Detection of Tumor-Specific PTPmu in Gynecological Cancer and Patient Derived Xenografts.

Jason Vincent,Stefanie Avril,Jyosthna Narla,Susann M Brady-Kalnay,Sonya E L Craig,Analisa Difeo,Mette L Johansen

doi:10.3390/diagnostics11020181

Abstract

Background: We developed a fluorophore-conjugated peptide agent, SBK4, that detects a tumor-specific proteolyzed form of the cell adhesion molecule, PTPmu, found in the tumor microenvironment. We previously demonstrated its tissue specific distribution in high-grade brain tumors. To extend those studies to other aggressive solid tumor types, we assessed the tissue distribution of PTPmu/SBK4 in a set of matched gynecologic cancer patient derived xenografts (PDXs) and primary patient tumors, as well as a limited cohort of tumors from gynecological cancer patients. PDXs isolated from the tissues of cancer patients have been shown to yield experimentally manipulatable models that replicate the clinical characteristics of individual patients’ tumors. In this study, gynecological cancer PDXs and patient biopsies were examined to determine if tumor-specific proteolyzed PTPmu was present. Methods: We used the peptide agent SBK4 conjugated to the fluorophore Texas Red (TR) to label tumor tissue microarrays (TMAs) containing patient and/or PDX samples from several high-grade gynecologic cancer types, and quantified the level of staining with Image J. In one TMA, we were able to directly compare the patient and the matched PDX tissue on the same slide. Results: While normal tissue had very little SBK4-TR staining, both primary tumor tissue and PDXs have higher labeling with SBK4-TR. Matched PDXs and patient samples from high-grade endometrial and ovarian cancers demonstrated higher levels of PTPmu by staining with SBK4 than normal tissue. Conclusion: In this sample set, all PDXs and high-grade ovarian cancer samples had increased labeling by SBK4-TR compared with the normal controls. Our results indicate that proteolyzed PTPmu and its novel peptide detection agent, SBK4, allow for the visualization of tumor-specific changes in cell adhesion molecules by tissue-based staining, providing a rationale for further development as an imaging agent in aggressive solid tumors, including gynecological cancers.

Highlights

There are many distinct gynecological cancers that can be divided into groups based on their tumor location, and are primarily ovarian, endometrial, and cervical
Individual tumor samples were obtained from the distinct patient derived xenografts (PDXs) models and stained with the SBK4-Texas Red (TR) agent to investigate whether the PTPμ biomarker was present
One ovarian endometrioid PDX grew in the ovary and metastasized to the intraperitoneal lining (Figure 1I,J)

Summary

Introduction

There are many distinct gynecological cancers that can be divided into groups based on their tumor location, and are primarily ovarian, endometrial, and cervical. Cervical cancer is the most rare of the three gynecologic tumor types, with 13,170 estimated new cases diagnosed in 2019 in the U.S, and a 65.8% five-year relative survival rate [4]. Methods: We used the peptide agent SBK4 conjugated to the fluorophore Texas Red (TR) to label tumor tissue microarrays (TMAs) containing patient and/or PDX samples from several high-grade gynecologic cancer types, and quantified the level of staining with Image J. Matched PDXs and patient samples from high-grade endometrial and ovarian cancers demonstrated higher levels of PTPmu by staining with SBK4 than normal tissue. Our results indicate that proteolyzed PTPmu and its novel peptide detection agent, SBK4, allow for the visualization of tumorspecific changes in cell adhesion molecules by tissue-based staining, providing a rationale for further development as an imaging agent in aggressive solid tumors, including gynecological cancers

Methods

Results

Discussion

Conclusion