The emergence of cancer genomics, combined with increased understanding of the molecular basis of oncogenesis, has stimulated hope that treatment will improve by becoming more targeted and individualized in nature. Cancer genomics studies established a number of critical cancer genes, leading to a number of successful targeted therapies (e.g. Gleevec, Herceptin and Plexxikon). Despite these successes, most cancers do not have a targeted therapy and when one exists, response is highly variable, even among patients that share the targeted mutation and tumor type. To move cancer into the era of personalized therapies, it becomes important to identify the alterations driving tumor progression in each tumor, determine the network that links these aberrations, and identify factors that predict sensitivity to targeted therapies. As projects such as The Cancer Genome Atlas (TCGA) amass cancer cell genomes at a breathtaking pace, a staggering genetic complexity is revealed. To interpret cancer genomes, a key computational challenge is to separate the wheat from the chaff and define both what are the key alterations likely to be functionally driving cancer and then, after defining such genes, begin to identify mechanisms of action and therapeutic implications. Leveraging components from our published methods, CONEXIC (Akavia et.al Cell 2010) and LirNet (Lee et.al, PLOS Gen 2009), we will develop machine-learning algorithms that integrate cancer genomic data to do just that. We will apply the methods we develop to melanoma, glioblastoma, ovarian, breast and colon cancer and experimentally follow up on our computational findings, towards a better understanding of each of these deadly cancers. The approaches developed in this grant will accelerate discovery to rapidly extract the maximal value from modern genomic studies and help carry cancer genomics from the diagnostic to the therapeutic realm.

Public Health Relevance

This work aims to develop methods that help dissect the genetic complexity of individual cancers. For each tumor we aim to identify which mutations arm a cell with the abilities to abnormally grow or evade drug treatment, providing a foundation of tools towards personalized cancer treatment. We will apply these methods for discovery in some of the most aggressive cancers that currently lack good therapeutic solutions including glioblastoma, ovarian cancer and melanoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA164729-01A1
Application #
8371751
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Li, Jerry
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$399,632
Indirect Cost
$148,151
Name
Columbia University (N.Y.)
Department
Biology
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Setty, Manu; Tadmor, Michelle D; Reich-Zeliger, Shlomit et al. (2016) Wishbone identifies bifurcating developmental trajectories from single-cell data. Nat Biotechnol 34:637-45
Marcotte, Richard; Sayad, Azin; Brown, Kevin R et al. (2016) Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance. Cell 164:293-309
Litvin, Oren; Schwartz, Sarit; Wan, Zhenmao et al. (2015) Interferon α/β Enhances the Cytotoxic Response of MEK Inhibition in Melanoma. Mol Cell 57:784-96
Chen, Bo-Juen; Litvin, Oren; Ungar, Lyle et al. (2015) Context Sensitive Modeling of Cancer Drug Sensitivity. PLoS One 10:e0133850
DiGiuseppe, Joseph A; Tadmor, Michelle D; Pe'er, Dana (2015) Detection of minimal residual disease in B lymphoblastic leukemia using viSNE. Cytometry B Clin Cytom 88:294-304
Levine, Jacob H; Simonds, Erin F; Bendall, Sean C et al. (2015) Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis. Cell 162:184-97
Lu, Yao; Xue, Qiong; Eisele, Markus R et al. (2015) Highly multiplexed profiling of single-cell effector functions reveals deep functional heterogeneity in response to pathogenic ligands. Proc Natl Acad Sci U S A 112:E607-15
Sanchez-Garcia, Félix; Villagrasa, Patricia; Matsui, Junji et al. (2014) Integration of genomic data enables selective discovery of breast cancer drivers. Cell 159:1461-75
Bendall, Sean C; Davis, Kara L; Amir, El-Ad David et al. (2014) Single-cell trajectory detection uncovers progression and regulatory coordination in human B cell development. Cell 157:714-25
Amir, El-ad David; Davis, Kara L; Tadmor, Michelle D et al. (2013) viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat Biotechnol 31:545-52

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