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Spatial Sequencing Technologies with Single Cell Resolution for Cancer Research Research


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 9 months; Phase II: up to $2,000,000 for up to 2 years Page 79 PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary It is commonly viewed that cancer originates from an accumulation of mutations in oncogenes and tumor suppressors such that cell growth becomes unregulated and invasive. The identification of genomic, epigenomic, and transcriptomic changes in cancer has led to precise classification, biomarker discovery, and mechanical understanding of cancer, and has played an essential part in cancer diagnosis, monitoring, and treatment. However, the up-to-now bulk sequencing without spatial information has limitations on the understanding of the tumor cells with neighbor cells and the tumor micro environment, for example, limitations on detecting the heterogeneity within a tumor. This limitation has important clinical consequences. For example, cancer is often composed of multiple clones, and the most aggressive clone is difficult to identify and target, and it may not be the one that metastasizes. New sequencing techniques adding spatial resolution to the molecular information could provide a deeper understanding of the relationship between a cell's genotype or gene expression program and its morphology and interaction with its local environment; therefore, this information could further our knowledge in cancer development and progression for better diagnosis and more efficient, individualized treatment. Project Goals The short-term goal of this concept is to stimulate the development of technologies that generate sequence information from slides without losing the histological context of the targets. These technologies must have the capability to identify thousands of genes in a tissue sample and must be able to select, visualize, and compare sequences in areas of interest. The long-term goal is to provide research tools to improve cancer early detection, diagnosis, and prognosis for precision medicine. Such tools could be used to identify the location of aggressive/mutated clones within the tumor; differentiate between the center and infiltrating edges of the tumor; find correlation between molecular changes and cytology or atypia; evaluate molecular changes in the stroma infiltrated by the tumor versus stroma outside the tumor; and discover epithelial mesenchymal transition. The activities that fall within the scope of this solicitation include the development of technologies that can sequence DNA or RNA within fresh frozen or fixed normal and tumor cells without destroying their spatial context, and can be used to directly link spatial features to particular genetic elements in native tissue or organoid specimens; integration of image modalities with cellular sequencing data; cellular mapping and characterization of tumor sequence information without losing the spatial distribution of the original microenvironment, including the complex organization of different cell types that are tightly regulated by the interplay of the individual cells within it. Activities outside the scope of this Topic: Technologies that are solely based in computational development are not appropriate for this solicitation. In situ and single cell technologies that do not have the capability of discovering new sequence variation in intact tissues would also not be considered as responsive, such as single cell fluorescence in situ hybridization (FISH) based technologies. Projects that propose to integrate image modalities with orthogonal -omics measurement other than sequencing information should respond to Topic for “Subcellular Microscopy and -Omics in Cancer Cell Biology”. Phase I Activities and Deliverables • Demonstrate sensitivity, resolution, reliability, robustness, and usability in basic and/or clinical cancer research. • If the technology is for RNA sequencing, it should be able to reveal RNA splicing and post-transcriptional modifications (e.g. methylation) while preserving their spatial context. • For DNA sequencing, the proposal should indicate how the sequence information is being used to determine Single Nucleotide Variation (SNV), Copy Number Variation (CNV), methylation patterns, gene rearrangements/translocations, microsatellite instability etc., while preserving the spatial context. • Provide the technology workflow and a working protocol, including the instrumentation, reagents and time needed for running samples, as well as estimations on speed of data generation and analysis. Phase II Activities and Deliverables Phase II activities should support the commercialization of the proposed technology, including but not limited by the following activities: • Demonstrate system performance and functionality against commercially relevant quantitative milestones: o Offerors should specify quantitative technical and commercially-relevant milestones that can be used to evaluate the success of the tool or technology being developed. o Offerors should also provide appropriate justification relevant to both the development and commercialization of these technologies. o Quantitative milestones may be relative metrics (e.g. compared to benchmarks, alternative assays) or absolute metrics (e.g. minimum level of detection in a clinically meaningful indication). • Demonstrate utility with benchmark experiments obtained across a range of generally accepted cancer indications. • Show feasibility to be scaled up at a price point that is compatible with market success and widespread adoption by the basic and/or clinical research community.
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