Novel approaches to support therapeutic development in ultra-rare cancers

The purpose of this program is to support new approaches that can be applied to facilitate therapeutic development in ultra-rare pediatric and adult cancers, including molecularly-defined subsets of more common cancers. Specific areas of interest include, but are not limited to, the following examples: • Development of infrastructure for a coordination network and data repository for patient-level data across institutions and internationally to support drug development and regulatory decision-making for one or more ultra-rare cancers. • Investigations to explore opportunities to develop and validate early clinical endpoints and other novel efficacy endpoints for evaluation of treatments for ultra-rare cancers. • Development and implementation of a collaborative multi-stakeholder effort to support generation and use of real-world data leveraging a registry framework for use in development of new therapies for pediatric patients with diffuse midline glioma (DMG) (including diffuse intrinsic pontine glioma, DIPG). • Innovative approaches to identify new biologically-driven opportunities for clinical development of previously approved drugs or biologics (hereafter referred to as drugs), including drugs for which development has been discontinued, in ultra-rare cancers. • Research to develop novel approaches to preserve the availability of drugs for which commercial developers have discontinued adult development that have strong potential in ultra-rare cancers but lack financial incentives for commercial development • Development of methods to incorporate use of telemedicine and/or pragmatic trial design elements (e.g., collecting laboratory and/or imaging data from local facilities) for patient assessments to facilitate enrollment of patients with ultra-rare cancers • Development of nanoparticle-based delivery approaches for therapeutic nucleic acids targeting onco-fusion transcription factors in metastatic tumor animal models using targeted bioPROTAC degradation or genomic editing strategies. Successful efforts should demonstrate effective delivery and expression in-vivo to tumor cells, and downregulation of the target transcription factor protein while minimizing off-target effects and limiting sequestration of the nanoparticle by the liver, spleen, and lungs. • Research to exhaustively characterize the plasma-membrane protein expression (surfaceome) of an ultra-rare cancer and the presumed healthy tissue of origin, as well as the resident-tissue stem cells, by single-cell transcriptomics and proteomics. These studies, and available correlative database analyses, should be designed to identify possible combinatorial signatures of plasma membrane proteins unique to the ultra-rare tumor. Tumors of interest include Sclerosing epithelioid fibrosarcoma and atypical teratoid rhabdoid tumors (ATRT).