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Contract Topics

271 Development of Molecular Pharmacodynamic Assays for Targeted Therapies

Number of anticipated awards: 3

(Fast-Track proposals will be accepted.)

Budget (total costs): Phase I: $150,000;
Phase II: $750,000

(Note: It is strongly suggested that Proposals adhere to the above budget amounts. Proposals with budgets exceeding the above amounts may not be funded. Phase I project periods may last a maximum of 9 months.)

The deadline for receipt of all contract proposals submitted in response to this solicitation is: November 9, 2009.

Summary:
The NCI requests that qualified small businesses submit proposals to develop pharmacodynamic assays for measuring drug response of a number of high-priority molecular targets. A list of the targets of interest to NCI is shown below. The short-term goal of this contract topic is to develop new robust, validated assays to measure molecular-level responses to treatment in conjunction with preclinical development of new candidate therapeutic agents. These assays should quantify the 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 early clinical trial setting are highly desirable. Ideally, these assay measurements should have a correspondence to tumor modulation in animal efficacy models via 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 below.) 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.

It is envisioned that the NCI will assist SBIR contractors developing robust pharmacodiagnostic assays for immediate clinical needs via collaboration and partnership. An example of this collaboration would be the contribution of bulk critical reagents, calibrators, and positive and negative controls generated in NCI's laboratories and in GMP-grade contracting and manufacturing facilities. The provision of high quality assay kit components is essential for ensuring successful analytical validation of the assay. Furthermore, these assays will undergo "clinical proof of concept" studies in NCI Phase 0/I drug trials, which may lead to the generation of FDA-quality data. The clinical demonstration of assay performance is often critical to capture market share through widespread clinical adoption, as well as obtaining coverage by healthcare insurers. Although the type of partnership/collaboration will be unique for each assay, the NCI will be able to assist the company in defraying some of the costs and speed up the timeline for generating data required for CLIA laboratory adoption and/or 510K or PMA approval by leveraging the NCI's resources.

Project Goals:
The long-term goal of this contract topic is to provide a mechanism to develop a series of molecular pharmacodynamic assays to confirm clinical target modulation for a wide array of cancer therapeutics, to determine earlier in the drug development process if the target is modulated as intended, 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 validated with human tumor/tissue samples.

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. It is expected that companies will extend this work into developing research kits or diagnostic reagents to stratify patients for clinical trial selection or to evaluate response to new therapeutic agents. 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. 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.

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. 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:

1. Multiplexed assays for obtaining multiple, integrated PD readouts from tumor in a single biopsy specimen (any technology platform-microscopy, immunoassay of laser capture micro dissected tissue, etc), for example:
   1. Interrogate multiple targets within a molecular pathway, such as PTEN/Akt/PI3K/mTORC1 & 2; Wnt/ Frizzled; Notch/Jagged/gamma-secretase; SHH/Smoothened/Gli, or NF-kB/IKK.
   2. Interrogate across multiple core signaling pathways of human cancer types identified by genome-wide analyses, pathway module signatures, or other types of global analyses of the cancer genome, such as, the twelve core pathways in pancreas cancer (see Jones et al, Science 321, 1801 [2008]) or the three core pathways in glioma (see The Cancer Genome Atlas Research Network, Nature 455, 1061 [2008]).
   3. Quantify the number of target molecules containing important combinations of post-translational modifications, for example, activating, and suppressing modifications of individual Akt isozymes.
2. Multichannel quantitative immuno-fluorescence, -infrared, -far infrared microscopy assays with companion image analysis methods, and other tissue visualization methods, for difficult PD evaluations in biopsy specimens, for example:
   1. Identification of tumor stem cells using specific monoclonal antibodies to three or more stemness markers on a single slide, e.g., ALDH 1A1, SOX2, OCT 3/4, NANOG, CD44v6, CD133, CD166, CD49b, Olfm4 and/or innovative stemness markers already established scientifically by the company.
   2. Restricted PD evaluation of two or more PD endpoints to tumor stem cells identified by multiple markers.
   3. Restricted PD evaluation of cell surface receptor tyrosine kinases to the plasma membrane compartment.
   4. Restricted PD evaluation of nuclear markers to the inner nuclear membrane.
   5. Quantitative evaluation of low prevalence molecular targets (~5,000-10,000 molecules per cell) against the backdrop of high prevalence targets (~100,000-1,000,000 molecules per cell).
3. Assays for quantifying important phosphorylated sites on members of the Met protooncogene family other than Met, and/or their specific enzymatic products (e.g., RON, STK, SEA).
4. Assays for quantifying new nuclear markers that are early indicators of apoptotic commitment of tumor cells, preferably immunofluorescence, although other assay formats will be considered.

Sample Standard Operating Procedures (SOPs)
The following sample Standard Operating Procedures (SOPs) demonstrate the level of rigor expected for pharmacodynamic assay development activities under this contract topic. They are not meant to indicate a preference for a particular technology platform.

• Sample Standard Operating Procedure (SOP): Preparation of Blood Samples
• Sample Standard Operating Procedure (SOP): Pharmacodynamic Assay