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Colon Cancer Disease Oriented Team (CC-DOT)

Colon Cancer Surveillance and Prevention
Colon Cancer Diagnostics/Research Support
Colon Cancer Therapeutics
Translational Research
Leadership

UC Irvine’s Chao Family Comprehensive Cancer Center (CFCCC) is one of only 41 NCI-Designated Comprehensive Cancer Centers in the United States and Orange County. The Cancer Center’s robust translational research in biomarker validation and oncologic imaging, a multi-disciplinary robotics surgery platform, and the intra-operative hyperthermic perfusion chemotherapy program are notably unique to UC Irvine. More importantly, for those individuals living in Orange County and surrounding areas, access to the nation’s highest profile phase I-III clinical trials are available at this Cancer Center.

The Colon Cancer Disease Oriented Team (CC-DOT) brings together the collective expertise in basic, translational, and clinical research for the prevention and treatment of colorectal cancer (CRC).  Members of the CC-DOT include physicians and scientists from the Schools of Medicine, Biological Sciences, Physical Sciences, and Engineering.  The Co-Leaders of the CC-DOT will continue to build a translational framework in order to foster collaborative research and facilitate access to institutional resources.  Immediate short term goals include increasing patient accrual to (and completion of) on-going clinical trials, and bringing together interdisciplinary groups of CRC researchers, increasing new collaborations.  Long term goals include increasing levels of extramural funding in the form of program project and multi-investigator-initiated awards to UC Irvine; provide mentoring and support to junior CRC-oriented clinical and research faculty. CC-DOT will accomplish clinical and translational research under the auspices of the Chao Family NCI-Designated Comprehensive Cancer Center.

Colon Cancer Surveillance and Prevention

The Cancer Surveillance and Prevention component of the CC-DOT will foster ongoing and new CRC prevention trials at UC Irvine, each targeting a different aspect of colorectal carcinogenesis.  Therapeutic prevention of gastrointestinal malignancies continues to be strength of the cancer prevention program at UC Irvine’s CFCCC.  In particular, colorectal cancer prevention research is an active area of study.  After a series of phase I/II studies using eflornithine (difluoromethylornithine, DFMO) as therapeutic prevention for colorectal adenomas, a  landmark phase III double-blind, randomized, placebo-controlled trial of eflornithine and sulindac for prevention of sporadic colorectal adenomas was conducted at UC Irvine under direction of Dr. Frank L. Meyskens. The primary1 and secondary2-5 analyses have been published, and the very positive results has led to a  renewed interest in utilizing polyamine inhibition to effect colorectal cancer prevention.

Currently offered clinical trials involve Investigator Inititiated Trials (IIT) early phase studies funded via the NCI-funded Southern California Chemoprevention Consortium, and phase 0 and III IIT trials funded through either NCI grant mechanisms or the NCI cooperative oncology group system (SWOG). 

Southern California Chemoprevention Consortium:

The Southern California Chemoprevention Consortium (SCCC) is a member of the National Cancer Institute’s Consortia for early phase cancer prevention trials.  The overall objective of the SCCC is to conduct early phase (Phase I and Phase II) clinical trials of cancer prevention agents using the robust infrastructure that has been developed over the past decade at the CFCCC.  The main focus of these trials is to assess the cancer preventive potential of various compounds by evaluating their effects on molecular, biological, or imaging endpoints. 

The SCCC was founded in 2003 and includes physicians and medical practitioners from across the country.  These physicians began their efforts with a focus on conducting cancer chemoprevention clinical trials in the colon, oral cavity, gynecologic (primarily cervix), prostate and skin.  The primary approach has been to identify molecular targets and define a correlation with clinically relevant endpoints, including pathologic changes and imaging characteristics.   An additional goal is to explore combinations of agents developed by the pharmaceutical industry provided to the NCI for collaborative development, as well as commercially available agents and new compounds that we may propose.

The SCCC now includes over 16 collaborative sites working together with the CFCCC to reach the needed populations.  The SCCC coordinates Phase I and Phase II clinical trials designed to prevent cancers of the skin, colon, liver, and pancreas. The goal of the SCCC is to conduct clinical trials and to find ways to prevent cancer from developing in people who are at a higher risk of developing cancer.

Colorectal Cancer Diagnostics and Research Support

Colorectal Cancer Diagnostics and Research Support component will coordinate the clinical and molecular diagnostics required for direct patient care, with biospecimen procurement, annotation, and distribution for use in clinical and translational research studies. The Department of Pathology at UC Irvine Medical Center is committed to supporting the patient care and research efforts of the CC-DOT. As an example, Dr. Edwards is a GI pathologist who operates the Pre-Clinical and Translational Core (PCTC). In addition to providing routine diagnostic services for GI specimens and facilitating incorporation of new molecular diagnostic tests for GI malignancies, Dr. Edwards’ role in the PCTC is to ensure that research material procurement for CRC investigators is streamlined from the operating room all the way to the research bench. Through close interaction with each of the CC-DOT projects, the Pathology Department will constantly update and improve tissue acquisition procedures, and quickly identify and solve problems with reagents. 

In addition to crucial biospecimen acquisition and processing, an annotated CRC Tumor Bank has been developed (600 cases) which is cross-referenced to the California Cancer Registry, thereby linking basic and translation studies on CRC specimens to patient outcomes.

Another CC-DOT element is facilitating investigators’ use of the Pathology Research Services Core, which provides technical and interpretive histopathology services; consultation on the use of cell and animal-based models for CRC study, and assistance with regulatory and compliance issues related to such studies.

Colorectal Cancer Therapeutics

The Therapeutics component will unify a patient-centered colon care environment with new and on-going colorectal cancer therapeutic trials.  Along with the CFCCC’s recent expansion of physician faculty members in Colorectal Surgery (Drs. Pigazzi, Carmichael) and Gastrointestinal Medical Oncology (Drs. Seery, Nangia, Chiu), UC Irvine has developed a patient-centered approach to colorectal disease. The Cancer Center’s significant investment in the DaVinci multi-disciplinary robotics surgery platform and the intra-operative hyperthermic perfusion chemotherapy (HIPEC) program are unique to UC Irvine.

A multi-disciplinary approach to care is required for proper management of GI malignancies, and effective teams have been formed across UC Irvine’s various clinical disciplines that include: surgery, medical oncology, radiation oncology, gastroenterology, pathology, radiology. These teams are served by two separate tumor boards: the Gastrointestinal Tumor Board (meets weekly), and the Hepatobiliary Tumor Board (meets bi-weekly) which foster a coordinated approach to patient care. Additionally, clinical outpatient schedules have been aligned to foster better patient care. The colorectal cancer specific GI medical oncologists currently hold clinics during the same times as our colorectal surgery outpatient clinics, and three of the GI medical oncologists have clinic space in the Comprehensive Digestive Disease Center (CDDC) along with the colorectal surgeons and gastroenterologists.

This patient-centered approach has been incorporated into an expanded array of clinical trial offerings for patients with gastrointestinal malignancies.  Currently, the Cancer Center has 13 clinical trials open, which are specific to patients with various gastrointestinal malignancies.  In the newly-organized CC-DOT, open clinical trials for CRC patients will be expanded in a patient-centered manner, with a multidisciplinary approach to planning and implementation. The goal will be to identify gaps in the current or future clinical trials implemented on a continuous basis, and to realize novel CRC clinical trials with early input from all CC-DOT members.  The goal of such coordination will be to increase translational research opportunities, which in turn will lead to new opportunities for research collaboration and competitive research proposals.

For information on clinical trials here at the Cancer Center, please follow this link.

Colorectal Cancer Translational Research

Colorectal cancer is a complex and heterogeneous disease, which defies simple reductionist explanations of its clinical behavior. A critical challenge in advancing our understanding of the biology of CRC is to bring together teams of cell biologists, clinicians, mathematical modelers, biostatisticians, and bioengineers in order to bring novel approaches and more accurate models to CRC research.  UC Irvine has a rich environment of investigators with expertise relevant to studying CRC. This expertise is particularly strong in the fields of colonic epithelial cell signaling, tumor metabolism, angiogenesis, epithelial-stromal interactions, extracellular matrix and tumor microenvironment, microfluidics, and microscale tumor modeling. 

The Translational Research component of the CC-DOT, with fiscal support from the Cancer Center, is supporting multiple new collaborations in the area of colorectal cancer. Examples of this support include:

1.    An interdisciplinary group of CC-DOT members (Waterman, Hughes, George, Edwards) are preparing an NIH P01 application focusing on epithelial, stromal, and angiogenic signaling in the tumor microenvironment in CRC.  This project involves surgeons, pathologists, basic scientists, mathematicians, biomedical engineers, and biostatisticians, all of whom are contributing to the development of a microfluidic device in which CRC tumor microenvironments incorporating epithelia, stroma, and a perfused vasculature can be modeled and manipulated. Human colonic epithelium and stroma (IRB protocol 2010-7947) are incorporated into the model, Data from these experiments are used to inform mathematical models of CRC cell self-renewal, proliferation, and differentiation, and compared with data from animal models of CRC, clinical samples obtained at surgery and colonoscopy at UC Irvine Medical Center and with outcomes data from the California Cancer Registry in the CFCCC.

2.    Another project supported by the tissue procurement portion of the CC-DOT involves an aim of the P50 grant renewal of UCI’s Center for Complex Biological Systems (CCBS) (Arthur Lander, PI). In this aim, primary human intestinal crypts are cultured under conditions that allow precise mechanistic modeling of non-transformed cell lineage control and self-renewal. This work has direct implications for understanding how the loss of growth control occurs in aberrant crypt foci, early in CRC development.

3.    A third supported project is a response to a DARPA Broad Agency Announcement (BAA-11-73) which calls for modeling of vascularized human tissues in microfluidic devices. Primary intestinal tissue from the PCTC serves as the source material for this effort. 

GLOBAL BENCHMARKS OF SUCCESS OF THE CC-DOT:
Short term:
1.    To stimulate patient accrual and completion of ongoing CRC-related clinical trials
2.    To stimulate ongoing and new collaborations between investigators at UC Irvine and UC Irvine Medical Center.
Long term:
1.    Increasing extramural funding (program project and multi-investigator-initiated awards)
2.    Mentoring and support to CRC-oriented junior clinical and research faculty.

2013 Colon DOT Leadership

EdwardsDR.  ROBERT EDWARDS CO- LEADER
Professor, Department of Pathology, School of Medicine
Dr. Robert Edwards’ research interests include inflammatory bowel disease, Colon Cancer, and the tumor microenvironment & translational research.  Dr. Edwards is interested in the relationship between chronic inflammation and colorectal carcinogenesis in human and animal models.  There are two general areas of study in the laboratory. First, his work has highlighted inflammatory and hypoxia signaling network links between the epithelial, lymphoid, and stromal compartments and their contributions to the IBD and colon cancer phenotype in Gi 2-/-and other transgenic mice.  Second, in a number of interdepartmental collaboration with clinicians, biophysicists, and bioengineers, he has utilized new advances in primary intestinal culture to study the development and differentiation, metabolism, and carcinogenesis in     mouse and human intestinal tissues grown in a more physiologic milieu.

ZellDR.  JASON A. ZELL  CO-LEADER
Assistant Professor, Department of Medicine, School of Medicine
Dr. Zell is a translational oncology researcher in the UC Irvine Chao Family Comprehensive Cancer Center.  His particular clinical and research interest is in colorectal cancer (CRC) survivorship and tertiary CRC prevention (i.e., preventing the risk of new cancers, or pre-cancers among CRC survivors).  In addition to performing CRC-focused genetic epidemiology-based research, he is Principle Investigator or co-Investigator for multiple NIH-funded phase II and phase III clinical trials involving CRC patients or patients at risk for CRC.  Nationally, Dr. Zell serves as PI for a phase III CRC tertiary prevention trial being launched through NCI-SWOG, and serves as the SWOG Cancer Prevention & Control Liaison to the Gastrointestinal Committee.