Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 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 agerelated diseases is cellular senescence and its associated secretory phenotype (SASP). Senescence is a complex cellular state characterized by stress-induced replicative arrest, heterochromatization and transcriptional reprogramming. While senescence and the SASP play important short-term beneficial roles in orchestrating tumor suppression by blocking the proliferation of damaged cells, it also contributes to long-term detrimental effects if not readily removed. The oncogenic and tumor aggressive effects of senescence are driven by the SASP-associated anti-apoptotic, pro-inflammatory and invasive cytokines, growth factors and matrix-degrading enzymes. Aging tissues accumulate senescent cells; and the in vivo selective elimination of age-dependent/spontaneously emerging senescent cells is documented to delay tumor formation and deterioration of cardiac, renal and adipose tissue function. Furthermore, senescence is induced by a range of cancer treatments, including radiation, chemotherapy, and several targeted therapies. Therapy-induced senescence (TIS) and SASP-induced field cancerization may in turn promote invasive and metastatic phenotypes. In contrast, elimination of TIS cells is reported to reduce many side effects of cancer drugs in pre-clinical models, including bone marrow suppression, cardiac dysfunction, fatigue, and also reduce cancer recurrence. A number of research groups and companies are developing senotherapeutics, agents that exploit senescent cells for therapeutic benefit. Senotherapeutics include senolytics, pharmacologic agents that eliminate senescent cells, and senomorphics, agents that suppress senescent phenotype without cell-killing. A variety of agents have been reported to have senolytic activity and have demonstrated promising results in animal models. Despite the progress, senotherapeutic agents are not represented in the NCI’s SBIR portfolio and/or extensively tested as anti-cancer agents. Thus, the goal of this contract topic is to support small businesses developing senotherapeutics and catalyze the development of this class of drugs to improve outcomes for cancer patients Project Goals The purpose of this contract topic is to support the basic and pre-clinical development of senotherapeutic agents for use in research, neoadjuvant, adjuvant, or combination cancer therapy. Projects supported under this contract topic should extend the pre-clinical development of senotherapeutics as anticancer agent(s). Projects intending to enhance the efficacy of cancer therapies (including radiotherapy) or reduce the toxicities or the severity and duration of adverse effects by the use of senotherapeutics will also be supported. Such agents may include radiation-effect modulators and mitigators that reduce senescence associated side-effects. Responsive projects should have hit or lead compounds in hand, and offerors should use clearly defined parameters and accepted markers of senescence to define the population of senescent cells and senescent phenotypes being targeted by their agent(s). 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; animal efficacy testing; pharmacokinetic, pharmacodynamic, and toxicological studies. Phase I Activities and Deliverables: Phase I projects should focus on the optimization of the senotherapeutic agent(s), or combinations, and demonstrate proofof-concept by showing senolytic or senomorphic activity, and benefits in terms of efficacy and/or reduction of side effects when combined with appropriate cancer 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(s) 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. At the end of Phase I, in vivo efficacy should be demonstrated in an appropriate animal model. • Demonstrate in vitro efficacy for the agent(s) in human cancer-appropriate models. Appropriate endpoints Page 68 include demonstration of enhanced anticancer activity in combination with other therapeutic approaches (e.g. chemotherapy or radiotherapy), or the reduction of cancer therapy side-effects. • Conduct structure-activity relationship (SAR) studies, medicinal chemistry, and/or lead biologic optimization (as appropriate). • Optimize formulation of senotherapeutic agent(s) (as appropriate). • Perform animal efficacy studies in an appropriate and well-justified animal model of human cancer, for TIS, or aged mouse models that have accumulated senescent cells through aging and increased risk for cancer, and conduct experiments to determine whether senotherapeutic agent(s) confer benefits with respect to reduced side effects and/or cancer therapy efficacy. Phase II Activities and Deliverables: 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; animal efficacy testing; pharmacokinetic, pharmacodynamic, and toxicological studies. • Conduct structure-activity relationship (SAR) studies, medicinal chemistry, and/or lead biologic optimization (as appropriate). • Perform animal toxicology and 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 mitigation of adverse side effects to normal tissues and/or enhanced cancer therapy efficacy. • Perform other IND-enabling studies as appropriate for the agent(s) under development.