Research

Research Mission Statement

"Uniting basic science concepts, translational genomic studies, and clinical trials to develop improved strategies to detect, diagnose, and treat cancers of the kidney."

Research Summary

The focus of our research group is the understanding of the tumorigenesis of renal cell carcinoma, and translating these findings into clinical practice. We tackle this problem using a variety of approaches, utilizing tumor specimens, genetically engineered cells and mice. These models provide tools with which we are able to investigate the effects of the von Hippel-Lindau and other important genes on processes integral to tumorigenesis including angiogenesis, vasculogenesis, hypoxic response signaling, extracellular matrix remodeling, glucose metabolism, and cell cycle signaling. These genetic models additionally provide the platform for the generation of a series of VHL mutant mice as an in vivo model of the human disease. Our cell culture and mouse models provide excellent models for exploring the pathogenesis of renal cancer as well as serving as tools for drug development.

Clinically, my focus is the treatment of genitourinary cancers, focusing on renal cell carcinoma. Using the information we are able to glean from the experimental models in the laboratory our goal is to provide superior care to patients with renal cell carcinoma, and to use those models to support a program of drug discovery and innovative ways of using available drugs targeting this particular cancer. To that end, I oversee a clinical research program within the multidisciplinary genitourinary oncology group that offers biologically active treatment protocols to patients with renal cell carcinoma at most stages of disease.

Ongoing Projects

Basic Research in Renal Cancer Genetics and Molecular Biology

We use genetically engineered mice, and cells from these mice to investigate the central activities that drive renal tumor growth. These studies explore how mutations in the von Hippel-Lindau gene contribute to different aspects of VHL disease, a rare inherited condition of familial clear cell kidney cancers and central nervous system and retinal hemangioblastoma.

Renal Cancer Genomics and Epigenetics

Our lab is interested in understanding the molecular and genetic effects of mutations occurring in kidney cancer, and we have approached this challenge in a variety of ways. We have identified robust signatures of transcribed genes that allow clear cell renal cancers to be subdivided into two dominant subtypes, clear cell A and B (ccA and ccB). These signatures are closely related with clinical outcomes, and provide a valuable prognostic biomarker of this cancer. Ongoing work continues to explore effects of gene mutations or other events in renal cancer to influence the resulting transcriptional products.

Ror2: The Receptor Tyrosine Kinase-like Orphan Receptor-2

Our lab discovered the association of this little known developmentally-regulated kinase with renal carcinoma cells (ref), and remains very interested in understanding the complex signaling that this Wnt receptor participates in to promote tumor growth. This kinase is normally expressed in the early developing embryo in the limb bud, heart, nervous system, and kidney. Expression in adult tissues is very limited, but this kinase emerges in kidney cancers as a result of sustained signaling by the HIF transcription factors, which are classically stabilized in clear cell kidney tumors. Ror2 is upregulated in a variety of other tumor types as well. In renal cell carcinoma, Ror2 is associated with promoting anchorage independent growth and cellular migration. The signaling pathways impacted by Ror2 to support cancer growth and metastasis are a source of continued study as well as identifying strategies to inhibit this kinase for therapeutic benefit.

Using Novel Imaging Strategies to Improve the Detection and Diagnosis of Kidney Cancers

Various Imaging Strategies

We have previously investigated the impact of metabolic positron emission tomography (FDG-PET) scans and creative uses of contrast enhancement with conventional computed tomography to understand how targeted therapies affect individual tumors. We are currently pioneering the use of combined magnetic resonance imaging with FDG-PET to render three-dimensional maps of tumors to merge tumor regional metabolic activity with tumor perfusion. This information will help physicians to make more accurate predictions about how tumors are likely to behave and to select regions of tumor optimal for biopsy. The use of contrast enhancement of ultrasound using microbubbles is another innovative new technology that extends the imaging capacity of ultrasound to potentially serve as a valuable new techinique for detecting early small tumors on the kidney.

VHL and Familial Kidney Cancers Specialty Clinic

This special multidisciplinary clinic is led by Dr. Rathmell and Mary Dunn, NP, and is open to patients and their families with VHL disease, Birt-Hogg-Dube, Tuberous Sclerosis, and other disorders. The clinic brings together genetic counselors, and a diverse array of specialists (including neurosurgery, otolaryngology, endocrinology, pediatrics, and others) and patient support staff to provide a comprehensive longitudinal care plan for patients and their families. UNC is recognized as a VHL Clinical Care Center by the VHL Family Alliance and is a part of their patient services task force. If you would like to make a referral to the VHL Clinic, please click here.

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