study examines cell surface ROR1 expression in human tumors and normal tissues. ROR1 is considered a promising target for cancer therapy due to putative tumor-specific expression, and multiple groups are developing antibodies and/or chimeric antigen receptor-modified T cells to target ROR1. On-target, off-tumor toxicity is a challenge for most nonmutated tumor antigens; however, prior studies suggest that ROR1 is absent on most normal tissues.Experimental Design: Our studies show that published antibodies lack sensitivity to detect endogenous levels of cell surface ROR1 by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded tissues. We developed a ROR1-specific monoclonal antibody (mAb) targeting the carboxy-terminus of ROR1 and evaluated its specificity and sensitivity in IHC.Results: The 6D4 mAb is a sensitive and specific reagent to detect cell surface ROR1 by IHC. The data show that ROR1 is homogenously expressed on a subset of ovarian cancer, triple-negative breast cancer, and lung adenocarcinomas. Contrary to previous findings, we found ROR1 is expressed on several normal tissues, including parathyroid; pancreatic islets; and regions of the esophagus, stomach, and duodenum. The 6D4 mAb recognizes rhesus ROR1, and ROR1 expression was similar in human and macaque tissues, suggesting that the macaque is a suitable model to evaluate safety of ROR1-targeted therapies.Conclusions: ROR1 is a promising immunotherapeutic target in many epithelial tumors; however, high cell surface ROR1 expression in multiple normal tissues raises concerns for on-target off-tumor toxicities. Clinical translation of ROR1-targeted therapies warrants careful monitoring of toxicities to normal organs and may require strategies to ensure patient safety. Clin Cancer Res; 23(12); 3061-71. ©2016 AACR.

SUBMITTER: Balakrishnan A

PROVIDER: S-EPMC5440207 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues.

Balakrishnan Ashwini A Goodpaster Tracy T Randolph-Habecker Julie J Hoffstrom Benjamin G BG Jalikis Florencia G FG Koch Lisa K LK Berger Carolina C Kosasih Paula L PL Rajan Anusha A Sommermeyer Daniel D Porter Peggy L PL Riddell Stanley R SR

Clinical cancer research : an official journal of the American Association for Cancer Research 20161116 12

<b>Purpose:</b> This study examines cell surface ROR1 expression in human tumors and normal tissues. ROR1 is considered a promising target for cancer therapy due to putative tumor-specific expression, and multiple groups are developing antibodies and/or chimeric antigen receptor-modified T cells to target ROR1. On-target, off-tumor toxicity is a challenge for most nonmutated tumor antigens; however, prior studies suggest that ROR1 is absent on most normal tissues.<b>Experimental Design:</b> Our ...[more]

PMID: 27852699

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Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues.

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Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues.

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