Therapeutic Targeting of PTK7 is Cytotoxic in Atypical Teratoid Rhabdoid Tumors

Abstract

Novel discoveries involving the evaluation of potential therapeutics are based on newly identified molecular targets for atypical teratoid rhabdoid tumors (ATRT), which are the most common form of infantile brain tumors. Central nervous system ATRTs are rare, aggressive, and fast growing tumors of the brain and spinal cord and carry a very poor prognosis. Currently, the standard of care for ATRT patients is based on surgical resection followed by systemic chemotherapy and radiation therapy, which result in severe side effects. Since protein tyrosine kinases have proven to be actionable targets that reduce tumor growth in a number of cancers, we examined how inhibiting tyrosine kinases affected ATRT tumor growth. Here, we examine the therapeutic efficacy of the broad spectrum tyrosine kinase inhibitor Vatalanib in the treatment of ATRT. Vatalanib significantly reduced the growth of ATRT tumor cell lines, both in two-dimensional cell culture and in three-dimensional cell culture using a spheroid model. Since Vatalanib had a remarkable effect on the growth of ATRT, we decided to use a transcriptomic approach to therapy by examining new actionable targets, such as tyrosine kinases. Next generation RNA sequencing and NanoString data analysis showed a significant increase in PTK7 RNA expression levels in ATRT tumors. Inhibition of PTK7 by short interference RNA treatment significantly decreases the viability of ATRT patient-derived tumor cell lines. Implications These studies provide the groundwork for future preclinical in vivo studies aiming to investigate the efficacy of PTK7 inhibition on ATRT tumor growth.

Long non-coding RNA DSCR8 acts as a molecular sponge for miR-485-5p to activate Wnt/β-catenin signal pathway in hepatocellular carcinoma

“…Frizzled-7 (FZD7) is one of the receptors for Wnt signaling pathway 13 . It has been strongly confirmed that FZD7 is highly expressed in multiple cancers, including HCC 14 – 16 . And overexpressed FZD7 promotes the progression of cancers by inducing the activation of Wnt signaling pathway 13 , 17 .…”

Biphasic regulation of tumorigenesis by PTK7 expression level in esophageal squamous cell carcinoma

“…The inhibition of PTK7 has been suggested as a novel therapeutic target for various cancers such as colorectal cancer and atypical teratoid rhabdoid tumors 31 , 32 , and some anticancer agents under development involve PTK7-targeted antibody-drug conjugates 33 or PTK7 aptamers 34 . However, caution should be used with this strategy when considering the evidence showing PTK7 can biphasically regulate tumorigenesis, as the inhibition of PTK7 activity or removal of PTK7-positive cells may induce tumor progression.…”

4SC-202 as a Potential Treatment for the Pediatric Brain Tumor Medulloblastoma

“…Upregulation of target proteins identified by analysis of the microarray data may be important targets for future therapies for medulloblastoma. As we have previously demonstrated, upregulation of PTK 7 may indicate that it is an important target for pediatric cancers [ 3 ]. LSD1, HDAC2, and HDAC3 are key targets for 4SC-202, and thus upregulation of these targets across the studied medulloblastomas makes 4SC-202 a more actionable therapeutic.…”

“…However, there are few effectual treatments and surgery on children is not effective as the removal of the entire brain tumor is difficult. Recently, transcriptome profiling of malignancies of the central nervous system (CNS) have provided important insights into potential targets for therapies [ 2 , 3 , 4 ]. Here, we examine how transcriptome profiling of pediatric medulloblastomas reveals targets for potential therapies.…”