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245 Assay Systems for Drug Efficacy in Cancer Stem Cells

Number of anticipated awards: 4-6
(Fast-Track proposals will be accepted.)
Budget (total costs): Phase I: $150,000;
Phase II: $1,000,000

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

Cancer stem cells (CSC) are central to tumor development. Although research on CSC is currently in the discovery phase, the clinical potential of CSC is becoming more apparent. Evidence for the presence of CSC has been found for a number of tumor sites, including brain, breast, colon and leukemia. CSC are self-renewing, able to give rise to a xenograft tumor from a single cell, and able to recapitulate all cell types in the resultant tumor. Interaction of CSC with their microenvironment (niche), including their response to signals from specific cell types, supports cancer development.

Although CSC identification is currently very early in its development, the universality of CSC occurrence in cancer is an accepted fact. It is, therefore, fair to assume that CSC are present at all stages of cancer development enabling a paradigm shift toward the control of CSC in a 'prevention mode'. The fact that the number of CSC may be limited in individuals predisposed to cancer, or in early lesions or in lesions at risk for recurrence, may be an advantage for preventive intervention, as is the much greater accessibility compared with site-contained or malignant cancers. The observations that CSC are presumed to be largely quiescent and, therefore, exist in a 'pseudo-synchronized state' should be of benefit as well. For example, preventive intervention approaches should enable the use of 'synthetic lethality' wherein 'pseudo-synchronized' CSC populations in early cancers are induced to proliferate, followed by chemopreventive modalities. Potential chemopreventive modalities for the treatment of CSC may include use of minimally toxic differentiation agents, anti-inflammatory agents, anti-angiogenic agents, and transgenes, applied topically or systemically, whether individually or in combination.

Eradication of CSC is thought to be essential for cancer control. Current therapies are able to eradicate rapidly dividing tumor cells in some cases, but these treatments frequently fail to eradicate CSC, resulting in tumor recurrence. CSC are few in number, estimated at between 0.1%-5% depending on tumor type and stage of development, appear to be largely quiescent, and are enriched for the ATP-binding cassette (ABC) drug resistant genes. These attributes would, presumably, reduce the ability of many anti-cancer drugs to control CSC. Understanding of CSC resistance to current therapies should lead to the development of new strategies, including the identification of relevant molecular targets for cancer prevention.

Project goals:

  • Establish CSC-based assay systems in vitro.
  • Establish CSC-based assay systems able to monitor drug toxicity and efficacy in vitro.
  • Establish CSC-based assay systems able to monitor drug toxicity and efficacy in vivo.
  • Develop high-throughput CSC-based assay systems in vitro.
  • Develop high-throughput CSC-based assay systems able to monitor drug toxicity and efficacy in vitro.
  • Investigate the effect of a select number of potential agents viz. CSC systems, both in vitro and in vivo, to demonstrate reproducibility, sensitivity, and specificity.
  • Validate the in vitro and in vivo CSC-based assay systems as appropriate for commercialization of the assays.

Phase I activities and expected deliverables:

  • Establish CSC-based assay systems able to monitor drug toxicity and efficacy in vitro.
  • Develop high-throughput CSC-based assay systems able to monitor drug toxicity and efficacy in vitro.

Phase II activities and expected deliverables:

  • Continue to pursue Phase I activities.
  • Establish CSC-based assay systems able to monitor drug toxicity and efficacy in vivo.
  • Investigate the effect of a select number of potential agents viz. CSC assay systems, both in vitro and in vivo, to demonstrate reproducibility, sensitivity, and specificity.
  • Validate the in vitro and in vivo CSC-based assay systems as appropriate for commercialization of the assays.

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