Wnt pathway in atypical teratoid rhabdoid tumors

Chakravadhanula, Madhavi; Hampton, Chris; Chodavadia, Parth; Ozols, Victor; Zhou, Li; Catchpoole, Daniel; Xu, Jingying; Erdreich‐Epstein, Anat; Bhardwaj, Ratan D.

doi:10.1093/neuonc/nou229

Cited by 19 publications

(9 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SMARCB1, which has decreased expression in ATRT tumors (28,29), appears in Cluster 1. PTK7 shows significant upregulation across all three ATRT samples and is found in the same cluster as both transcripts of WNT5B, which was previously found to be upregulated in ATRT tumor tissue (24). A gene set enrichment analysis of our four gene clusters into biological function using gene ontology (GO) shows 86 genes involved in the top ten biological processes of each cluster.…”

Section: Resultssupporting

confidence: 57%

“…While the role that overexpression of PTK7 plays in malignancies such as colon, breast, gastric, and lung cancer has been studied, no studies to date have evaluated the role of PTK7 expression in ATRT (17–23). Prior studies in this laboratory have demonstrated that the Wnt signaling pathway has a critical role in ATRT tumor growth (24), and this present study will further evaluate how components of the Wnt pathway, such as PTK7, are involved in ATRT growth.…”

Section: Introductionmentioning

confidence: 91%

See 1 more Smart Citation

Therapeutic Targeting of PTK7 is Cytotoxic in Atypical Teratoid Rhabdoid Tumors

Messerli

Hoffman

Gnimpieba

et al. 2017

Molecular Cancer Research

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 57%

Section: Introductionmentioning

confidence: 91%

Therapeutic Targeting of PTK7 is Cytotoxic in Atypical Teratoid Rhabdoid Tumors

Messerli

Hoffman

Gnimpieba

et al. 2017

Molecular Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interestingly, an independent study using human NPC obtained from discordant dizygotic twins for congenital Zika syndrome found a similar involvement of the Wnt signaling pathway regarding differential sensitivity of NPC to ZIKV BR infection (29). Translating these results to the clinical setting, patients with aggressive AT/RT and medulloblastoma should be good candidates for a future oncolytic therapy with ZIKV BR , because Wnt pathway activation plays an important role in the biology of both tumor types (27,30), contributing to stemness and therapeutic resistance (31,32). Importantly, observed metastasis remission also suggests that a possible treatment exploring ZIKV BR oncolytic effects could benefit patients with advanced and disseminated disease.…”

Section: Discussionmentioning

confidence: 89%

“…Unbalanced regulation of Wnt signaling effectors, like CTNNB1, is common in AT/RT (27). The relevance of Wnt signaling pathway to normal neural development is also well established (28).…”

Section: Discussionmentioning

confidence: 99%

Zika Virus Selectively Kills Aggressive Human Embryonal CNS Tumor Cells In Vitro and In Vivo

et al. 2018

View full text Add to dashboard Cite

Zika virus (ZIKV) is largely known for causing brain abnormalities due to its ability to infect neural progenitor stem cells during early development. Here, we show that ZIKV is also capable of infecting and destroying stem-like cancer cells from aggressive human embryonal tumors of the central nervous system (CNS). When evaluating the oncolytic properties of Brazilian Zika virus strain (ZIKV) against human breast, prostate, colorectal, and embryonal CNS tumor cell lines, we verified a selective infection of CNS tumor cells followed by massive tumor cell death. ZIKV was more efficient in destroying embryonal CNS tumorspheres than normal stem cell neurospheres. A single intracerebroventricular injection of ZIKV in BALB/c nude mice bearing orthotopic human embryonal CNS tumor xenografts resulted in a significantly longer survival, decreased tumor burden, fewer metastasis, and complete remission in some animals. Tumor cells closely resembling neural stem cells at the molecular level with activated Wnt signaling were more susceptible to the oncolytic effects of ZIKV Furthermore, modulation of Wnt signaling pathway significantly affected ZIKV-induced tumor cell death and viral shedding. Altogether, these preclinical findings indicate that ZIKV could be an efficient agent to treat aggressive forms of embryonal CNS tumors and could provide mechanistic insights regarding its oncolytic effects. Brazilian Zika virus strain kills aggressive metastatic forms of human CNS tumors and could be a potential oncolytic agent for cancer therapy. .

show abstract

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

This project involves an examination of the effect of the small molecule inhibitor 4SC-202 on the growth of the pediatric brain cancer medulloblastoma. The small molecule inhibitor 4SC-202 significantly inhibits the viability of the pediatric desmoplastic cerebellar human medulloblastoma cell line DAOY, with an IC50 = 58.1 nM, but does not affect the viability of noncancerous neural stem cells (NSC). 4SC-202 exposure inhibits hedgehog expression in the DAOY cell line. Furthermore, microarray analysis of human medulloblastoma patient tumors indicate significant upregulation of key targets in the Hedgehog signaling pathway and Protein Tyrosine Kinase (PTK7).

show abstract

Wnt pathway in atypical teratoid rhabdoid tumors

Abstract: These promising therapeutic options will be studied further before starting a translational clinical trial. The success of these options will improve care for these patients.

Cited by 19 publications

References 48 publications

Therapeutic Targeting of PTK7 is Cytotoxic in Atypical Teratoid Rhabdoid Tumors

Therapeutic Targeting of PTK7 is Cytotoxic in Atypical Teratoid Rhabdoid Tumors

Zika Virus Selectively Kills Aggressive Human Embryonal CNS Tumor Cells In Vitro and In Vivo

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

Contact Info

Product

Resources

About