This opportunity supports novel, patient-focused approaches to accelerate therapeutic development for ultra-rare pediatric and adult cancers, including molecularly defined subsets of more common cancers. Funded work may include building patient-data coordination and repositories, validating early or alternative clinical endpoints, using real-world data and registries, repurposing or re-enabling previously discontinued drugs/biologics, and improving trial feasibility with telemedicine or pragmatic designs. It also supports advanced translational R&D such as nanoparticle delivery for nucleic-acid therapeutics targeting onco-fusion transcription factors and deep single-cell profiling to discover tumor-specific plasma-membrane protein signatures for combination strategies.

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).