Scientific Accomplishments

The Molecular Biology & Cancer Genetics (MBCG) research program is one of 
OSUCCC–James' six highly interactive cancer research programs. The programs comprise more than 200 leading scientists from 13 different colleges within Ohio State and affiliated academic institutions. The MBCG includes 49 cancer-focused scientists.

With a focus on promoting clinical application of gene identification that leads to improved cancer screening, diagnosis, prognosis and treatment, MBCG members have successfully contributed to or led multiple P01 grants and a new SPORE (P50) award.

Other accomplishments include:

Programmatic Funding

NCI Program Project Grant, "Role of 11q23 chromosome abnormalities in the causation of acute leukemia"-PI: Carlo Croce, MD

NCI Program Project Grant, “Genetics & Signaling Pathways in Thyroid Cancer” – PI:Matthew Ringel, MD

NCI P01 Grant, “Genetic Analysis of the Breast Tumor Microenvironment” – PI: Michael Ostrowski, PhD
 
NCI U54 Grant "Interrogating epigenetic changes in cancer genomes". PI: Tim Hui-ming Huang, PhD

T32 Training Grant in Cancer Genetics - PI: Albert de la Chapelle, MD, PhD

MBCGPR PUBLICATION 2005-2009

Total: 996
Intra-Programmatic: 21 %
Inter-Programmatic: 29 %
Increase since 2000-2004: 64 %

Selected Findings and Developments

  • Development of Microarray Platforms for Analyzing miR Expression in Cancer (enabling precise correlate expression of miRs with cancer risk in leukemias and solid tumors (Liu C-G, et. al.  PNAS 101:9740, 2004)
  • Founder Mutation of MSH2 Gene & Hereditary Nonpolyposis Colorectal Cancer in the US.  Discovery that a sizable proportion of all HNPCC on the American continent appears to be caused by a large deletion in the MSH2 gene, introduced as a founder mutation in North America by an immigrant couple in 1729. This founder mutation has changed the way in which testing for HNPCC is performed in the United States. Lynch HT, et. al. JAMA  291:718, 2004. [JCR Impact Factor: 25.547]
  • MicroRNA Signature Associated with Prognosis & Progression in Chronic Lymphocytic Leukemia.  MBCG members provided one of the first demonstrations that miR expression can predict cancer outcome in leukemia patients. The studies suggest that microRNAs are important players in tumorigenesis and point to the crucial role of post-transcriptional genetic mechanisms that are mediated by microRNAs. Calin GA, et. al.  N Engl J Med 353:1793, 2005. [JCR Impact Factor: 52.589]
  • Screening for Lynch Syndrome in Colon Cancer Patients in Columbus, OH. Population- based studies of colon cancer patients, carried out through the Division of Human Cancer Genetics, demonstrate the efficacy of screening all colon cancer patients for mutations that cause Lynch Syndrome and suggest the best strategies for systematic screening. Hampel H, et. al. N Engl J Med  352:1851, 2005. [doi 10.1056/NEJMoa043146] [pubmed 15872200][JCR Impact Factor: 52.589]
  • A Regulatory Link Between Muscular Dystrophy & Cancer Cachexia.  An MBCG team demonstrated that tumor-induced alterations in the muscular dystrophy-associated dystrophin glycoprotein complex represent a key early event in cachexia. Acharyya S, et al. Cancer Cell 8:421, 2005. [JCR Impact Factor: 23.858]
  • Tumor Suppressor PP2A is Functionally Inactivated by BCR/ABL in Blast Crisis CML. A multidisciplinary team provided a new mechanism by which the BCR/ABL oncogene functions to induce and maintain chronic myelogenous leukemia (CML). PP2A reactivation by genetic and/or pharmacological means resulted in BCR/ABL activity suppression, increased apoptosis and decreased leukemogenesis. Thus, PP2A is essential for BCR/ABL leukemogenesis and may be an attractive molecular target for translational applications. Neviani P, et. al. Cancer Cell  8:355, 2005. [JCR Impact Factor: 23.858]
  • Ultra-Conserved Regions Encoding ncRNAs are Altered in Human Leukemias and Carcinomas. MBCG members demonstrated that just like oncogenes, tumor suppressor genes and microRNAs, ultra-conserved RNAs (UCRs) can contribute to cancer development. The work provides a new set of markers for cancer prognosis and novel molecular targets for future therapies.  Calin GA, et. al. Cancer Cell 12:215, 2007. [doi 10.1016/j.ccr.2007.07.027][pubmed 17785203][JCR Impact Factor: 23.858]
  • Germline Allele-Specific Expression of TGFßR1 Confers Increased Colorectal Cancer Risk. This work shows that in an Ohio-based population, TGFR1 is a potential candidate gene conferring ~9-fold increased cancer risk in up to 10 percent of colon cancer patients. Although the causative mutation in TGFR1 has not yet been identified, these findings may lead to clinical applications given the strong increase in cancer risk for this dominantly inherited quantitative trait. Valle L, et. al. Science  321:1361, 2008. [JCR Impact Factor:]

Recognition, Initiatives, Honors & Awards (2008 & 2009)

Program Project Grant

The Program Project Grant (PPG) is an $8.7 million, NCI-awarded grant to investigate Genetic Analysis of the Tumor Microenvironment. MBCG Co-Leader Michael C. Ostrowski, Ph.D., is the principal investigator.

P01 Grant

MBCG member Carlo Croce, MD, was awarded a P01 grant for mechanistic/translational studies on 11q23 chromosome abnormalities in acute leukemia. 

K23 Awards
MBCG member Kristi Blum, MD, received a K23 training award to study the effects of HDAC inhibitors on CLL in Phase I trials. She is also NCI R21 funded to study the effect of a flavopiridol and lenalidomide combination in CLL patients’ refractory to standard treatments. 

MBCG member William Blum, MD, received a K23 award to study the effect of HDAC and DNA-methylation inhibitors in AML.

R21 Award
MBCG member William Blum, MD, was awarded an R21 (ARRA) to study the efficacy of the DNA-methylation inhibitor decitabine as a maintenance therapy in AML following a first remission. 

MBCG member Daniel Schoenberg, PhD, and his team have demonstrated that the c-Src pathway in breast cancer cells targets PMR1, and direct phosphorylation of PRM1 by C-src is required to recruit PMR1 to polysomes. This work provides the first direct link between RNA decay and oncogenic signaling in cancer cells (Peng Y and Schoenberg DR. Mol Cell; 25:779, 2007). 

First Center for RNA Director Named
MBCG member Daniel Schoenberg, PhD, has been named the first director of the Center for RNA, a group of OSU faculty members who study RNA in many different processes and diseases, including cancer.

Program Project Grant (PPG): Genetic Analysis of the Tumor Microenvironment
PI: Michael C. Ostrowski, PhD
The microenvironment’s role in tumor progression is an emerging research area with important clinical implications for human carcinoma diagnosis and treatment.

Normal epithelial cell conversion to metastatic tumor cells is a multi-stage process requiring progressive genetic alterations within the epithelial tumor cell, and it has been the focus of intense investigation. Many other cell types in the tumor microenvironment, however, are increasingly appreciated as components of a complex biological network, akin to an organ system, that are critical for tumor progression.
PPG members will use human genetic approaches and mouse genetic models to study gene action from two cell types in the tumor microenvironment: tumor stromal fibroblasts and macrophages.

The program consists of three interactive projects supported by four Cores:

Project 1 will use human genetic approaches and laser capture microdissection to analyze genetic alterations occurring in the stromal compartment of human breast cancer samples.

Projects 1, 2 and 3 will develop and use mouse models to experimentally test the role of three genetic pathways: Pten, Rb/E2F and ras/ets-2 in the tumor microenvironment.

This work will be supported by the Transgenic/Knockout Core, the Mouse Pathology Core, the Research Methods & Biostatistics Core and the Administrative Core.

The PPG’s major, immediate goals are:

1. To identify, on a genome-wide scale, genetic alterations that occur in mammary tumor stromal cells isolated from human mammary tumor samples and the correlation of genetic changes found in mammary tumor stroma with clinical outcome of breast cancer patients;
2. To experimentally verify the essential role of gene action from mammary stromal cells during mammary tumor progression.

This involves creating mouse models that allow gene action in microenvironment cells to be tested and should more accurately reflect mammary tumor progression in humans at the genetic level.

The PPG’s long-term goal is to use the information gained from increased understanding of the tumor microenvironment role in breast cancer progress to improve strategies for breast cancer diagnosis, prognostication and treatment.

Discoveries & Inventions

Non-Coding RNA Expression

MBCG member Carlo Croce, MD, and his team discovered that expression of a second class of small, non-coding RNAs transcribed from ultra-conserved regions of the human genome are also frequently misregulated in human leukemia and carcinoma  and are potentially useful for predicting cancer risk (Calin GA, et. al. Cancer Cell 12:215, 2007).

miR Overexpression Can Lead to Cancer

MBCG member Carlo Croce, MD, and his team were the first to demonstrate that overexpression of an miR can lead to cancer. The team developed a transgenic model in which miR-155 was overexpressed in B-cells, leading to leukemia (Costinean S, et. al. PNAS 103:7024, 2006). 

CLL Model Generated by TCL-1 Gene Overexpression in B-Cells
MBCG member Carlo Croce, MD, and his team were the first to generate a CLL model by overexpressing B-cells’ TCL-1 gene. The model was characterized for preclinical studies with Experimental Therapeutics Research Program members Michael Grever, MD, and John Byrd, MD (Johnson AJ, et. al. Blood 108:1334, 2006). 

Paradigms for Translational Research
The studies of MBCG Co-Leader Albert de la Chapelle, MD, PhD, on the molecular genetics of familial colorectal cancer are a paradigm for translational research in human cancer genetics. Using central Ohio populations to discover new founder mutations associated with hereditary nonpolyposis colorectal cancer in the United States (Lynch HT JAMA 2004; 291(6):718-724) and to screen colon cancer patients to discover HNCC alleles, the team was able to identify at-risk family members who can benefit from cancer genetic counseling (Hampel H, et. al. N Engl J Med 352:1851-, 2005). The team was also able to demonstrate that allele-specific expression of TGFR1 confers a seven-fold increase in colorectal cancer risk in up to 10 percent of all colon cancer patients (Valle L, et. al. Science 321:1361, 2008).   

Akt Pathway Critical for Tumor Metastasis
MBCG member Matthew Ringel, MD, demonstrated that the Akt pathway is critical for tumor metastasis in a mouse model of thyroid cancer (Kim CS, et. al. Endocrinology 146:4456, 2005).

Prkar1a Gene Deletion in Mice Successfully Models Carney Syndrome
MGCG member Larry Kirschner, MD, PhD, and his team have demonstrated that Prkar1a gene deletion in mice successfully models Carney Syndrome, an autosomal dominant cancer syndrome caused by mutations in the regulatory subunit of Protein Kinase A (Kirschner LS, et. al. Cancer Res 65:4506, 2005).

Papillary Thyroid Tumors Distinguished from Follicular Thyroid Tumors by Expression of 5 Genes
A collaboration between MGCG member Sissy Jhiang, PhD, and program Co-Leader Albert de la Chapelle, MD, PhD, on a microarray analysis of thyroid tumors demonstrated that papillary thyroid tumors can be distinguished from the less aggressive follicular thyroid tumors by the expression of five genes (Aldred MA, et. al. J Clin Oncol  22:3531, 2004). 

Microenvironment Determines Lineage Commitment in CD34+ Cells
MBCG member James Mulloy, PhD, who uses CD34+ progenitor cells with specific chromosomal abnormalities to study mixed lineage AML, has demonstrated that the microenvironment determines lineage commitment in CD34+ cells obtaining the MLL-AF9 fusion. Targeting the Rac signaling pathway by pharmacologic or genetic means in this model resulted in rapid and specific apoptosis of MLL-AF9 cells, suggesting that the Rac signaling pathway may be a valid therapeutic target in MLL-rearranged AML (Wei J, et. al. Cancer Cell 13:483, 2008). 

APC Tumor Suppressor Inhibits DNA Replication
MBCG member Joanna Groden, PhD, and her team have demonstrated that the APC tumor suppressor inhibits DNA replication by directly binding to DNA via its carboxyl terminus (Qian J, et. al. Gastroenterology; 135:152, 2008).

Mismatch Repair Discoveries
MBCG member Rick Fishel, PhD, and his team have discovered a sequence-specific effect for activation of the mismatch repair complex hMSH2-hMSH6 (Mazurek A, et. al. PNAS 106:4177, 2009). The team has shown that nitric oxide-donating aspirin derivatives can suppress microsatellite instability in mismatch repair-deficient HNPCC cells (McIlhatton M, et. al. Cancer Res 67:10966, 2007).

BRCA1’s E3-Ubiquitin Ligase Activity Regulates Centrosome Duplication & Function
MBCG member Jeff Parvin, MD, PhD, and his team have demonstrated that the E3-ubiquitin ligase activity of BRCA1 regulates the duplication and function of centrosomes (Sankaran S ,et. al. Mol Cell Biol; 25:8656, 2005).

Aurora Kinase A Indirectly Regulates Centrosome Duplication & Genomic Stability
MBCG member Jeff Parvin, MD, PhD, and his team have demonstrated that Aurora kinase A regulates BRCA1 activity during the cell cycle and therefore indirectly affects centrosome duplication and genomic stability (Sankaran S et. al. Cancer Res 2007).

Msp1 Kinase Role in Centrome Duplication & Genomic Stability in Human Cells
MBCG member Harold Fisk, PhD, and his team have demonstrated that preventing the degradation of Mps1 at centrosomes is sufficient to cause centrosome reduplication in human cells (Kasbek C, et. al. Mol Biol Cell 18:4457, 2007). His lab also recently demonstrated that Msp1 can directly link centrosome duplication and genomic stability (Kasbek C, et. al. Environ Mol Mutagen 2009; in press). 

New Models Developed to Characterize BRCA1 and BRCA2 Variants
MBCG member Amanda Toland, PhD, combines human genetics and mouse models to study rare genetic variants and genetic modifiers of cancer phenotypes. Dr. Toland’s lab has developed clinically relevant models to characterize BRCA1 and BRCA2 variants in breast cancer (Spearman AD, et. al.  J Clin Oncol 26:53932008).

ets-1 & ets-2 Play Essential & Redundant Role in Endothelial Cell Function During Embryonic Angiogenesis
MBCG Co-Leader Michael Ostrowski, PhD, and his team, in collaboration with the Experimental Therapeutics Research Program, have identified an essential and redundant role for ets-1 and ets-2 in endothelial cell function during embryonic angiogenesis. Ets-1 and ets-2 coordinate endothelial cell movement, which is essential during angiogenesis, with cell survival by regulating key genes in both processes (Wei G, et. al. Blood 114:1123, 2009). 

Slit-2 Can Modulate Tumor Cell Growth & Migration
MBCG member Ramesh Ganju, PhD, and his team have demonstrated that the factor slit-2 can modulate tumor cell growth and migration by interacting with its receptor Robo-1 (Prasad A, et. al. J Biol Chem 283:26624, 2008).

New Algorithms Improve Follicular Lymphoma Grading
MBCG member Metin Gurcin, Ph.D., and his team recently created algorithms that significantly improve grading of follicular lymphoma (Sertel O, et. al. J Signal Processing Systems 55:169, 2009). 

Troglitazone Inhibits Breast Cancer Cell Migration & Adhesion
MBCG member Joseph Pinzone, MD, has demonstrated in preclinical studies that the PPAR-gamma inhibitor troglitazone inhibits breast cancer cell migration and adhesion (Wang P-S, et. al.  Mol Carcinog 47:905, 2008). 

Inhibiting WNT Signaling Pathway Modulates Breast Tumor Metastasis
MBCG member Joseph Pinzone, MD, has found in preclinical studies that using the DKK1 gene to inhibit wnt signaling modulates breast tumor metastasis.

Glioma Tumor Cells Secrete ECM Component That Promotes Tumor Migration & Invasiveness
MBCG member Mariano Viapiano, PhD, and his team have shown that brevican, an ECM component secreted by glioma tumor cells, promotes tumor migration and invasiveness (Hu B, et. al. J Biol Chem 283:24848, 2008). 

Mechanism for Estrogen Imprinting Discovered
MBCG member Tim Huang, PhD, who studies epigenetic changes in breast stem cells and cancer initiating cells, has demonstrated that estrogen treatment of normal breast progenitor cells results in a cancer-like DNA methylome. This provides a mechanism for “Estrogen Imprinting,” a phenomenon in which early developmental exposure to endocrine disruptors increases breast cancer risk later in adult life (Cheng ASL, et. al. Cancer Res 68):1786, 2008). The findings suggest that epigenetic therapies may provide an effective means to counter the deleterious effects of such early exposure.

NF-kB Signaling Promotes Muscle Degeneration
MBCG member Denis Guttridge, PhD, and his team have shown that NF-kB signaling in both macrophages and myofibers promotes muscle degeneration (Acharyya S, J Clin Invest 117:889, 2007).  Recent work demonstrates a key role for NF-kB signaling in controlling mir-29 expression in both muscle differentiation and in rhabdomyosarcoma. (Wang H, et. al. Cancer Cell 14:369, 2008).
 
First Vertebrate mRNA Endonuclease Identified, Purified & Cloned
MBCG member Daniel Schoenberg, PhD, and his team identified, purified and cloned the first vertebrate mRNA endonuclease, PMR1, and continues work on characterizing this enzyme.

Dr. Schoenberg’s lab demonstrated that PMR1 is selectively targeted to polysomal mRNA (Yang F and Schoenberg DR. Mol Cell 14:435, 2004). 

First Direct Link Identified Between RNA Decay & Oncogenic Signaling in Cancer Cells
MBCG member Daniel Schoenberg, PhD, and his team have demonstrated that the c-Src pathway in breast cancer cells targets PMR1, and direct phosphorylation of PRM1 by C-src is required to recruit PMR1 to polysomes. This work provides the first direct link between RNA decay and oncogenic signaling in cancer cells (Peng Y and Schoenberg DR. Mol Cell; 25:779, 2007). 

EFG Receptor Signaling Role in Neurofibromatosis-Related Peripheral Nerve Tumorigenesis
MBCG member Nancy Ratner, PhD, and her team were the first to demonstrate a role for EFG receptor signaling in neurofibromatosis-related peripheral nerve tumorigenesis (Ling BC, et. al. Cancer Cell 7:65, 2005). Dr. Ratner’s lab has shown synergy between loss of NF1 and active desert hedgehog signaling in neurofibromas (Wu J, et. al. Cancer Cell 13:105, 2008). The group has also demonstrated that NF1 mutation expands an EGFR-dependent peripheral nerve progenitor that confers neurofibroma tumorigenic potential (Williams JP, et. al. Cell Stem Cell 3:658, 2008). 

MicroRNA Expression Patterns Differentiate Pancreatic Adenocarcinoma from Normal Pancreas and Chronic Pancreatitis
An MBCG team identified miRNAs that differentiate pancreatic cancer from chronic pancreatitis with 93 percent accuracy and that predict patient outcome. This data provides a molecular signature that differentiates between patients with better or worse prognoses and therefore may help guide the clinician when determining who should or should not receive aggressive therapy. The data also may eventually be used to design specific targeted therapies for pancreatic cancer. Bloomston M, et. al. JAMA  297:1901, 2007. [doi 10.1001/jama.297.17.1901] [pubmed 17473300][JCR Impact Factor: 25.547]

Collaborations

The Molecular Biology & Cancer Genetics (MBCG) research program is one of  six highly interactive cancer Research Programs. The programs comprise more than 200 leading scientists from 13 different colleges within OSU and affiliated academic institutions.

MBCG investigators collaborate with several OSUCCC–James Shared Resources, including 
the Biomedical Informatics Shared Resource, of which MBCG member Jeff Parvin, MD, PhD, is co-director, as well as the Microarray Shared Resource, the Proteomics Shared Resource, and the Small Animal Imaging Shared Resource. 

Other collaborations include:

Intra-Programmatic Collaborations

  • MBCG Co-Leader Albert de la Chapelle, MD, PhD and MBCG member Daniel Schoenberg, PhD and his team demonstrated that an miR146a polymorphism associated with thyroid cancer was shown to affect processing of the pre-miR to mature miR146a (Jazdzewski  K, et. al. PNAS 105:7269, 2008).
  • MBCG member Gregory Otterson, MD collaborated with MBCG members Gustavo Leone, PhD and Thomas Rosol, DVM, PhD, in studies demonstrating bone morphogenetic protein 3B silencing in non-small-cell lung cancer (Dai Z, et. al. Oncogene 23:3521, 2004).
  • MBCG member Huey-jen Lin, PhD, in a collaborative study with MBCG Co-Leader Michael Ostrowski, PhD, and MBCGRP member Tim Hui-ming Huang, PhD, demonstrated that tumor fibroblasts can stimulate gene silencing in the normal breast cell line MCF-10A. The mechanism involves activation of the Akt pathway within the breast epithelial cells (Lin H-JL, et. al. Cancer Res; 68:10257, 2008).
  • MBCG member Dawn Chandler, PhD, collaborated with fellow MBCG members Denis Guttridge, PhD, and Carlo Croce, MD, to define miR-29 as an NF-kB regulated tumor suppressor in RMS.   is a new recruit with interest in how alternative RNA splicing is regulated and how this contributes to cancer progression and muscle wasting associated with muscular dystrophy and cancer cachexia.
  • MGCG member Larry Kirschner, MD, PhD, and his team, in collaboration with MBCG member Sung Ok Yoon, PhD, demonstrated that conditional deletion of Prkar1a in Schwann cells leads to down-regulation of the NF1 tumor suppressor gene and schwannomas (Jones GN, et. al. Neoplasia 10:1213, 2008).
  • MBCG member Sung Ok Yoon, PhD, collaborated with fellow MBCG member Mariano Viapiano, PhD, and demonstrated that the P75 NGF receptor was overexpressed at the leading edge of human glioblastoma tumors.
  • MBCGRP member Kay Huebner, PhD, and her team collaborated with fellow MBCGRP member Carlo Croce, MD, and generated knockout mouse models for both the FHIT gene and the WWOX gene. Analysis of FHIT-deficient mice reveals increased susceptibility to lung cancer that is increased when the tumor suppressor VHL is haplo-insuffcient (Zanesi N, et. al. Cancer Res  65:6576, 2005).
  • MBCG member Danilo Perrotti, MD, PhD, and his team, in collaborative studies with fellow members Clara Bloomfield, MD, Michael Caligiuri, MD, and Guido Marcucci, MD, demonstrated that the tumor suppressor PP2A  is inactivated in blast crisis CML through the BCR/ABL-regulated SET protein (Neviani P, et. al., Cancer Cell  8:355, 2005).
  • Collaborative work involving multiple MBCG members demonstrates that NF-KB target mIR29 promotes muscle differentiation and is down-regulated in RMS.  Re-expression of miR-29 in RMS inhibits tumor growth. These results indicate that NF-KB may be an effective target in RMS. Wang H, et. al. Cancer Cell; 14:369, 2008. [doi 10.1016/j.ccr.2008.10.006] [pubmed 18977326][JCR Impact Factor: 23.858]
  • In collaboration with fellow MGCG members Gustavo Leone, PhD, and Thomas Rosol, DVM, PhD, Co-Leader Michael Ostrowski, PhD, and his the group developed a system specifically to delete genes in stromal fibroblasts. The system was used to study the role of epithelial-mesenchymal transition (EMT) in several mouse models of breast cancer by genetically marking cells that had undergone EMT. These studies demonstrated that EMT was rare and associated specifically with myc oncogene overexpression. Human genetic studies indicated that EMT is rare in human breast cancer as well, but again associated with myc overexpression (Trimboli AJ, et. al. Cancer Res 68:937, 2008).
  • MBCG member Tsonwin Hai, PhD, in a collaborative study with fellow member Denis Guttridge, PhD, used mouse models she developed to demonstrate that ATF3 is a negative regulator of Toll-like receptor 4 in macrophages (Gilchrist M, et. al. Nature 441:173, 2006). Additionally, they demonstrated that ATF3 is involved in stress-induced beta-cell apoptosis (Hartman MG, et. al. Mol Cell Biol 24:5721, 2004).   

Inter-Programmatic Collaborations

  • Mouse Development with a Single E2F Activator. An inter-programmatic study used elegant mouse genetics to demonstrate that the key Rb targets E2Fs are redundant for mouse embryonic development. Tsai S-Y, et. al. Nature  454:1137, 2008. [doi10.1038/nature07066] [pubmed 18594513][JCR Impact Factor: 28.751]
  • MBCG member Daniel Schoenberg, PhD, and his team collaborated with a Viral Oncology Research Program team and identified RNA helicase A as a factor necessary for translating select mRNAs, including the mRNA encoding the protocongene junD (Hartman TR, et. al. Nat Struct Mol Biol 13:509, 2006)
  • Loss or Silencing of Death-Associated Protein Kinase 1 in the Majority of Chronic Lymphocytic Leukemia Patients. An MBCG-led inter-programmatic study identified a non-coding mutation in DAPK1 in a rare, inherited form of CLL and subsequently demonstrated this gene is epigenetically silenced in the majority of sporadic cases of CLL. Raval A, et. al. Cell 129:879, 2007. [doi 10.1016/j.cell.2007.03.043][pubmed 17540169][JCR Impact Factor: 29.887]
  • MicroRNA Expression in Cytogenetically Normal Acute Myeloid Leukemia. An MBCG-led inter-programmatic study identified 12 miRs whose expression predicts outcome in the largest myeloid leukemia patients group. Bioinformatic analysis of the mIR targets suggest genes involved in innate immunity are potential targets, providing a mechanism for miR action. Marcucci G, et. al. N Engl J Med  358:1919, 2008. [doi 10.1056/NEJMoa074256] [pubmed 18450603][JCR Impact Factor: 52.589]
  • Global Assessment of Promoter Methylation in a Mouse Model of Cancer Identifies a Putative Tumor-Suppressor Gene in Human Leukemia. The MBCGRP collaborated with Experimental Therapeutics Research Program members, and using a mouse model of T-cell acute lymphoblastic leukemia, reproducibly assessed global promoter methylation. These model studies identified ID4 as a putative tumor-suppressor gene that is also epigenetically silenced in the majority of human leukemias tested. Information obtained from the mouse model helped identify genes that undergo methylation during cancer, providing new potential biomarkers and suggesting epigenetic-based therapies. Yu L, et. al. Nat Genet  37:265, 2005. [JCR Impact Factor: 25.556]
  • MBCG members Patrick Nana-Sinkam, MD, and Gregory Otterson, MD, collaborated with Experimental Therapeutics Research Program member Gerard Nuovo, MD, and Innate Immunity Research Program member Clay Marsh, MD, to identify miRs associated with lung cancer. The work identified miR133B and miR 126 as potential new therapeutic targets in pre-clinical studies (Crawford M, et. al. Biochem Biophys Res Commun  373:607, 2008: Crawford M, et. al.  Biochem Biophys Res Commun 2009 in press).
  • In collaborative basic science studies with Experimental Therapeutics Research Program member Miguel Villalona, MD, MBCG member Gregory Otterson, MD, and his group demonstrated that the DNA-methylation inhibitor 5-aza-2’deoxycytidine inhibits cell proliferation by activating the p53/p21 cip pathway (Zhu W-G, et. al. J Biol Chem 279:15161, 2004).
  • MBCG member Gregory Otterson, MD, led a Phase I study, which included Experimental Therapeutics Research Program Co-Leader Michael Grever, MD, and ETRP members Miguel Villalona, MD, and Manisha Shah, MD. The study use feretinide combined with paclitaxel and cisplatin. (Otterson GA, et. al. Invest New Drugs 23:555, 2005). A Phase II study, which included Dr. Villanova, evaluated the combination of docetaxel and capecitabine in previously treated patients with non-small cell lung cancer. (Kindwall-Keller T, et. al. Clin Cancer Res 11:1870, 2005).
  • In collaboration with Experimental Therapeutics Research Program members Mark Parthun, PhD, Michael Freitas, PhD, and ETRP Co-Leader John Byrd, MD, MBCG member Rick Fishel, PhD, the group has established techniques for liquid chromatography/mass spectrometry profiling of histones. (Su X, et. al. Chromatogr B Analyt Technol Biomed Life Sci  850:440, 2007).
  • In studies with Experimental Therapeutics Research Program member Charles Shapiro, MD, MBCGRP member Kay Huebner, PhD, and her team demonstrated that both FHIT and WWOX genes are silenced in basal phenotype, triple negative breast cancer  tumors (Guler G, et. al. Cancer 115:899, 2009).
  • In collaboration MBCG members Mark Bloomston, MD, and Carlo Croce, MD, and Innate Immunity Research Program member Wendy Frankel, MD, MBCG member Kay Huebner, PhD, observed fragile site gene expression loss in pancreatobiliary cancers  (Bloomston M, et. al. Ann Surg Oncol 16:2331, 2009).
  • MBCGRP member Kay Huebner, PhD, collaborated in a study with fellow MBCG member Carlo Croce, MD,  and Experimental Therapeutics Research Program members Kenneth Chan, PhD, and Guido Marcucci, MD, that showed expression of miR-29 in lung cancer cells could revert aberrant DNA methylation by targeting DNA methyltransferases 3A and 3B (Fabbri  M, et. al. PNAS  104:15805, 2007).
  • In a collaborative study with biologists and bioinformaticists, MBCG member Jeff Parvin, MD, PhD, revealed a link between breast cancer susceptibility and centrosome dysfunction (Pujana MA, et. al. Nat Genet  39:1338, 2007).
  • In collaboration with Experimental Therapeutics research program member Guido Marcucci, MD, MBCG members Clara Bloomfield, MD, and Michael Caligiuri, MD, demonstrated that a novel recessive gain-of-function mutation associated within the MLL partial tandem duplication identifies an acute myeloid leukemia patient subgroup that can benefit from molecular targeted therapy (Whitman SJ, et. al. Blood  106:345, 2005).
  • A study that included MBCG members Clara Bloomfield, MD, Michael Caligiuri, MD, Danilo Perrotti, MD, PhD, Co-Leader Albert de la Chapelle, MD, PhD, and Experimental Therapeutics Research Program member Guido Marcucci, MD, demonstrated that overexpression of the ETS-related gene, ERG, predicted worse outcome in acute myeloid leukemia with normal karyotype (Marcucci G, et. al. J Clin Oncol  23:9234, 2005).
  • Collaborative studies led by MBCG member Michael Caligiuri, MD, and including MBCG member Mica Gustavo Leone, PhD, and Experimental Therapeutics research program member Guido Marcucci, MD, demonstrated that tandem MLL partial tandem duplication (PTD) expression in mice altered Hox gene expression boundaries, resulting in axial skeletal defects and increased numbers of hematopoietic progenitor cells. The mice overexpressed several Hox genes in blood progenitors, and the increased expression correlated with an increase in positive histone marks in the overexpressed genes, indicating that the MLL PTD operates through an epigenetic mechanism (Yu L, et. al.  J Clin Invest  116:2707, 2006).
  • MBCG members Danilo Perrotti, MD, PhD, Clara Bloomfield, MD, Michael Caligiuri, MD, and Guido Marcucci, MD, collaborated with Experimental Therapeutics Research Program Co-Leader John Byrd, MD, and ETRP member Ching-Shi Chen, PhD, to assess the therapeutic potential of the PP2A activator FTY720 in CML-BC and Ph1 ALL patient cells and to use in vivo models of these BCR/ABL+ leukemias. The data indicate that FTY720 induces apoptosis and impairs clonogenicity of imatinib/dasatinib-sensitive and -resistant p210/p190(BCR/ABL) myeloid and lymphoid cell lines and CML-BC(CD34+) and Ph1 ALL(CD34+/CD19+) progenitors but not of normal CD34+ and CD34+/CD19+ bone marrow cells (Neviani P, et. al.  J Clin Invest 117:2408, 2007).
  • MBCG Co-Leader Michael Ostrowski, PhD, has collaborated with fell member Gustavo Leone, PhD, and Molecular Carcinogenesis & Chemoprevention Research Program member Thomas Rosol, DVM, PhD, on the NCI P01 grant, “Genetic Analysis of the Breast Tumor Microenvironment.”
  • In collaboration with Gustavo Leone, PhD, and Experimental Therapeutics Research Program member Raj Muthusamy, DVM, PhD, MBCG Co-Leader Michael Ostrowski, PhD, and his lab have identified an essential and redundant role for ets-1 and ets-2 in endothelial cell function during embryonic angiogenesis. Ets-1 and ets-2 were shown to coordinate endothelial cell movement essential during angiogenesis with cell survival by regulating key genes in both processes (Wei G, et. al. Blood 114:1123, 2009).
  • MBCG member Gustavo Leone, PhD, collaborated with Co-Leader Michael Ostrowski, PhD, fellow members Metin Gurcan, PhD, and Thomas Rosol, DVM, PhD, and Molecular Carcinogenesis & Chemoprevention Research Program member Lisa Yee, MD, and demonstrated that Pten in tumor fibroblasts can suppress epithelial tumor cell growth. Deletion of Pten in fibroblasts drastically alters the tumor microenvironment and leads to an increase in the size and composition of the extracellular matrix, increased inflammation and increased angiogenesis. Further, Pten suppresses transcription factor ets2, a critical target that modulates inflammation and angiogenesis. This Pten stromal pathway can also be found in human breast cancer and predicts poor patient outcome. Together, these studies are the first to successfully model the breast tumor microenvironment, providing a preclinical model for testing agents that target microenvironment components (Trimboli AJ, et. al. Nature; In Press).
  • In collaborative studies with MBCG member Michael Caligiuri, MD, and Viral Oncology Research Program member Pierluigi Porcu, MD, MBCG member Gustavo Leone, PhD, and his group demonstrated a tumor suppressor function for E2F2 in Myc-induced T cell lymphomagenesis (Opavsky R, et. al. PNAS 104:15400, 2007).
  • MBCG member Joseph Pinzone, MD, in collaboration with Molecular Carcinogenesis & Chemoprevention Research Program member Thomas Rosol, DVM, PhD, demonstrated that the bisphosphonate zoledrionic acid decreased osteolysis but not bone metastasis in a unique preclinical mouse/canine model of metastatic prostate cancer (Thudi NK, et. al.  Prostate 68:1116, 2008).
  • In collaboration with Experimental Therapeutics Research Program members Miguel Villalona, MD, and Manisha Shah, MD, MBCG member Denis Guttridge, PhD, demonstrated that tumor necrosis factor alpha blockade, which also will block NF-KB activation, was a successful intervention to improve dose-intensive chemotherapy tolerability in cancer patients. (Monk JP, et. al. J Clin Oncol  24:1852, 2006).

Inter-Institutional Collaborations

  • Johns Hopkins University: MBCG members are collaborating with JHU are collaborating on a study, “Trisomy at the Ets2 locus suppresses colon cancer in mouse models of Down’s syndrome,” provides experimental evidence in mouse models that trisomy of the Ets2 locus, a chromosome 21 gene, is sufficient to suppress colon cancer in mouse models. Sussan TE, et al. Nature 451:73, 2008. [doi 10.1038/nature06446] [pubmed 18172498][JCR Impact Factor: 28.751]
  • Cincinnati Children’s Research Institute: MGCG member Kay Huebner, PhD, collaborated with fellow MGCG members Michael Caligiuri, MD, and Carlo Croce, MD, as well as the CCRI’s Viral Vector Shared Resource to perform preclinical assessment of FHIT gene replacement therapy in human leukemia using a chimeric adenovirus (Pichiorri F, et. al. Clin Cancer Res 12:3494, 2006). Dr. Huebner’s group demonstrated that WWOX inhibits breast cancer growth using their mouse model in vivo and in human breast cancer lines in vitro (Iliopoulos D, et. al. Clin Cancer Res 13:268, 2007).
  • Dana Farber Cancer Institute: MBCG members Clara Bloomfield, MD, and Michael Caligiuri, MD, collaborated with DFCI’s Thomas Look, MD on a study showing that expression of HOX11 oncogenes in adults with T-cell acute lymphoblastic leukemia predicted a favorable patient outcome  (Ferrando  AA, et. al. Lancet  263:535, 2004).
  • NCI Integrative Cancer Biology Program: MBCG member Tim Hui-ming Huang, PhD, is the principal investigator on a U54 project.
  • MD Anderson Cancer Center: In collaborative studies with MD Anderson Cancer Center investigators, MBCGRP member Tim Huang, PhD, and his group helped demonstrate that in prostate cancer, gene silencing can occur through methylation of core histones without DNA methylation (Kondo Y, et. al. Nat Genet 40:741, 2008).   

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) 460 W. 10th Avenue, Columbus, OH 43210 Phone: 1-800-293-5066 | Email: jamesline@osumc.edu