The Hematology and Oncology Division Cancer Genetics and Genomics program, co-led by Drs. Sandy Markowitz and Lyndsay Harris, includes a vibrant young membership to complement the experience of the leadership.
With funding from the Case GI SPORE and VA Medical Center, Dr. Cheng Chee is currently conducting a pilot study, “Methylated vimentin DNA in blood as a novel biomarker in colorectal cancer.” This study is based on Dr. Sandy Markowitz’s work at CWRU which showed that using the methyl-BEAMing technology, methylated vimentin DNA fragments in blood increase with colorectal tumor stage. This prospective study is designed to evaluate the prognostic and predictive potential of methylated vimentin DNA in blood in patients with colorectal cancer. Dr Chee was also awarded the ASCO/ EORTC/NCI Markers in Cancer Meeting, Diagnostic Development Tutorial Grant for this study.
Dr. Lyndsay Harris’s lab is a translational laboratory with a focus on cancer genomics and novel therapeutics. She is actively involved in the application of Next Generation Sequencing to biospecimens in the context of clinical trials. The lab will continue to analyze genetic signatures in vivo (from tumor specimens) and ex vivo (tumor mammosphere cultures) to understand mechanism of action of commonly used drugs in breast cancer (trastuzumab, bevacizumab, taxanes) and develop predictive signatures/mutational profiles for therapy selection. Several abstracts have been presented on this work at AACR, ASCO and SABCS. Ongoing and future work is exploring the value of genomic signatures in clinical practice, and ex vivo study of the mechanisms of these drug resistance phenotypes.
Dr. Harris also directs the Seidman Breast Cancer Program with membership including a multidisciplinary team of specialists and allied professionals. Many have active research studies ongoing - Plecha (tomosynthesis, breast PET-MRI), Lyons (radiation dose delivery, re-irradiation), Baar (immunotherapy,), Shenk (Risk assessment clinic, preoperative therapy), Silverman (U/S guided node biopsy, cardiac risk, survivorship, CNS metastases), Owusu (Geriatric Oncology, dispartities). In addition, a number of members of other departments are actively involved in breast cancer research projects Keri – (breast cancer signaling pathways, novel therapeutics), Schiemann (metastasis, TGFb signaling), Thompson (breast density, miRNAs), Gilmore (preop therapy/genomics, primagrafts, CNS metastases), Jackson (normal mammary biologic, stem cells, stromal-epthelial interactions), Narla (novel therapeutics, genetic susceptibility) DeFeo (ovarian-TNBC studies). This group has developed many collaborative efforts in the last year including joint grant applications and publications. Several resources have been developed to facilitate translational research within the program, including primagrafts from breast cancer samples, and several annotated tissue cohorts. These include a cohort of CNS metastases and matched primary samples with a tissue microarray and nucleic acid extraction for gene expression and mutation profiling. In addition, infrastructure is being developed to database all new patients with collection of biospecimens and clinical data. The activities of this group will form the basis for the new developing Breast Cancer Program in the Case Comprehensive Cancer Center..
The Sanford Markowitz laboratory (Markowitz, Fink, Moinova) research program continues to focus on translational studies of human gastrointestinal cancers. Highlights of the work include:
i) Development and successful funding by the NCI of the CASE GI Cancers SPORE center award with Dr. Markowitz as P.I and Dr. Nathan Berger as co-PI. This award supports studies that include:
a) Studies of the role of the 15-PGDH tumor suppressor pathway in colon cancer, and drug development efforts targeting this pathway.
b) Studies of stool DNA technologies for early detection of colon cancer, taking this technology that was developed in the Markowitz laboratory forward into a clinical trial (in collaboration with Dr. Greg Cooper in GI and Dr. Li Li in Family Medicine). The technology is also being carried forward as part of a national multi-center trial sponsored by the NCI Early Detection Research Network, with Case participating in this multi-center trial also under the leadership of Drs. Cooper and Li.
c) Sequencing of the genome of metastatic colon cancers (in collaboration with Dr. Joseph Willis in Pathology and Dr. Zhenghe Wang in Genetics).
d) Studies of the genomes of families with inherited Barrett’s esophagus, in collaboration with Dr. Amitabh Chak and Dr. Robert Elston.
ii) Continued development of new technology for detecting methylated DNA (supported by an NIH Early Detection Research Network Award), including finding methylated vimentin as a highly sensitive biomarker for Barretts esophagus (published as a cover article in Cancer Epidemiology Biomarkers and Prevention in collaboration with Dr. Joseph Willis of Pathology, Dr. Amitabh Chak of G.I.),
iii) Initiation of studies to determine genetic susceptibility factors to development of cancer metastases (supported by an NIH Transformative RO-1 Roadmap Award);
iv) Translational studies of Barrett’s esophagus supported by a new Case Barrett’s Translational Research Network Award (Multi P.I. to Dr. Chak in Gastroenterology, Dr. Berger in Hematology-Oncology, Dr. Elston in Epidemiology, and Dr. Markowitz). The BETRNet TRC-F focuses on genetic, molecular, and physiologic studies that will develop better methods for detecting BE, predicting its progression to EAC, and eradicating BE that is at risk for developing EAC.
v) Studies of the role of chromatin epigenetic signatures in colon cancer (collaborative with the Scacheri laboratory in Genetics. Published in Science, supported by a new RO-1 award, Multi-PI. to Scacheri, Markowitz, Tesar).
vi) Studies in developing drugs that can modulate activity of the 15-PGDH growth regulatory pathway. The work is being supported by a Harrington Development Institute Scholar Innovator Award to enable the initial lead compounds that have been identified to be further developed and brought forward for human trials.
Dr. Nathan Berger is also studying gene-environment interactions with a focus on obesity and cancer. The goal of 5P40 RR012305-13 (Berger, PI) is to develop mouse chromosome substitution stains from C57 Bl/6J and 12953SvimJ mice in order to study genetic complex trait loci involved in genetic interactions with environment relative to all aspects of cáncer and obesity. In these studies, the Berger lab has used Consomic Congenic strains of mice bearing the APCmin/+ mutation to demonstrate that high fat diets promote intestinal neoplasia (increased tumor number and tumor mass) independent of obesity. Tumor promotion is dependent on type of fat and is mediated by development of inflammation. Thus dietary fat, both quantity and quality, are shown to be important in primary prevention of intestinal neoplasia as well as in secondary prevention of tumor progression in individuals with established tumors. Ongoing studies are focused on defining the mechanism of intestinal neoplasia associated with dietary fat induced inflammation.
Dr. David Sedwick was able to activate new funding for his work as Scientific Coordinator of a National Children’s Study Contract. During this Contract, more than $1.5 million of new equipment for the Integrated Core was installed in the Gene Expression and Genomics Facility, the DNA Sequencing Facility the Proteomics Facility and the Translational Research Core Facility. The new funding with Drs. Dorr Dearborn, Martina Veigl and other co-investigators supports work to complete studies using a variety of microarrays for molecular evaluation to optimize isolation and quality assurance of RNA ,DNA and protein macromolecules from human umbilical cord as a representative source of fetal tissue. Additionally, Dr. Sedwick has continued his work with Dr. Zhenghe Wang’s laboratory in the Department of Genetics. As part of this collaboration, Dr. Sedwick was a co-author of a paper published in Cancer Cell, Hao et al, “Gain of direct interaction with IRS1 by the helical domain mutations of p110α is crucial for their oncogenic functions", which describes a common mutation in colon cancer that provides a new avenue to cancer chemotherapy.
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