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Brain Cancer and New Interventions PowerPoint Presentation

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On : Feb 24, 2014

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  • Slide 1 - Pilot Program: Developing Reagents, Protocols, and Tools to Enable Translation of Discoveries from Large Scale Cancer Genomics Programs (TCGA, TARGET, Others) Daniela S. Gerhard, Ph.D.Office of Cancer GenomicsHenry Rodriguez, Ph.D., MBAClinical Proteomic Technologies for Cancer Anna D. Barker, Ph.D. Deputy DirectorNational Cancer InstituteNCI Board of Scientific AdvisorsJune 22, 2009
  • Slide 2 - Background for the Pilot Large scale genome characterization/sequencing programs are well under way (TCGA, TARGET, other whole genome sequencing programs) – creating large complex data sets for mining by the communities The programs are already identifying new genomic alterations – but perhaps of more importance – are providing unprecedented opportunities to analyze the multi-dimensional data for new potential cancer “signatures/targets” While some high-quality reagents exist for highly studied targets – the next era of cancer discovery and development will depend in large measure on the success of functional studies Looking ahead, the numbers of potential “targets” will be large – but reagents and tools will be limited, costly and difficult to access for many There is a critical need for highly-characterized reagents, protocols and other tools to support cancer researchers as they move to functionalize biologically and clinically important genomic alterations
  • Slide 3 - Overall Goals of the Pilot To develop a community-based process that will prioritize “signature/target” candidates (targets) from large-scale genomic programs To enable and accelerate functional studies through the development of broadly available highly-characterized reagents, protocols and tools to the selected targets To regularly evaluate the pilot – determine a longer term model for the future
  • Slide 4 - Each Sample Clinical Data TCGA = depth + data integration… Adopted from Cameron Brennan From Ron DePinho
  • Slide 5 - TCGA: Nature 2008 GBM Pathways (Characterization/Sequencing Continuing)
  • Slide 6 - Frequency of Mutations in Some Genes – Likely Specific for GBM Subtypes Verhaak et al., submitted
  • Slide 7 - Relevant New Discoveries in Pediatric Cancers -TARGET JAK mutations in “BCR-ABL1-like” ALL (TARGET) High risk childhood ALL - 67% cases have lesions in B-cell development pathway genes; IKZF1 (IKAROS) alterations in ~ 30% of cases JAK2 (n=16): 10 R683G; 3 non-R683G pseudokinase domain; 3 kinase domain JAK1 (n=3): 3 pseudokinase domain JAK3 (n=1): uncertain functional consequences
  • Slide 8 - Genomic Approaches/Reagents Exist for Historical Targets – New Insights Require New Reagents Source: TCGA Nature AOP 4 Sept 2008 PIK3R1 had anecdotal reports in the literature Cluster of mutations/indels in contact amino acids known to be important for interaction with PIK3CA
  • Slide 9 - Need to Expand Successful Mutation-Specific Antibody Reagent Models 85% to 90% of NSCLC-associated EGFR mutations are: In-frame deletions in exon 19 (E746_A750del) or point mutation in exon 21 (L858R) Monoclonal antibodies against synthetic peptides matching above aberrations recently developed and shown effective in IHC assays Such unique reagents are critical as patients with similar mutations shown responsive to EGFR inhibitors including gefitinib and erlotinib. Mutation-specific EGFR IHC assays using anti-peptide monoclonal antibodies Control EGFR mAb L858R specific mAb dEGFR specific mAb Patient 1 Patient 2 NSCLC patient samples with unknown genotype were stained with above mAbs. DNA sequence analysis confirmed the presence of the L858R mutation in Patient 1 and Patient 2 Yu et al, Clin. Cancer Res. 2009; 15 (9) 3023- 3028
  • Slide 10 - TCGA, TARGET, Other Data Sets Mining of Databases and Publications DNA, RNA and epigenetic candidates Protein candidates Development of Publicly Accessible Reagents, Protocols, Tools ONGOING GENOME WIDE DISCOVERY PROPOSED CONCEPT Trans NCI- Extramural Target Prioritization Working Group Overall Concept Design
  • Slide 11 - Vision for Target Selection Process - RFI to seek candidates from the broader scientific community - ongoing, iterative process - NCI-Extramural Target Prioritization Working Group (Representatives from the extramural community together with NCI division/program leadership) receive candidates along with supporting evidence – ensure synergy avoid duplication (Group to define process) Prioritized candidates vetted for functional evidence – also vetted in terms of feasibility for reagent production (academic and private laboratories) Final selection based on supporting technical evidence, community need and feasibility Ongoing evaluation to evaluate process – and future model (if feasible, high value and financially viable)
  • Slide 12 - Reagent/Protocol/Tools Development for Genomic/Proteomic Targets – Target Dependent Genomics targets/signatures - develop protocols to characterize specific/further define genomic targets (e.g., multiplex sequencing, digital mRNA profiling, etc.) Proteomic targets/signatures - Develop and comprehensively characterize (western blotting, IHC, epitope maps) monoclonal antibodies (mAbs); develop mAbs against peptide and/or selected protein fragments to functionalize targets Make resources available on all relevant websites (TCGA, TARGET, CPTAC, Other Portals)
  • Slide 13 - Value of Doing the Pilot Now With Nex-gen technologies, integrated multi-dimensional genomic data sets on large numbers of types (and subtypes) will drive large numbers of discoveries – defining and functionalizing potential targets will become rate limiting The pilot program will leverage knowledge from individuals and groups to enable the development of reagents, protocols and tools for broader community – may be prerequisite for effective translation Targets can be identified throughout pilot - “just-in-time” approach could speed discovery and development The pilot will support collaborative early scientific pipelines – to drive new target validation and development of more effective interventions We can evaluate the process before we are buried under data
  • Slide 14 - RFP Mechanism Chosen for the Pilot To ensure meeting milestones and deliverables Facilitate making of reagents and accompanying data freely available to the scientific community Best approach to include interested and qualified experts form both academic and private sectors Can be re-directed if needed
  • Slide 15 - How Might this Develop – Future Possibilities Possibility 1 – for a number of reasons (information sharing is limited; targets are easy – everyone makes everything they need; targets are really difficult to qualify and only a few people can proceed to leverage the data; or it’s too expensive, etc. – we decide not to continue the pilot program Possibility 2 - we decide that it is needed and of high value and we want to optimize it and scale it up – several scenarios are possible: We scale it up at government expense (likely not a popular choice) We scale it up using a cost recovery model We develop the concept as a public-private partnership (could also be cost recovery) With these possibilities in mind – the pilot must pay close attention to feasibility, time required, cost and ease of access and use by all of the relevant communities
  • Slide 16 - Proposed Timeline & Budget

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