Research Associate Professor, Medicine
- University of Arizona, 1999 (Ph.D., Cancer Biology)
- American Association of Cancer Research Pharmacia & Upjohn Young Investigator Award, 1999
- Cancer Biology Graduate Student Representative, 1998-1999
- Caldwell Health Sciences Scholarship, 1998
- American Association of Cancer Research Travel Award, 1997
- American Association of Cancer Research GlaxoWellcome Oncology Clinical Research Scholar Award, 1996
- American Association of Cancer Research Travel Award, 1994
My current projects include two recently funded five-year Program Projects where I am a core leader and a co-investigator. In the Skin Cancer Prevention Program Project my core serves as a collection and distribution point for all biological samples related to the grant. The core develops, optimizes, and performs methods for pathologic review of premalignant tissue and for analytical and immunohistochemical assays in support and in collaboration with each project. In the area of skin carcinogenesis, my laboratory has developed immunohistochemical markers of proliferation and p53 protein expression and we have shown that these markers are expressed with increasing frequency in UVB-induced skin carcinogenesis. I have also shown that p53 protein expression can be inhibited by a chemoprevention agent, DFMO, and this reduction correlated with a reduction in the number of the premalignant lesions of SCC, actinic keratosis or AK. Additionally, I have demonstrated that DFMO inhibits polyamine synthesis in the skin and that both polyamines and p53 expression are reproducible markers. Some of this work will be presented at an AACR Frontiers in Cancer Prevention Meeting in November. Most recently, my laboratory has worked closely with Dr. Timothy Bowden to determine whether his findings in a mouse model of UVB-induced carcinogenesis also apply to human skin exposed to damaging doses of UVB. My laboratory developed immunohistochemical assays to measure components of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI-3 Kinase) signal transduction pathways using the phosphorylated form of the proteins. Validation that similar pathways and/or targets are activated in animal and human systems is essential for development of effective chemopreventive strategies. A second phase of this project will address components of UVA signaling pathways.
Prevention of melanoma is another focus of the skin cancer program project. In support of this, my laboratory has been leading an effort to develop standardized pathologic review of the purported premalignant lesion of melanoma, the dysplastic or atypical nevi (DN). This remains a controversial area and we have assembled a group of expert dermatopathologists with the goal of developing a clinically useful grading system. In order to facilitate the review, I have developed a relationship with DMetrix, a company established by scientists from the University of Arizona Optical Sciences and Pathology Departments, that has developed an innovative virtual slide system for viewing and archiving images. I am also developing biomarkers for use in DN and have exciting preliminary data showing that VEGF is upregulated in DN compared to common nevi (BN) and intermediate between BN and melanoma. This work is currently being expanded to examine other VEGF family members and receptors and a manuscript is in preparation. Portions of these preliminary findings have been incorporated into a melanoma SPORE grant and I have been added as a co-investigator on a project focusing on the development of improved predictive markers of progression in thin melanomas (<1 mm in thickness). Currently there is not a clearly defined approach to sentinel lymph node biopsy in this group of patients with melanomas less than 1 mm in thickness and a significant number are later found to have progressive disease. Improved predictive markers would significantly impact the clinical care of these patients. I have been invited to present this work at an upcoming melanoma working group meeting at the Eastern Cooperative Oncology Group meeting in November.
The second program project that I am involved in is the Colorectal Cancer Prevention Program Project. The functions of the Analytical and Genotyping Core for this grant are very similar to those described for the Skin Cancer Program Project with extensive pathology review of tissue samples related to the grant as well as development and performance of assays critical to each project. A decade of research into the pathogenesis and prevention of colorectal adenomas through our Colon Cancer Prevention Program Project has contributed to the understanding that the vast majority of adenomas have little potential for progression or malignancy. In collaboration with Dr. Stanly Hamilton from the MD Anderson Cancer Center, we are exploring serrated adenomas, which have a distinctive molecular pathogenesis, including a high frequency of K-ras or BRAF mutations as well as hypermethylation of multiple gene promoters, and reduced expression of mismatch repair gene products hMLH1 and hMSH. Currently the precise criteria for classification of these serrated polyps relative to their current terminology, their biology and risk for recurrence, their molecular pathogenesis and epidemiology, and their implications for prevention strategies, including chemoprevention, remain to be established and are important issues that this grant will address.
In preliminary work, we have identified serrated adenomas as a novel indicator for adenoma recurrence, especially for another serrated adenoma. In addition, at a molecular level, we have recently identified K-ras mutation and methylation as genomic markers for advanced adenomas. We have also developed the hypothesis of a high-risk adenoma phenotype where a subset of individuals is highly predisposed to developing advanced colorectal pre-neoplastic lesions. In another collaborative project with Drs. Hamilton and Arthur Schatzkin at the NCI loss of imprinting (LOI) of the insulin/insulin-like growth factor 2 (IGF2) gene in peripheral blood lymphocyte will be explored and may represent an important subset of subjects who may be more likely to present with the high risk colorectal adenoma phenotype. A clinically important blood-based biomarker of risk could be developed if validation of the association were achieved.
In a previous collaboration with Drs. Jean-Pierre Issa and Stanley Hamilton from the MD Anderson Cancer Center we explored the concept that there are two distinct pathways to colon cancer involving specific epigenetic and genetic events: one is associated with the CpG-island methylator phenotype (CIMP) that is characterized by the methylation of specific CpG islands; and the other which does not involve altered DNA methylation. We recently published a manuscript in the Journal of the National Cancer Institute on MGMT methylation and colorectal cancer. Colorectal cancers with MGMT promoter methylation also had substantial MGMT methylation in apparently normal mucosa and in addition, cancers with MGMT methylation had a higher rate of G-to-A mutation in the K-ras than those without MGMT methylation. These data suggest that a proportion of colorectal cancers arise through a field defect defined by epigenetic inactivation of MGMT and mutation of K-ras. I developed the IRB approved protocol to collect the colorectal cancers, adjacent normal-appearing mucosa, and distant mucosa used in this publication and to date we have collected a resource of 100 colorectal cancers with both fixed and frozen tissue as well as clinical, demographic, and lifestyle information as well as follow-up information. This resource will be the basis for several small grant proposals looking at predictive biomarkers.
Additional manuscripts are in preparation based on the analysis of more than1000 colorectal adenomas for the methylation a specific set of cancer related genes, mutation of K-ras, and p53 overexpression in relation to baseline characteristics and risk of adenoma recurrence. This work has been presented at the 2005 annual AACR meeting.
I also have a number of other active collaborations. I am a co-investigator on a phase II trial funded by the Arizona Disease Control Research Commission that will assess the safety and efficacy of topical perillyl alcohol on skin biomarkers. This initial trial will lead to a larger study to determine the efficacy of topical perillyl alcohol in subjects with actinic keratosis. I am the principal investigator on a contract from Amplimed Corporation, an Arizona based company founded by investigators from the University of Arizona Cancer Center. This small contract will test the chemotherapeutic efficacy of imexon and a novel group of compounds collectively known as Azonifides in combination with other antineoplastic agents on human cancer xenographs. Finally, I am a co-investigator on two prostate cancer prevention grants. The first is a phase III trial of selenium for prostate cancer prevention that will determine the safety and efficacy of daily selenium supplementation versus placebo as a chemoprevention agent in men at high risk of prostate cancer. The second is another phase III trial of selenium supplementation in men who have chosen watchful waiting for the clinical management of localized prostate cancer. My role in both of these projects utilizes my expertise with tissue biomarkers.
Experience in research projects, laboratory, and data analysis.
Matthew Wharton (MSRP 2013): "Pilot Study to Evaluate the Signaling Pathway Modulation Demonstrated by Tropical Sulforaphane by Acutely Exposing Human Skin to Solar Simulated Light."