Development of Molecular Pharmacodynamic Assays for Targeted Therapies

Number of anticipated awards: 6
(Fast-Track proposals will be accepted.)
Budget (total costs): Phase I: $150,000;
Phase II: $750,000

The deadline for receipt of all contract proposals submitted in response to this solicitation is: 5:00 p.m. Eastern Standard Time Monday, November 5, 2007

The NCI requests that qualified small businesses submit proposals to develop pharmacodynamic assays for measuring a number of high-priority molecular targets. (For a list of the targets of interest to NCI, please see: http://sbir.cancer.gov/). The short term goal of this contract is to develop new rigorous, validated assays to measure molecular-level response to treatment in conjunction with preclinical development of new candidate therapeutic agents. These assays should measure modulation of molecular targets upon treatment with investigational anticancer therapeutics and support pharmacodynamic studies in animal models and in human tumor and surrogate tissue samples. Real-time assays that could be used to rapidly assess response to treatment in the clinic in conjunction with a clinical trial are highly desirable. Ideally, these assays should also have a known correspondence to tumor modulation in animal efficacy models for the same target. Standard operating Procedures (SOPs) for these assays must be developed and be provided to the NCI along with all supporting data. (To view sample SOPs, please see: http://sbir.cancer.gov/.)

Small businesses may also submit proposals for the development of assays that measure molecular targets relevant to oncology therapeutics development which have been identified by the small business.

Project goals: The long term goal of this contract is to provide a mechanism to develop a series of molecular pharmacodynamic assays to allow clinical target validation for a wide array of cancer therapeutics to determine earlier in the drug development process if the intended target is modulated and whether this corresponds to either tumor stasis or regression. In addition to the assay itself, the contract recipient will develop and provide to the NCI SOPs that have been fully qualified or validated with human tumor/tissue samples. In addition, the goal is for companies to extend this work into developing research kits or diagnostic agents to stratify patients for clinical trial selection or to evaluate response to new therapeutic agents.

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 validating molecular targets for cancer prognosis, metastasis, treatment response and cancer progression as a strategic priority (Strategy 4.2). Part of this strategy includes creating a library of validated molecular target assays in order to advance broad development of targeted anti-tumor agents. Grant mechanisms thus far have not been an effective method of developing these assays, as they have little publication value. Market analysis indicates that pharmacodynamic assay development is a valuable first step for eventual commercialization of cancer diagnostics and laboratory assays, in addition to serving the needs of cancer therapeutic development.

Two different tracks will be considered:

Track 1 will focus on the development of pharmacodynamic assays for measuring a number of high priority molecular targets. (For a list of the molecular targets of high priority to NCI, please see http://sbir.cancer.gov/.)

This list of molecular targets is being actively pursued by NCI’s researchers; thus assays developed under this topic will be good candidates for beta testing at NCI laboratories and clinics. The NCI will determine and periodically re-prioritize the list of molecular targets to be addressed in subsequent years based on the needs of both intramural and extramural investigators.

For Track 2 small businesses are invited to submit proposals for the development of assays that measure molecular targets relevant to oncology therapeutics development which have been identified by the small business.

All proposals will be reviewed by NCI, and overall priority will be given to proposals to develop pharmacodynamic assays of high priority to NCI.

Both tracks will have the following deliverables.

Phase I Activities and expected deliverables:

1. Develop a research pharmacodynamic assay for the molecular target described.
2. Characterize assay reproducibility, variability and accuracy.
3. Deliver to NCI the SOP of the research pharmacodynamic assay for the molecular target described.

Phase II Activities and expected deliverables:

1. Develop a qualified or validated molecular pharmacodynamic assay for the target described. The assay should be applicable in the clinical setting.
2. Perform studies to characterize the correlation between the resulting assay in tumor versus surrogate tissues (e.g. blood, serum), if applicable.
3. Perform studies to characterize the correlation between the resulting assay in human versus animal tissues.
4. Make available to NCI all SOPs for this assay.

Fast-Track justification:
While not necessary for all offerors, there are specific situations where fast-track funding would be appropriate and greatly increase the speed of assay development. For example, if the small business recipient has already developed a platform technology for assay development, or similar assays for other molecular targets, the proof of principle can be demonstrated more rapidly.

1. Tangible and specific Phase I deliverables that show significant progress toward development of the technology will be required. The following Phase I deliverables will be used as milestones for continued Phase II funding:
1. The SBIR recipient must deliver research assay SOPs within 3-6 months.
2. Demonstrate acceptable real-time assay performance in animal tumor tissue.
2. Before any Phase II funding is awarded, the contract manager must receive both of the tangible milestones written above and verify that the research conducted and SOPs are complete and accurate. Once verified, the contract manager may approve additional Phase II funding.

Molecular Pharmacodynamic Targets of Interest to NCI

The following molecular pharmacodynamic targets have been identified as high priority for the NCI, based on the current pipeline of therapeutic agents under development (for many of these targets, both non-phospho-specific and phospho-specific antibodies are of interest):

* Akt
* P38
* MKK3/6
* AMPK
* RhoB
* KLF2
* KLF6
* p21
* TRB1
* CD55

* CD59
* Hif-1 alpha
* Pgp (ABCB1, MDR1)
* Syk
* Gsk-beta
* Mek
* Erk
* Tdp1
* VEGF
* VEGF Receptor(s)

* Nox1
* Nox3
* Nox4
* Nox5
* Duox 1
* Duox 2
* JNK
* Stat(s)
* PTP1B

Additional areas of interest include:

1. B-Raf
2. c-Met
3. SF/HGF
4. Cathepsin
5. Hedgehog signaling pathway
6. AGT
7. General assays for replication index/cell cycle
8. Assays to assess the role of complement-mediated death in response to therapeutic antibodies
9. Phospho-specific antibodies that can be used in IHC or protein lysate arrays

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