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232 Development of Anticancer Agents

Number of anticipated awards: 7
(Fast-Track proposals will not be accepted.)
Budget (total costs): Phase I: $150,000;
Phase II: $1,500,000

The deadline for receipt of all contract proposals submitted in response to this solicitation was:
5:00 p.m. Eastern Standard Time
Monday, November 6, 2006

The short term goal of this SBIR contract topic is to create a mechanism whereby candidate therapeutic agents of interest to NCI can be further developed by small businesses. (For a list of the compounds of interest to NCI, please click here.) (If required, commercialization licenses must be separately negotiated with NIH's Office of Technology Transfer (OTT) and could take the form of a Commercial Evaluation License, a Non-Exclusive License or an Exclusive License to perform pre-clinical development.) Work scope may include animal efficacy testing, SAR, medicinal chemistry, formulation, production of GMP bulk drug and clinical product, pharmacokinetic, pharmacodynamic, and toxicological studies. These data will establish the rationale for continued development of the experimental therapeutic agent to the point of filing an IND. Ownership of all intellectual property generated in these experiments will be determined by patent law although it is anticipated that experimental data generated by the small business will be owned by the small business, and it may use this information to continue developing the agent independently, or partner with academia or industry in bringing this agent to the clinic (if required, Non-exclusive or Exclusive Licenses must be separately negotiated with the OTT). Successful projects will also be eligible for further development at NCI, including early-stage clinical trials via the Joint DCTD-CCR Early Therapeutic Development Program. Non-confidential summaries of compounds available for development will be available on the following web site. Potential applicants will submit a letter of intent and sign a confidentiality agreement in order to receive confidential data on these compounds. For more information, please contact:

Ms. MaryAnne Golling
Contracting Officer
Office of Acquisitions
National Cancer Institute
Fort Detrick; P.O. Box B
244 Miller Drive, Room 118
Frederick, MD 21702
Phone: (301) 228-4215
Fax: (301) 228-4240
Email: gollingm@mail.nih.gov

Companies may also submit proposals for the development of their own agents that are in mid to late pre-clinical development. The development plan, targeted to oncologic indications, will be reviewed by NCI. Overall priority will be given to proposals to develop NCI compounds.

The goal of the NCI SBIR program is to fund small businesses to develop commercially viable products that advance the research and development needs of the Institute. The NCI Strategic Plan identifies integrating clinical trial structures to expedite identification of the most promising treatment opportunities and rapid execution of the necessary clinical trials as a strategic priority (Strategy 4.5). Part of this strategy includes creating an integrated infrastructure to accelerate the implementation of high-priority clinical trials. The long term goal of this contract is to enable a small business to bring a fully developed cancer therapeutic agent to the clinic and eventually to the market.

The NCI's new joint DCTD-CCR initiative for oncology therapeutics development (The Joint DCTD-CCR Early Therapeutic Development Program) seeks to address this strategic objective by reviewing a broad range of candidate therapeutic agents of interest to NCI's basic and clinical investigators, with the goal of capitalizing on FDA's Exploratory IND Guidance to initiate clinical testing at the earliest feasible point in a compound's development.

TRACK I would focus on the development of compounds identified by NCI. The agents being made available by NCI under this solicitation will be in mid to late preclinical development stages (expected time to clinic 1-3 years). NCI has an expressed interest in further development of these agents. Awardees will benefit in several ways:

  1. Recommended IND-directed development plan will be prepared by NCI. The contractor is free to propose any procedures or innovative approaches that can shorten the drug development timeline.
  2. NCI IP available for licensing - small businesses will be able to capitalize on the investment that NCI has already put into these compounds.
  3. Potential for an early-stage clinical development partnership with NCI upon project completion.

Phase I Activities and expected deliverables:

  1. Specific activities will range from SAR and medicinal chemistry to animal toxicology and pharmacology, depending on the agent selected for development. Click here for a list of the available agents.
  2. Mutually agreed-upon development plan that describes in detail the experiments necessary to file an IND or an exploratory IND.
  3. Demonstrate ability to deliver results for the initial set of experiments (project-specific, according to the development plan above).

Phase II Activities and expected deliverables:

  1. Complete all experiments according to the development plan (can be re-evaluated if needed).
  2. If warranted, provide sufficient data to NCI to file an IND or an exploratory IND for the candidate therapeutic agent in question (oncologic indications).
  3. Demonstrate the ability to produce a sufficient amount of clinical grade materials suitable for an early clinical trial (according to FDA's Exploratory IND guidance). http://www.fda.gov/cder/guidance/7086fnl.htm
  4. A comprehensive IP and development plan, outlining how the small business will develop and commercialize the subject therapeutic agent. If relevant, finalize clinical co-development agreement with NCI.

TRACK II would allow the development of compounds identified from within the company. The agents should be in mid- to late-stage preclinical development (expected time to clinic 1-3 years). Overall priority will be given to proposals to develop NCI compounds. However, TRACK II awardees will also benefit in several ways:

  1. If appropriate, NCI will provide assistance to the small business in its development of an IND-directed development plan. Assistance might include assistance in study design and identification of necessary studies that would be appropriate for filing of an IND;
  2. Potential for further collaboration with NCI inventors/investigators;
  3. Potential for an early-stage clinical development partnership with NCI upon project completion.

Phase I Activities and expected deliverables:

  1. Specific activities will range from SAR and medicinal chemistry to animal toxicology and pharmacology, depending on the agent selected for development.
  2. Mutually agreed-upon development plan that describes in detail the experiments necessary to file an IND or an exploratory IND.
  3. Demonstrate ability to deliver results for the initial set of experiments (project-specific, according to the development plan above).

Phase II Activities and expected deliverables:

  1. Complete all experiments according to the development plan (can be re-evaluated if needed).
  2. If warranted, provide sufficient data to file an IND or an exploratory IND for the candidate therapeutic agent in question (oncologic indications).
  3. Demonstrate the ability to produce a sufficient amount of clinical grade materials suitable for an early clinical trial (according to FDA's Exploratory IND guidance). http://www.fda.gov/cder/guidance/7086fnl.htm
  4. A comprehensive IP and development plan, outlining how the small business will develop and commercialize the subject therapeutic agent. If relevant, finalize clinical co-development agreement with NCI.

Compounds of Interest to NCI

Inhibitors of tyrosyl-DNA phosphodiesterase (Tdp1)

Tdp1 presents an attractive target for anticancer drug development: it is an enzyme that removes phosphotyrosyl moieties bound to the 3' end of DNA, a process likely involved in the repair of damage produced by agents targeting topoisomerases. Cells lacking Tdp1 are hypersensitive to camptothecin, suggesting a promising rationale for combination therapies with Tdp1 inhibitors. Model organism studies also suggest that Tdp1 may play a broader role in repairing many types of base damage to DNA, not limited to Top1-mediated DNA damage.

To date, no pharmacological inhibitors of Tdp1 have been developed.

NCI has identified several compounds that inhibit Tdp1. The proposed development plan includes structure activity analysis to understand the mechanism of action of these agents, crystallization of lead compounds with Tdp1, combination studies to test for hypersensitivity in preclinical model systems, studies of Tdp1 phosphorylation sites and their change in status upon treatment, etc.

Inhibitors of Hdm2

As a ubiquitin protein ligase, Hdm2 (Mdm2 in mice) promotes the ubiquitination and degradation of p53 and acts as a major regulator of p53 level in cells. Since Hdm2 gene is amplified in many tumors (7% overall, 20% soft tissue tumors), which usually contains wild type p53, inhibition of Hdm2 ligase activity may lead to activation of p53 and tumor-specific cell killing.

Through high throughput screening of chemical libraries, NCI has identified a family of compounds that inhibit Hdm2 auto-ubiquitination in vitro. In cells, they increase the levels of Hdm2 and p53 in a dose-dependent manner (IC50 5 ~ 10 µM) and activate p53-dependent transcription. As a result, these compounds selectively induce apoptosis in transformed cells, particularly in cells expressing wild type p53.

The proposed development plan includes structure activity analysis to understand the mechanism of action and modification of these compounds to increase solubility and potency for studies in preclinical model systems, etc.

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