? Project 1 Each year, tens of thousands of people in the United States are diagnosed, and die, as a result of acute myeloid leukemia (AML) and glioblastoma multiforma (GBM). Despite intensive therapies, the five-year survival rate for both tumors is abysmal and has remained unchanged for the last fifty years. Both of these malignancies are characterized by rapid cell division and genetic instability. The goal of Project 1 is to identify clonal and subclonal mutations, present in these malignancies prior to therapy, that may promote proliferation, treatment resistance, and relapse. We have developed a highly accurate and sensitive sequencing protocol, Duplex Sequencing, which takes advantage of the double- stranded nature of DNA to detect mutations, even when present at a frequency of less than one in 10 million. Using our established Duplex Sequencing platform, we have detected subclonal mutations in both AML and GBM that cannot be accurately identified by routine next-generation DNA sequencing. We will pursue the following Aims in Project 1: 1) determine the types of subclonal mutations in AML and GBM; 2) determine how the overall mutation load or presence of specific subclonal mutations correlate with prognosis, response to therapy, and likelihood of relapse (in the case of GBM, we will also determine the geographical heterogeneity of mutations within tumors); and 3) identify potent drugs that prevent the accumulation of these mutations by screening libraries of small molecules. In coordination with other the Projects and Cores, we will analyze how these mutations alter the functions of the encoded genes in these malignancies.
- Project 1 Our objective is to establish new therapeutic approaches for the treatment of acute myeloid leukemia and glioblastoma, two common lethal cancers. We will determine if mutation load and the types of mutations in cells from these tumors correlate with response to therapy, and are an early indication of impending relapse. We also aim to identify new nucleoside analogues that retard tumor progression.
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| Schmitt, Michael W; Pritchard, Justin R; Leighow, Scott M et al. (2018) Single-Molecule Sequencing Reveals Patterns of Preexisting Drug Resistance That Suggest Treatment Strategies in Philadelphia-Positive Leukemias. Clin Cancer Res 24:5321-5334 |
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| Salk, Jesse J; Schmitt, Michael W; Loeb, Lawrence A (2018) Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat Rev Genet 19:269-285 |
| Davis, Luther; Zhang, Yinbo; Maizels, Nancy (2018) Assaying Repair at DNA Nicks. Methods Enzymol 601:71-89 |
| Yu, Ming; Heinzerling, Tai J; Grady, William M (2018) DNA Methylation Analysis Using Droplet Digital PCR. Methods Mol Biol 1768:363-383 |
| Knijnenburg, Theo A; Wang, Linghua; Zimmermann, Michael T et al. (2018) Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep 23:239-254.e6 |
| Kamath-Loeb, Ashwini S; Zavala-van Rankin, Diego G; Flores-Morales, Jeny et al. (2017) Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype. Sci Rep 7:44081 |
| Oshima, Junko; Sidorova, Julia M; Monnat Jr, Raymond J (2017) Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev 33:105-114 |
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