Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Atypical teratoid/rhabdoid tumors (AT/RT) are rare embryonal central nervous system malignancies that occur in early childhood and are lethal. Current treatment strategies for children diagnosed with AT/RT are limited to surgery, radiation, and chemotherapy, but to date, none of these have successfully improved survival beyond 18 months, and most are associated with significant toxicities given the young age of patients. Genetic inactivation of the SWI/SNF chromatin remodeling complex underlies AT/RT tumorigenesis; thus, targeted therapies that can correct the epigenetic dysregulation in AT/RT present a compelling therapeutic strategy if these agents can be selectively delivered to tumor cells in the brain. Peptide-drug conjugates (PDCs) are one treatment modality that can accomplish this by linking target-specific peptides to strong cytotoxic drugs to enhance site-specific delivery and tumor-specific therapeutic effects, while limiting exposure of the drug to healthy surrounding tissues. To leverage this approach for AT/RT, NightHawk Biosciences, Inc. has developed a 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 targeted treatment of AT/RT. In this Phase I STTR, NightHawk will partner with Dr. Nadia Dahmane’s laboratory at Weill Cornell Medicine to test two investigational anti-IGF-1R PDCs, one conjugated to the antimitotic toxin monomethyl auristatin E (MMAE), and a second conjugated to the pan-HDAC inhibitor panobinostat, in cell and animal models of AT/RT. In preliminary studies, anti-IGF-1R PDCs are efficacious against IGF-1R-expressing and AT/RT cell lines in vitro. Further, a single intratumoral injection of 429-MMAE significantly reduced tumor volumes following flank implantation of A431, an IGF-1R-expressing epithelial carcinoma. To validate the potential of this approach for AT/RT and define the optimal drug to be used in the final PDC format, we propose to examine anti-IGF-1R PDCs for therapeutic efficacy against human AT/RT cells and in an in vivo orthotopic tumor model. In Aim 1, anti-IGF-1R PDC candidates will be tested against an expanded panel of human AT/RT cell 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 response relationships 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 that completion of the proposed aims will determine potential for achieving therapeutic benefit in AT/RT and identify a lead PDC candidate to advance to IND-enabling studies.
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