title: Profiling pathway-specific novel therapeutics in preclinical assessment for central nervous system atypical teratoid rhabdoid tumors (CNS ATRT): favorable activity of targeting EGFR- ErbB2 signaling with lapatinib.
abstract: Despite intensifying multimodal treatments, children with central nervous system atypical teratoid/rhabdoid tumor (CNS ATRT) continue to endure unacceptably high mortality rates. At present, concerted efforts are focusing on understanding the characteristic INI1 mutation and its implications for the growth and survival of these tumors. Additionally, pharmaceutical pipeline libraries constitute a significant source of potential agents that can be taken to clinical trials in a timely manner. However, this process requires efficient target validation and relevant preclinical studies. As an initial screening approach, a panel of 129 small molecule inhibitors from multiple pharmaceutical pipeline libraries was tested against three ATRT cell lines by in vitro cytotoxicity assays. Based on these data, agents that have strong activity and corresponding susceptible cellular pathways were identified. Target modulation, antibody array analysis, drug combination and in vivo xenograft studies were performed on one of the pathway inhibitors found in this screening. Approximately 20% of agents in the library showed activity with IC(50) values of 1 μM or less and many showed IC(50) values less than 0.05 μM. Intra cell line variability was also noted among some of the drugs. However, it was determined that agents capable of affecting pathways constituting ErbB2, mTOR, proteasomes, Hsp90, Polo like kinases and Aurora kinases were universally effective against the three ATRT cell lines. The first target selected for further analysis, the inhibition of ErbB2-EGFR pathway by the small molecule inhibitor lapatinib, indicated inhibition of cell migration properties and the initiation of apoptosis. Synergy between lapatinib and IGF-IR inhibition was also demonstrated by combination index (CI) values. Xenograft studies showed effective antitumor activity of lapatinib in vivo. We present an experimental approach to identifying agents and drug combinations for future clinical trials and provide evidence for the potential of lapatinib as an effective agent in the context of the biology and heterogeneity of its targets in ATRT.
authors: Pediatric Oncology Experimental Therapeutics Investigators Consortium (POETIC), Laboratory for Pre-Clinical and Drug Discovery Studies, University of Calgary, Calgary, Alberta, Canada.
authors: Anjali
authors: A
authors: Singh
authors: Xueqing
authors: X
authors: Lun
authors: Aarthi
authors: A
authors: Jayanthan
authors: Halah
authors: H
authors: Obaid
authors: Yibing
authors: Y
authors: Ruan
authors: Douglas
authors: D
authors: Strother
authors: Susan N
authors: SN
authors: Chi
authors: Amy
authors: A
authors: Smith
authors: Peter
authors: P
authors: Forsyth
authors: Aru
authors: A
authors: Narendran
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002648:Child; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007223:Infant; D000077341:Lapatinib; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D018335:Rhabdoid Tumor / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases
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