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139th National Cancer Advisory Board

Yates, University of Washington/Scripps, helped establish the multi-dimensional protein identification technology, MudPIT, that supports the transition from 2-D gel electrophoresis to 2-D liquid separation techniques. (4) Dr. Mark Chee, then with Illumina, made important contributions to the ultra-high- throughput Illumina bead platform to allow researchers to simultaneously assay more than 100,000 points for gene expression, alternative splice detection, and protein expression. (5) Dr. David Krizman, Expression Pathology, has developed new technology that permits effective, high-throughput discovery and analysis of protein biomarkers in formalin fixed paraffin embedded (FFPE) tissue. (6) Dr. Robert H. Daniels, Quantum Dot Corp. (Invitrogen), focused on quantum dots (semi-conductor nanocrystals) as photostable labels that emit extremely bright light in a range of colors enabling researchers to monitor complex interactions within living cells or in situ on tissue microarrays.

The IMAT program also is focusing on overcoming technical barriers to research productivity, with attention paid to nucleic acids (micro RNAs, RNAi, epigenomics, alternative splicing, genomic regulatory factors, and mutation detection) and proteins (localization, fractionation and quantitation, identification of low abundance and transient proteins, small molecule interactions, protein interactions, and structure/function modifications). Additionally, molecular interactions (pathways and networks, transient complexes, real-time macro molecular interactions, and metabolite detection/quantification) and molecular device/chemistry (nanotechnology, microfluidics, surface chemistries, sensors, and platform integration) are being examined. In addressing these barriers, IMAT has introduced a paradigm shift that includes: increased sensitivity, improved labeling tools, increased throughput, reduced cost, more quantitative focus, single molecule/cell approach, reduced sample size, rare entity isolation, and parallel processing.

Dr. Downing acknowledged the efforts of the IMAT program management team and referred the NCAB members to visit http://imat.cancer.gov for further information.

Developing Tests for Bcr-Abl and Gleevec® Resistance in CML Patients—Dr. Stephen J. Kron

Dr. Kron described the development of tests for Bcr-Abl activity and Gleevec® resistance in chronic myeloid leukemia (CML) patients. This project is an intersection of technology and translation and involves numerous collaborators from many disciplines. Dr. Janet Rowley, University of Chicago, provided the first molecular understanding of a cancer by identifying that chromosome 9/22 balanced translocation in almost every CML. From this, it was hypothesized that genetic changes were underlying other cancers, leading to cytogenetic testing that looked for the Philadelphia chromosome and the wild type 9 to perform molecular diagnosis for CML and monitor patients during therapy. Approximately 10 years later, Dr. Owen Witte, then a postdoctoral with David Baltimore, and colleagues identified the translocation and discovered that it was a characteristic breakpoint that clustered around the transposition between the Abl gene, named after a virus identified by Dr. Herbert Abelson at NIH, now at the University of Chicago, and the Bcr breakpoint cluster region gene on 22, and that created a new gene on the Philadelphia chromosome, BCR-ABL. This finding made it clear that the CML patients make a new gene product called Bcr-Abl that can be found as an RNA in their CML cells; Dr. Witte and others recognized that Bcr-Abl was encoding an activated kinase, an enzyme, that uses ATP to phosphorylate other proteins and therefore is a potential drug target.

About 10 to 15 years later, a drug was developed that provided a good prognosis for CML patients. That drug was named STI571, renamed Imatinib, and sold as Gleevec® by Novartis, thanks to the patients of Dr. Brian Drucker, now at Oregon Health Sciences. Dr. Kron shared graphics that showed how Abl embraces the Gleevec molecule to displace ATP and inactivate the kinase. There has been a fair amount of discussion since 2002 about Imatinib-resistant kinase mutations in Bcr-Abl patients. These patients, who initially may have benefited from Gleevec®, develop mutations that lower affinity for


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