Atypical teratoid/rhabdoid tumors (AT/RT) are rare embryonal central nervous system malignancies that occurin early childhood and are lethal. Current treatment strategies for children diagnosed with AT/RT are limited tosurgery, radiation, and chemotherapy, but to date, none of these have successfully improved survival beyond18 months, and most are associated with significant toxicities given the young age of patients. Geneticinactivation of the SWI/SNF chromatin remodeling complex underlies AT/RT tumorigenesis; thus, targetedtherapies that can correct the epigenetic dysregulation in AT/RT present a compelling therapeutic strategy ifthese agents can be selectively delivered to tumor cells in the brain. Peptide-drug conjugates (PDCs) are onetreatment modality that can accomplish this by linking target-specific peptides to strong cytotoxic drugs toenhance site-specific delivery and tumor-specific therapeutic effects, while limiting exposure of the drug tohealthy surrounding tissues. To leverage this approach for AT/RT, NightHawk Biosciences, Inc. has developeda PDC strategy that combines a novel binding peptide ("429") against the Insulin-like Growth Factor 1 Receptor(IGF-1R), which is highly expressed on the surface of AT/RT cells, with potent cytotoxic drugs for targetedtreatment of AT/RT. In this Phase I STTR, NightHawk will partner with Dr. Nadia Dahmane's laboratory at WeillCornell Medicine to test two investigational anti-IGF-1R PDCs, one conjugated to the antimitotic toxinmonomethyl auristatin E (MMAE), and a second conjugated to the pan-HDAC inhibitor panobinostat, in cell andanimal models of AT/RT. In preliminary studies, anti-IGF-1R PDCs are efficacious against IGF-1R-expressingand AT/RT cell lines in vitro. Further, a single intratumoral injection of 429-MMAE significantly reduced tumorvolumes following flank implantation of A431, an IGF-1R-expressing epithelial carcinoma. To validate thepotential of this approach for AT/RT and define the optimal drug to be used in the final PDC format, we proposeto examine anti-IGF-1R PDCs for therapeutic efficacy against human AT/RT cells and in an in vivo orthotopictumor model. In Aim 1, anti-IGF-1R PDC candidates will be tested against an expanded panel of human AT/RTcell lines for effects on cell viability, apoptosis, cytotoxicity, and cell migration and invasion. In Aim 2, systemic(intravenous) and direct (intratumoral) drug delivery strategies will be explored to define dose-exposure responserelationships and to determine the maximum tolerated dose. Aim 3 will evaluate in vivo efficacy of the anti-IGF-1R PDCs on tumor inhibition and survival in an established orthotopic mouse model of AT/RT. We expect thatcompletion of the proposed aims will determine potential for achieving therapeutic benefit in AT/RT and identifya lead PDC candidate to advance to IND-enabling studies.
Public Health Relevance Statement: NARRATIVE
Atypical teratoid/rhabdoid tumors (AT/RT) are rare but lethal childhood brain cancers that lack effective and
safe targeted therapies. NightHawk Biosciences, Inc. has developed an anti-IGF-1R peptide-drug conjugate
(PDC) to link an AT/RT-targeting peptide to strong cytotoxic drugs for enhanced delivery and tumor specific
treatment. NightHawk has partnered with N. Dahmane's laboratory at Weill Cornell Medicine examine the
potential of this therapeutic approach for AT/RT.
Project Terms: <0-11 years old> | | | | | | | | | | 