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NIH/NCI 366: Clonogenic High-Throughput Assay for Screening Anti-Cancer Agents and Radiation Modulators

Fast-Track proposals will not be accepted.

Direct to Phase II will not be accepted.

Number of anticipated awards: 3-5

Budget (total costs, per award):

Phase I: up to $300,000 for up to 9 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

The ultimate goal of any cancer treatment modality is to specifically eradicate cancer cells by inducing cell death by mechanisms that include metabolic death, cell apoptosis, and/or reproductive death (clonogenic death). Clonogenic death is defined as the indefinite loss of the proliferative ability of a cancer cell and is best assessed by colony-forming assays. Colorimetric and metabolic assays for determining cell viability and apoptosis measure short-term endpoints, but are subject to artifacts since they do not measure the clongenic potential of cancer cells. Clonogenic assays are longer-term and are more labor-intensive, but are less susceptible to these artifacts.

Over the past several decades in vitro high-throughput screening (HTS) systems have evolved and are routinely used to screen agents for cytotoxicity. However, current HTS methodologies do not directly measure clonogenic potential and are thus not able to accurately predict the efficacy of an agent either in subsequent preclinical animal model testing or in clinical trials. Further, it is well known that cancer recurrence is a common problem after treatment. This results from the re-population and redistribution of surviving tumor cell clonogens. Direct measurement of a tumor’s clonogenic potential provides an integrated output of all cell death mechanisms and measures any capacity of residual cells to regrow; the definition of treatment failure.  HTS systems to screen agents based on their ability to inhibit clonogenic potential of cells have been developed mostly in the academic setting. Advances in automated microscopy and robotics are facilitating these efforts. Further development, integration of robotics and softwares and commercialization of HTS clonogenic assay for screening anti-cancer agents and radiation modulators could greatly enhance the predictive power of HTS results and be applied to chemotherapeutic, radiologic or combined modality treatment testing.

Chemotherapy is used for both solid and hematologic malignancies. In addition, more than half of US cancer patients undergo radiotherapy alone or in combination with drugs; percentage of which is expected to only increase. Screening that allows for more accurate testing of chemotherapeutic and combinatorial treatments will better focus development to more promising agents and accelerate development of drug and drug-radiotherapy combinations. With expanded global access to radiotherapy and increased utilization rate, pharma and academics will be further incentivized to discover agents with anti-cancer and radiation sensitizing properties. Assays that are adaptable to the incorporation of molecular targeting, imaging, and evaluation of genetically defined cell panels for drug screening and discovery will be required with ongoing precision medicine initiatives. Companies can utilize clonogenic HTS assays to screen for new agents and to test newly identified agents in combination for radiation. Results from this type of screen should improve success in subsequent in-vivo model testing and will accelerate translation.

 

Program Goals

The purpose of this contract topic is to: (i) promote stronger academic industry partnerships in radiobiology to develop clonogenic survival-based HTS systems (ii) to exploit recent advances in the technical maturity of HTS technologies and combine them with advances in clonogenic assays, (iii) encourage small businesses to specifically develop HTS systems for screening potential anti-cancer agents based on a clonogenic endpoint, and (iv) integrate relevant technologies. Colony-forming assay survival experiments currently involve the use of several drug and/or drug + radiation doses as well as several plated cell numbers for each cell line and hence the assays are labor and material intensive. Further, developing a HTS system with a clonogenic endpoint will enhance screening/cross validating chemotherapeutic agents as well as radiation effect modulators and combinatorial treatments, while reducing labor and costs.

To apply for this topic, offerors need may design integration of robotic instrumentation, micro-fluidics, thermal and gas control, colony counting microscopic imaging and image analysis. An integrated system may also require the development of “bridging” components and graphic user interfaces. Offerors are required to develop standard operating procedures matched to validated cell lines for use with the integrated system.   Offerors must include an integration of microfluidics/culture system with radiation exposure under conditions allowing precise dosimetry, which is critical.  Offerors are also required to integrate and adopt software to capture and calculate survival.  This solicitation is not intended for development of systems with non-clonogenic endpoints.

 

Phase I Activities and Expected Deliverables

  • Delivery of a prototype system with validated SOPs that are translatable to other laboratories.
  • Defined cell line panels that have been shown to be appropriate for use with the system and the clonogenic endpoint. Validation of representative “hits” using conventional clonogenic assay.
  • Licensing of individual components for use in the system as needed.

 

Phase II Activities and Expected Deliverables

  • Demonstration of system validation with manually assessed comparator(s) using drugs, radiation and combinations of known activity (e.g. Cis-platinum, radiation and combined treatment)
  • Demonstration of software integration for analysis and output of clonogenic survival data in an easily interpretable format.
Posted: August 1, 2016