Novel Therapeutics and Therapeutic Modalities Research Program

NOVEL THERAPEUTICS AND THERAPEUTIC MODALITIES (NTTM): ABSTRACT The Novel Therapeutics and Therapeutic Modalities (NTTM) Program was established in 2023 to create a cross-disciplinary platform for development of non-immunological cancer therapies from inception to early phase clinical studies. Created by expansion of the former Experimental Therapeutics Program to encompass non-immunomodulatory components of the gene/virus therapy portfolio as well as emerging areas of scientific strength in radiotherapies, the NTTM Program will lead the Mayo Clinic Comprehensive Cancer Center (MCCCC) strategy of developing more effective and less toxic treatments for neoplastic diseases through pursuit of three overarching aims: 1) Lead preclinical development of novel treatments, including targeted small molecules, biologics, nanomedicines, gene therapies, radiotheranostics (including alpha radiopharmaceuticals), and external beam therapy (including proton and carbon particles), as monotherapies or in novel combinations; 2) Identify predictors of sensitivity, resistance, and/or toxicity to these therapies; and 3) Conduct early phase clinical trials, from first-in-human to phase II studies, of these therapies, including multimodality combinations. Illustrative scientific accomplishments over the past five years include preclinical development of a MET kinase proteolysis targeting chimera and novel chelators for radio-immunoconjugate development (Aim 1); identification of homologous recombination as a determinant of response to proton therapy (Aim 2); and completion of a first-in-human phase I trial of WSD0922-FU, a brain-penetrant inhibitor of mutant EGFR (Aim 3). NTTM fosters collaboration between 62 members (45 MCR, 6 MCA, 11 MCF) spanning 20 departments. Program members hold $10.6M/year (direct costs) in peer-reviewed funding ($6.5M from NCI) and $12.9M/year in industry and non-peer-reviewed funding. NTTM members collaborate extensively with the Cancer Genomics, Signaling and Metastasis (CGSM), Cancer Immunology and Immunotherapeutics (CII), and Advanced Clinical Trials and Translational Sciences (ACTS) Research Programs; the MCCCC Disease Groups that oversee selection and prioritization of clinical trials; and the Community Outreach and Engagement Office (COE) to ensure that research is responsive to catchment area needs and includes patient and community input from concept to discovery dissemination. From 2019-2023, NTTM members accrued 3665 patients to interventional treatment trials and published 1548 peer-reviewed papers, with 15% intra-programmatic, 42% inter-programmatic, 39% inter-institutional and 23% in high impact journals (Impact Factor 10). Over the proposed funding period, NTTM members will continue to train and mentor future investigators and MCCCC emerging leaders, while simultaneously striving to increase the efficacy and diminish the toxicity of cancer therapy by developing novel small molecules, neutralization-resistant Vesiculovirus-based gene/virotherapies, multi-layered nanoparticles, alpha-PET radio-immunoconjugates, carbon ion-based treatments, innovative spatially inhomogeneous radiotherapies, and mechanism-based multi-modality combinations.