Description:
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
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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.
