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NIH/NCI 457 – Technologies for Detecting Tumor-Derived Cell Clusters

Fast-Track proposals will be accepted.

Direct-to-Phase II proposals will NOT be accepted.

Number of anticipated awards: 3-5

Budget (total costs, per award):

Phase I: up to $400,000 for up to 12 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

Technologies that can assess metastatic risk early and facilitate prompt interventions can significantly improve cancer outcomes because most cancer deaths are due to metastasis. Currently, very few markers are available for predicting metastatic risk. Disseminated tumor cells that enter circulation are pivotal in the metastatic cascade, and circulating tumor cells (CTCs) are being used as putative markers for monitoring tumor dynamics and treatment response. However, accumulating evidence suggests that tumor-derived cell clusters (TDCCs) may be a more important factor in metastasis and associated poor progression-free survival and overall survival. Clustering is an adaptive mechanism that enhances CTC survival and migration in the harsh conditions of the bloodstream, confers stemness, immune evasiveness, and increases their metastatic potential.

TDCCs are reported to consist of either homotypic clusters composed of only cancer cells; or heterotypic clusters made of stromal cells or immune cells including fibroblasts (CAFs), macrophage-like cells (CAMLs), endothelial cells (TECs), tumor-macrophage hybrid cells (TMHCs), and neutrophils, along with tumor cells. Compared to single CTCs, TDCCs have been shown to have distinct molecular features, exhibit a higher proliferation rate, and 20 to 230-fold more metastatic potential than individual CTCs. Overall, these data suggest that composition and heterogeneity of TDCCs may be more informative for assessing metastatic risk or for predicting and following treatment response than assays based on single CTCs.

The biology of formation, dissemination, and metastatic mechanisms associated with TDCCs are poorly understood because currently, very few technologies exist to study TDCCs. Studies that detect TDCCs or elucidate their biology merely adapt existing CTC-based technologies that are grossly inadequate for heterotypic clusters. There is an unmet need for technologies that combine cluster enrichment, enumeration, and downstream molecular analysis to better understand biology and the role of different cells in metastasis.

Project Goals

The goal of this concept is to encourage offerors to develop in vitro technologies that can enumerate and identify cell types in TDCCs with or without enrichment. Offerors may employ a combination of biophysical and biochemical approaches for this purpose. Offerors may also opt to develop non-invasive or minimally invasive in vivo modalities for frequent monitoring of TDCCs. When isolating and enriching, integrity of the TDCCs must be ensured for downstream analysis including enumeration of clusters and the cells of different cell types in the clusters, molecular profiling, and/or drug-sensitivity testing. In Phase I, offerors must demonstrate reproducibility, accuracy, and significance of enumeration and identification of different cell types in the TDCCs. They may use experimental animal models for this purpose. In Phase II, the utility of the cluster enumeration and identification in assessing metastatic risk should be explored using retrospective (if TDCCs are stable during storage) or prospective clinical samples from primary and metastatic cancer cases. Offerors should demonstrate the utility of their platform by using a sufficient number of samples from at least two cancer types, and samples from multiple race/ethnic groups should be included to ensure the technology is broadly applicable. For both experimental animal and clinical studies in Phase I and II, offerors are encouraged to characterize the TDCCs and investigate correlations between TDCC parameters and response to relevant cancer therapies.

Activities not responsive to this announcement:

Developing technologies for CTCs or individual cells of tumor origin; and development of computational tools that decipher heterogeneity without the accompanying biophysical or biochemical technology  

Phase I Activities and Deliverables:

  • Assemble a multidisciplinary team of investigators with appropriate expertise in cell and/or clusters isolation, enrichment, enumeration, molecular and cellular analysis, functional analysis, drug/immunotherapy sensitivity testing, assay/method/device design and engineering, oncology, and other areas of expertise as appropriate for the proposed project.
  • Define quantitative milestones to be met at each step of the technology’s development.

In vivo TDCCs monitoring technologies:

  • Develop minimally invasive (e.g., sensors embedded in a catheter; continuous, real-time, antibiofouling, and calibration-free devices) or non-invasive sensor-based devices for continuously monitoring TDCCs.
  • Demonstrate reproducibility and accuracy of the in vivo monitoring.

In vitro technologies (device/assay/method/technology) for TDCCs:

  • Develop sample preparation protocols, including appropriate blood drawing (phlebotomy or finger prick) and handling of blood.
  • Develop TDCCs isolation, enrichment and enumeration technologies, and protocols while ensuring the clusters integrity.
  • Assess reproducibility and accuracy of the workflow and demonstrate the TDCCs purity.

In vitro imaging methods:

  • Develop in vitro imaging methods for TDCCs analysis, and demonstrate specificity and sensitivity, reproducibility, and accuracy.

Common for all the above modalities:

  • Establish working prototypes.
  • Demonstrate usability of the in vivo or in vitro technology in an experimental animal model (bear in mind the morphological and molecular markers selected for technology development should be applicable to human monitoring).  
  • Establish collaborations with investigators who can provide access to cancer cases and controls.
  • Establish robust quality control and quality assurance protocols.
  • Submit SOPs to NCI SBIR.

Phase II Activities and Deliverables:

  • Demonstrate the technology using cancer cases and controls. Investigators: i) should justify the sample number and the statistical power, and ii) MUST validate the technology using cases and controls from multiple race/ethnic groups to make the technology broadly applicable.
  • Assess usabilities (such as technology acceptability, ease of use), and clinical utility of the technologies in profiling clusters and predicting metastatic risk.
  • Characterize the clusters by multiomics, immunohistochemistry, and/or functional analysis.
  • Assess the clusters metastatic potential in experimental animal models.
  • Demonstrate the TDCCs preparation in drug/immunotherapy sensitivity testing (may use blood samples from animal models or patients for this purpose).
  • Develop commercial prototypes.
  • Develop the plan for regulatory agency approval for clinically relevant technologies.
  • Develop the plan for commercialization of the technologies.
  • Submit final SOPs to NCI SBIR.

 

Receipt date: November 14, 2023, 5:00 p.m. Eastern Standard Time

Apply for this topic on the Contract Proposal Submission (eCPS) website.

View the full PHS2024-1 Contract Solicitation.

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