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

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.

Patient-derived xenograft models capture genomic heterogeneity in endometrial cancer

“…To understand the suitability of pre-clinical PDXs models to study EC, we undertook an in-depth genomic characterization of patient primary and matched serial PDX tumor samples of EC. Immunohistochemistry studies in small panels of EC PDX models have been reported previously [ 46 , 47 ]; however, no molecular or genomic analysis of these models was included. The Amant laboratory has reported some molecular characterization of EC PDXs (e.g., microsatellite stability versus instability) with WES reported for four models [ 42 ].…”

A novel binding pocket in the D2 domain of protein tyrosine phosphatase mu (PTPmu) guides AI screen to identify small molecules that modulate tumour cell adhesion, growth and migration

“…We have identified small molecules predicted to interact with a unique regulatory site within the D2 domain of PTPμ that inhibit PTPμ‐dependent adhesion, glioma cell migration, sphere formation and growth in 3D culture. These compounds may serve as the basis for developing new treatments for cancers where the function of PTPμ is dysregulated, including glioblastoma 18 and gynaecological cancers 55 …”

Small molecule antagonists of PTPmu identified by artificial intelligence-based computational screening block glioma cell migration and growth

“…Targeting the wedge domain of PTPμ is an attractive strategy for treating malignancies. PTPμ expression is reduced in several forms of cancer (prostate [ 42 ], ovarian [ 43 ], endometrial [ 43 ], melanoma [ 44 ], and glioblastoma [ 45 ]). This suggests that PTPμ acts as a tumor suppressor, possibly by regulating adhesive interactions necessary for contact-dependent suppression of cell migration and/or growth [ 6 , 8 , 9 ].…”