Developmental Therapeutics

Case Western Reserve University, Cleveland OH

Investigators

Linked publications & trials

Abstract

DEVELOPMENTAL THERAPEUTICS (DT) PROGRAM PROJECT SUMMARY / ABSTRACT The DT Program develops and evaluates rational therapeutic solutions for advanced, refractory, poor prognosis cancers, and particularly for malignancies in the catchment area of the Case Comprehensive Cancer Center (Case CCC), for which key metrics, such as late-stage diagnosis and survival, fall below the national average. DT members assess and advance novel therapeutics emerging from laboratory discoveries within the Case CCC, and new agents developed through collaboration with other NCI Centers and industry partners. These efforts coalesce into 3 major research themes: a) identifying new areas and targets for anticancer signaling pathway modulation; b) developing technologies and tools to both predict and overcome therapy resistance and therapy-related toxicity; and c) facilitating clinical research activities that advance novel treatments or combinations of anti-cancer agents emanating from Case CCC discoveries and rationally applied to catchment- related cancer problems. The approach of the DT program is to connect basic scientists, clinicians, and shared resources (SRs) to effectively move novel compounds and congeners from bench to bedside, to ensure the observations of clinical investigators inform basic research, and to conduct Phase I and Phase II proof-of-concept clinical trials. Major arcs of research are exemplified by the development of 1) noncytotoxic epigenetic therapies for cancer; 2) 15-PGDH inhibitors to reduce therapy-related toxicity (bone marrow and other organs; and 3) development and validation of genomic biomarkers of radiation response and therapy resistance. The DT program is organized around three specific aims: (Aim 1) Interrogate cancer pathways to identify targets for new and efficacious therapeutics; (Aim 2) Elucidate molecular mechanisms of therapy-resistance and identify biomarkers predictive of response; (Aim 3) Implement early phase clinical trials around novel targets, new agents, and combinatorial approaches. These aims reflect major working groups and initiatives that engage Case CCC investigators in preclinical and clinical research efforts, grants, and trial protocols. DT Co-Leaders John Letterio, Jordan Winter, and Jennifer Yu support the activity of 74 full members representing 24 different departments across the Case CCC consortium. Members captured a total of $23.8M in research grant funding (annual direct costs), of which $9.2M is peer-reviewed and $5.1M is NCI-funded. During this grant cycle, DT program members published 1,778 publications that included 42% inter-programmatic and 23% intra- programmatic, with 22% in high-impact journals. DT members have made major practice-changing contributions benefiting cancer patients. Examples include discoveries of first-in-class compounds such as TEAD inhibitors, PP2A activators, inhibitors of the 3-beta-HSD1 enzyme, SMARC5A inhibitors, and the base-excision repair targeting agent methoxyamine. The DT member-led development and validation of a novel genomic classifier now improves risk stratification in non-metastatic prostate cancer, and DT member-identified small cell lung cancer (SCLC) genetic subsets led to new clinical trials focused on high-risk, poor prognosis subsets of SCLC.