The Gray Laboratory explores mechanisms by which genomic, transcriptional and proteomic abnormalities occur in selected cancers, elucidates how these abnormalities contribute to cancer pathophysiology and assesses the ways in which these abnormalities influence responses to gene targeted therapies. Current studies focus on developing: (a) Genome wide analyses of the spectrum of recurrent abnormalities that influence cancer behavior. (b) Cancer systems biology approaches to elucidate mechanisms by which cancer-associated molecular abnormalities influence individual responses to therapeutic inhibitors (c) siRNA therapeutic approaches to treat breast or ovarian cancer subpopulations that do not respond well to current aggressive chemotherapeutic strategies (d) Strategies for early detection of metastasis-prone breast cancer.
Cancer Genomics. We are assessing abnormalities associated with clinical outcome in breast cancers using a combination of comparative genomic hybridization (CGH), exon-level expression profiling, massively parallel sequencing and reverse phase protein lysate array/western analyses to assess protein and phosphoprotein levels1-4. These studies are being carried out in collaboration with investigators at UC San Francisco, UC Berkeley, the MD Anderson Cancer Center and the Buck Institute for Age Research. We are contributing to The Cancer Genome Atlas (TCGA) project managed by the NCI and NHGRI by assessing expression in ~1500 normal and 1500 glioblastomas, ovarian cancers and lung cancers using Affymetrix Exon 1.0 arrays2.
Stand Up To Cancer (SU2C). Emphasis in the SU2C project is on identifying “omic” abnormalities and microenvironmental signaling events that contribute to therapeutic resistance in the metastatic setting with the goal of developing therapeutic strategies that counter these resistance mechanisms. We are pursuing this on four fronts. 1. Applying massively parallel sequencing and bioinformatic approaches to compare omic aberrations in drug resistant primary and metastatic tissues and untreated primary tumors analyzed by the NIH TCGA project in order to identify aberrations associated with resistance. 2. Assessing responses to approved drugs and experimental therapeutic compounds measured in a collection of ~60 malignant and non-malignant breast cell lines grown in multiple microenvironments. The cell lines are being characterized in substantial molecular depth at the DNA, RNA and protein levels to allow identification of associations between responses to therapy and molecular features in order to identify molecular mechanisms of resistance. 3. Developing computational methods for selection of drugs/combinations for individualized treatment of patients based on the omic characteristics of their tumors. 4. Collaborating on the development of omic-marker-guided clinical trials to test therapies predicted to be effective in the metastatic setting. The Gray lab also has responsibility for organizing and coordinating the activities of the SU2C Bioinformatics Data Mining and Discovery (BDD) team. SU2 project website (username & password required): SU2 project at Harvard.
Cancer Systems Biology. We are developing experimental and computational models that will enable prediction of responses of therapeutic agents that can be used to guide the clinical introduction of experimental therapeutic agents and/or identify patients most likely to respond to existing therapeutic agents4. We focus on breast and pancreatic cancer and we use collections of well characterized cancer cell lines to model the molecular diversity found among primary tumors5-9. We have automated aspects of cell culture so we can measure quantitative responses of these cell lines to treatment with dozens of approved and experimental therapeutic agents. We are now using an adaptive spline statistical association approach to identify molecular abnormalities associated with biological response to therapeutic agents and pathway analysis tools including Bayesian network analysis, Pathway Logic and Ingenuity to identify pathways associated with response and resistance. These studies are being carried out in collaboration with investigators at UC San Francisco, UC Berkeley, the Netherland Cancer Institute, SRI International and the private sector. This work contributes to the NCI Integrative Cancer Biology Program (ICBP).
siRNA therapy. We are developing siRNA therapeutic approaches to treat breast and ovarian tumors that amplify and over express transcripts to which the tumors have become addicted. Current emphasis is on development of strategies to identify and inhibit functionally important genes in regions of amplification associated with poor outcome including PVT1, IKBKB, ADAM9, and several genes in regions of amplification at 11q13 and 20q13. This work is being carried out in collaboration with investigators at the MD Anderson Cancer Center and UC San Francisco. This work contributes to the MD Anderson Ovarian Cancer SPORE, the NCI Bay Area Breast Cancer SPORE and a siRNA therapeutics consortium supported by the NIH Foundation.
Early breast cancer detection. We are using information about genomic and transcriptional abnormalities in breast cancer to guide the development strategies that can detect metastasis prone breast cancers before they metastasized. In this “new” area of laboratory research, we are pursuing: (a) Detection of cancer specific proteins in the blood using mass spectrometry and capillary isoelectric focusing. We are giving special attention to detection of aberrant proteins that result from cancer specific alternative splicing revealed using Affymetrix arrays that interrogate expression in individual exons. (b) Detection of aberrant cancer cells in histological tissue sections using scanned ion beam mass spectrometry to identify aberrant proteins or transcripts. (c) Development of MRI and PET contrast reagents specifically targeted to cell surface receptors expressed on basal subtype breast cancers to facilitate anatomic detection of these breast cancers before they have metastasized. These studies are being carried out in collaboration with investigators at UC San Francisco, UC Berkeley, and the Buck Institute for Age Research and the Lawrence Livermore National Laboratory. This work contributes to the NCI Clinical Proteomic Technologies for Cancer (CPTAC) program and the DOD Innovator Award program.
Selected Recent Publications (from 330 total)
Chin, L and Gray, JW. (2008) Translating insights from the cancer genome into clinical practice. Nature. 452:553-63.
TCGA Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061-8.
Srivastava S, Gray JW, Reid BJ, Grad O, Greenwood A, Hawk ET; Translational Research Working Group. (2008) Translational Research Working Group developmental pathway for biospecimen-based assessment modalities. Clin Cancer Res.14:5672-7.
Rizki A, Weaver VM, Lee SY, Rozenberg GI, Chin K, Myers CA, Bascom JL, Mott JD, Semeiks JR, Grate LR, Mian IS, Borowsky AD, Jensen RA, Idowu MO, Chen F, Chen DJ, Petersen OW, Gray JW, Bissell MJ. (2008) A human breast cell model of preinvasive to invasive transition. Cancer Res. 68:1378-87.
Kenny PA, Lee GY, Myers CA, Neve RM, Semeiks JR, Spellman PT, Lorenz K, Lee EH, Barcellos-Hoff MH, Petersen OW, Gray, JW, and Bissell MJ. (2007) The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Molecular Oncology, 1(1): 84-96.
Guan Y, Kuo W-L, Stilwell J, Takano H, Lapuk A, Fridlyand J, Mao J-H, Yu M, Miller M, Santos J, Kalloger S, Carlson J, Ginzinger D, Celniker S, Mills GB Huntsman D., and Gray JW. Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer. Clinical Cancer Res. 13:5745-5755 (2007).
Neve RM, Chin K, Fridlyand J, Yeh J, Baehner F, Fevr T, Clark L, Bayani N, Coppe J, Tong F, Speed T, Spellman PT, Devries S, Lapuk A, Wang NJ, Kuo W-L, Stilwell JL, Pinkel D, Albertson DG, Waldman FM, McCormick F, Dickson RB, Johnson MD, Lippman M, Ethier S, Gazdar A, and Gray JW. (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell, 10:515-27.
Chin K, DeVries S, Fridlyand J, Spellman, P, Roydasgupta R, Kuo W-L, Lapuk A, Neve R, Qian Z, Ryder T, Chen F, Feiler H, Tokuyasu T, Kingsley C, Dairkee S, Meng Z, Chew K, Pinkel D, Jain A, Ljung B, Esserman L, Albertson D, Waldman F, and Gray JW. (2006) Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell, 10:529-41.
Hodgson JG, Malek T, Bornstein S, Hariono S, Ginzinger DG, Muller WJ, and Gray JW. (2005) Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling. Cancer Res., 65:9695-704.
Macrae M, Neve RM, Rodriguez-Viciana P, Haqq C, Yeh J, Chen C, Gray JW, and McCormick F. (2005) A conditional feedback loop regulates Ras activity through EphA2. Cancer Cell, 8:111-8.