Career Development

Director:
Juanita Merchant, M.D., Ph.D.

Translational research in gastrointestinal cancer is critically needed to enhance applications of the knowledge gained through the rapid expansion of our understanding of the genetic and molecular basis of the pathogenesis of cancer. A comprehensive faculty career development program is proposed to meet the urgent need for increased number of clinicians and basic scientists devoted to gastrointestinal cancer research. Although some of this need has been addressed through NIH T32 training grants for post-doctoral fellows, transition to an independent, funded research career in gastrointestinal cancer for full time faculty has been difficult. Direct funding of young investigators with outstanding new translational research programs relevant to gastrointestinal cancer is proposed to address this limitation. Focus on young faculty members will ensure attraction of new, energetic investigators, who when successful, will likely maintain a long-term research interest in gastrointestinal oncology. A rigorous selection process is outlined that includes University-wide recruitment, strong emphasis on recruitment of women and minorities and comprehensive basic and clinical science mentoring. Close evaluation and monitoring is achieved through monthly meetings and annual internal and external review for continued funding. In addition to tailored scientific mentorship of individual projects, the GI SPORE career development program establishes an educational process for young investigators that is closely integrated with existing programs within the Cancer Center, Medical School, and the Michigan Institute for Clinical and Health Research. A major emphasis is placed on salary support for clinician scientists to ensure adequate time commitment to their SPORE research program.

Career Development Program Pilots

 

 

Importance of Genetic Intra-tumor Heterogeneity in Colorectal Cancer Progression

Principle Investigator:
Karin Hardiman, M.D., Ph.D.
Assistant Professor of Surgery

Co-Investigator(s):
Eric Fearon, M.D., Ph.D.
Emanuel N. Maisel Professor of Oncology

Joel Greenson, M.D.
Professor of Pathology

Scott Tomlins, M.D., Ph.D,
Assistant Professor of Pathology

11/1/2011 - 10/31/2013

While advanced stage and certain other clinico-pathological features are well known to be associated with poor prognosis, there are many challenges in predicting which patients will have metastasis and recurrence as well as which patients will respond to particular therapies. Genetic heterogeneity may underlie in part the biological heterogeneity among CRCs, with differing levels of aggressiveness and response to therapy among the variant populations of cells within a patient's primary tumors as well as in the metastatic lesions. The researchers hypothesize the following: I) A significant fraction of primary colorectal cancers will exhibit dramatic intra-tumor heterogeneity as a result of distinct genetic defects; and II) Metastatic lesions in patients with high levels of intra-tumor heterogeneity in the primary cancer will manifest only a subset of the somatic mutations found in the primary tumor.

 

 

A Non-Invasive High Throughput Label Free Microfluidic Approach for Detection and Characterization of Circulating Tumor Cells in Pancreatic Cancer

Principle Investigator:
Sunitha Nagrath, Ph.D.
Assistant Professor

Co-Investigator(s):
Diane M. Simeone, M.D.
Professor, Department of Surgery

11/1/2012 - 10/31/2013

The significant challenges that exist in obtaining tissue from pancreatic cancer patients prevents early histological diagnosis and the inherent difficulty in obtaining and studying tumors and their pharmacodynamic responses during clinical trials limit the ability to develop predictive information about PDAC. One avenue that lends possibility to developing accurate predictive tools and pharmacodynamic biomarker information comes from the analysis of circulating tumor cells (CTCs). CTCs could be potential marker for pancreatic cancer not only because of their specificity, but also amenable to serial genotyping during the course of therapy. Establishing the CTCs as potential biomarker for early diagnosis, monitoring, staging, prognosis and therapeutics of cancer can drastically change the current paradigm of pancreatic cancer diagnosis and management. Furthermore, if the researcher can correlate the presence of CTCs to the risk of distant metastasis, one can classify the "druggable targets", thus allowing more rational selection for adjuvant therapies in localized pancreatic cancer.

 

 

Oncogenic Function of CD44 in Pancreatic Cancer Invasion and Metastasis Cancer

Principle Investigator:
Kevin Tri Nguyen, M.D., Ph.D., Assistant Professor
Department of Surgery

11/1/2012 - 10/31/2013

The goal of this research is to determine whether CD44, and its potential downstream target, MT1-MMP, are sufficient and/or necessary for the cancer cell formation, invasion and metastasis. Both CD44 and MT1-MMP are membrane proteins, for which blocking antibodies or small molecule inhibitors exist. Thus, understanding their role in pancreatic cancer has therapeutic implications as it would determine the potential benefit of targeting CD44 and MT1-MMP, individually or in combination, in pancreatic cancer patients. To combine the advantages of different approaches and thus maximize the preclinical relevance of these studies, the researcher will use different, complementary approaches: engineered mouse models (GEMMS), primary mouse pancreatic cancer cells derived from two different GEMMS, and primary human pancreatic cancer cells propagated in mice as xenografts.

 

 

Targeting Tumor Specific Outlier Kinases through Kinome Profiling of Pancreatic Cancers - A Pilot Study for Personalized Treatment of Primary Human Tumors Xenografts

Principle Investigator:
Chandan Kumar, Research Assistant Professor
Department of Pathology

Co-Investigator(s):
Arul M. Chinnaiyan, M.D., Ph.D., Professor Department of Pathology

Diane M. Simeone, M.D., Professor Department of Surgery

11/1/2011 - 10/31/2012

Evan as next generation high throughput sequencing techniques are beginning to deliver on the promise of providing a comprehensive landscape of molecular aberrations present in individual tumors, the ensuing challenge is to translate this information into clinical practice. The questions of driver versus passenger aberrations, clonal heterogeneity of tumors, role of stoma in tumora sustenance coding RNAs in disease and therapy are all expected to be unraveled in the coming days leading to profoundly novel insights, improved diagnostics and therapeutic approaches. Here, we are addressing a more immediate practical question: based on all that we already know, based on all the molecular targets that are already characterized and for which effective inhibitors are already in use (or undergoing clinical trials/ advanced preclinical evaluations), can we use the currently emergent molecular information from deep sequencing of tumors, to impact treatment and patient survival.

 

Hepatocellular Carcinoma Stem Cells and Microenvironmental Influence of Immune Cell Subsets

Principle Investigator:
Theodore Welling, M.D., Assistant Professor
Department of Surgery

11/1/2010 - 10/31/2012

In this study Dr. Welling proposed studies exploring the interactions between hepatocellular carcinoma (HCC) cancer stem cells and their microenvironment, with an emphasis on the immune response in the tumor microenvironment.

 

Targeting CDC25 phosphatases in gastrointestinal cancers

Principal Investigator:
Tomasz Cierpicki, Ph.D., Assistant Professor
Department of Pathology

11/1/2010 - 10/31/2012

The goal of Dr. Cierpicki's proposal is to identify and characterize small molecule inhibitors that disrupt CDC25B-CDKs/Cyclin binding as potential anticancer agents. By activation CDKs through removal of inhibitory phosphorylation, CDC25 family members play an essential role to ensure cell cycle progression. Dr. Cierpicki's lab has developed an NMR-guided approach to identify CDC25 inhibitors that disrupt the binding between CDC25 and CDKs/Cyclin and have identified a small molecule compound, 8H8 that binds to CDC25B.


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