Fast track proposals will be accepted. Direct-to-Phase II proposals will not be accepted. Number of anticipated awards: 3-4 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Age is a well-recognized risk factor for cancer development, and older patients pose a growing healthcare challenge since they are prone to developing more aggressive and therapy-resistant tumors. A key biological contributor to aging and age-related diseases is cellular senescence - a complex state characterized by not only its role in wound healing and tumor suppressive function via stress-induced replicative arrest, but also in driving neoplastic transformation and tumor aggressiveness downstream of its anti-apoptotic effect and expression/secretion of wide-ranging pro-tumorigenic cytokines, growth factors, and matrix-degrading enzymes. Aging tissues accumulate senescent cells, and the in vivo selective elimination of spontaneously emerging, age-associated senescent cells has been documented to delay tumor formation and deterioration of cardiac, renal, and adipose tissue function. Furthermore, senescence is induced by a range of cancer therapies, including radiation, chemotherapy, and several targeted therapies. In certain cancer types, this therapy-induced senescence (TIS) promotes invasive and metastatic phenotypes. Eliminating TIS cells has been reported to reduce many side effects of cancer drugs, including bone marrow suppression, cardiac dysfunction, fatigue, and also to reduce cancer recurrence. For research purposes, several genetically encoded methods to eliminate senescent cells have been developed and have proved critical in understanding the biology of senescence. More recently, attention has turned to the development of pharmacologic agents that selectively kill senescent cells (i.e., senolytic agents). A variety of agents have been reported to have senolytic activity and have demonstrated promising results in animal models. Project Goals The purpose of this contract topic is to support the pre-clinical development of senolytic agents for use in neoadjuvant and/or adjuvant/combination cancer therapy. Projects supported under this contract topic should further the pre-clinical development of senolytic agent(s). To apply for this topic, offerors should: • Identify a molecular target(s) and provide a clear rationale for how the proposed senolytic agent, or combination, will induce selective elimination of either spontaneously emerging or therapy-induced senescent cells, which are induced by relevant anti-cancer treatments (e.g., chemotherapy, radiation, etc.). Offerors should use clearly defined parameters and accepted markers of senescence to define the population of senescent cells being targeted by their agent. • Provide preliminary data or cite literature to support the proposed mechanism of action. • Demonstrate ownership of, or license for, at least one lead agent (e.g., compound or antibody) with preliminary in vitro data demonstrating senolytic activity. • Select and provide clear rationale for a specific indication that the senolytic agent will address (cancer type and context of treatment induced senescence). • Identify and provide justification for the choice of human cancer-relevant in vitro assays and in vivo models. Phase I projects should focus on the optimization of the senolytic agent, or combinations, and demonstrate proof-of-concept by showing selective elimination of senescent cells and benefits in terms of efficacy and/or reduction of side effects when combined with appropriate treatments (e.g., chemotherapy or radiotherapy) in human cancer-relevant animal models. Offerors should provide a justification and rationale for their choice of animal model for the proof-of-concept studies. The scope of work proposed may include structure activity relationships (SAR); medicinal chemistry for small molecules; antibody and protein engineering for biologics; formulation; and in vivo efficacy testing. Phase II projects should focus on IND-enabling pre-clinical studies. The scope of work may include further work on structure activity relationships (SAR); formulation; in vivo efficacy testing; or pharmacokinetic, pharmacodynamic, and toxicological studies. Phase I Activities and Deliverables • Demonstrate in vitro efficacy for the agent(s) in human cancer-appropriate models. • Conduct structure-activity relationship (SAR) studies, medicinal chemistry, and/or lead biologic optimization (as appropriate). • Optimize formulation of senolytic agent(s) (as appropriate). • Perform animal efficacy studies in an appropriate, and well justified animal model, for cancer therapy-induced senescence, or aged mouse models that have accumulated senescent cells through aging, and conduct experiments to determine whether senolytic agent(s) confer benefits with respect to side effects and/or cancer therapy efficacy. Phase II Activities and Deliverables • Conduct structure-activity relationship (SAR) studies, medicinal chemistry, and/or lead biologic optimization (as appropriate). • Perform animal toxicology and/or pharmacology studies as appropriate for the agent(s) selected for development. • Expand upon initial animal efficacy studies in an appropriate model for cancer therapy-induced senescence and conduct experiments to determine whether senolytic agent(s) confer benefits with respect to side effects and/or cancer therapy efficacy. • Other research and development activities necessary to submit an IND application.