Elizabeth Petri Henske, MD
Fox Chase Cancer Center
Philadelphia, PA 19111

Our laboratory studies two related disorders: tuberous sclerosis complex (TSC) and pulmonary lymphangiomyomatosis (LAM). TSC is an autosomal dominantly inherited disease with an incidence of approximately one in 10,000 births. Clinically, TSC is characterized by seizures, mental retardation, autism, and benign tumors or "hamartomas." These tumors can occur in virtually any organ system, particularly brain, kidney, heart, and skin. Malignant tumors can also occur in tuberous sclerosis, particularly in the kidney, although they are less frequent than benign tumors. Mutations in two tumor suppressor genes cause TSC: the TSC1 gene, on chromosome 9q34, which encodes a 140 kD protein called hamartin, and the TSC2 gene, on chromosome 16p13, which encodes a 200 kD protein, tuberin.

My laboratory is focused on the pathogenesis of the renal and pulmonary manifestations of TSC. Renal disease in TSC includes cysts, angiomyolipomas, and renal cell carcinomas, and is the most common cause of TSC-related death. Angiomyolipomas are benign tumors with vascular, smooth muscle, and lipomatous components. The renal cell carcinomas in TSC are pathologically heterogeneous, including tumors with clear cell, papillary, sarcomatoid, and chromophobe morphology. The etiology of renal cyst disease in TSC is not yet fully understood, but appears to involve both functional and genetic factors. Functionally, tuberin has recently been found to be required for the correct membrane localization of polycystin, the product of autosomal dominant polycystic kidney disease (ADPKD) gene, PKD. The TSC2 gene is immediately adjacent to PKD1 on chromosome 16p13. At least three findings suggest that genetic factors involving PKD1 play a role in cyst pathogenesis in TSC. First, a contiguous gene syndrome has been identified in which infants born with deletions of both TSC2 and PKD1 have severe PKD at birth. Second, many adults with TSC and clinically significant renal cystic disease have large deletions within the TSC2 gene, some of which extend into the adjacent PKD1 gene. Finally, TSC2 is somatically deleted in some PKD1 cysts as part of the "second hit" genetic event.

Pulmonary LAM is the third most frequent cause of TSC-related death. LAM can occur without other disease (sporadic LAM) or in association with TSC (TSC-LAM). LAM is of unusual interest biologically because it affects almost exclusively young women. We have found that somatic mutations in the TSC2 gene are a cause of sporadic LAM. The same TSC2 mutations were identified in both the renal angiomyolipomas and the LAM smooth muscle cells in the lung, but not in normal kidney, normal lung, or blood cells. This suggests the possibility of an unusual disease mechanism in LAM: metastasis of histologically benign smooth muscle cells from the renal angiomyolipoma to the lungs.

Our long-term goal is to understand the cellular pathways through which mutations in the TSC1 and TSC2 genes lead to renal and pulmonary disease. Therapeutic strategies directed at targets within these pathways may benefit patients with TSC. These pathways may also be involved, either directly or indirectly, in other neoplastic and non-neoplastic diseases. Hamartin and tuberin are expressed in most normal adult human tissues, and TSC affects nearly every organ system including the central nervous system. This suggests that the pathways in which hamartin and tuberin participate have broad biological relevance.

Currently the work in our laboratory can be grouped into four general areas:

1. Understanding the genetic features of sporadic and TSC-associated LAM.

A. We will determine if TSC1 mutations are associated with sporadic LAM in patients with angiomyolipomas.
B. We will determine if patients with pulmonary LAM who do not have renal angiomyolipomas have somatic TSC1 or TSC2 gene mutations.
C. We will determine if TSC1 or TSC2 mutations are a cause of extra-pulmonary LAM.

2. Understanding the genetics and biology of renal disease in TSC, including angiomyolipomas and renal cell carcinoma.

A. We will identify the germline "first hit" and somatic "second hit" mutations in TSC-associated renal cell carcinomas, and identify other somatic genetic events involved in the development of renal cell carcinoma in TSC patients.
B. We will use primary cell cultures derived from angiomyolipomas to understand the effects of estrogen and progesterone on angiomyolipoma cell growth and migration, and on downstream transcriptional targets of estrogen receptor alpha.

3. Elucidating the functions of the protein products of the TSC1 and TSC2 genes, particularly as they relate to the regulation of cell proliferation, migration, and invasion.

A. We will define the roles of the TSC1 and TSC2 genes in mammalian cell cycle regulation.
B. We will examine the effects stable expression of TSC2 in MDCK cells, which are a model for studying epithelial cell polarity.
C. We are exploring the role of TSC1 and TSC2 in cell growth in Schizosaccharomyces pombe.

4. Understanding the mechanisms of angiogenesis in TSC tumors.

A. We will determine, using laser capture microdissection, whether different types of vessels in TSC angiomyolipomas contain the "second hit" genetic event - i.e. are the vessels reactive or neoplastic?
B. We will use conditioned media from cells over-expressing TSC2 to determine whether tuberin regulates the secretion of angiogenic factors.
C. We will identify angiogenic factors involved in TSC tumorigenesis.

What opportunities will the Rothberg Award create in my laboratory?

An important limiting factor in the productivity of many laboratories is the recruitment and retention of bright, enthusiastic, well-trained, and motivated post-doctoral fellows. Currently I am extremely fortunate to have four outstanding fellows in the laboratory (Jane Yu, Aris Astrinidis, Marjon van Slegtenhorst, and Magdalena Karbowniczek). Three of these fellows are not US citizens and therefore not eligible for fellowships from the NIH or the American Cancer Society. In addition, regardless of citizenship it is often difficult to find independent funding for post-doctoral fellows after their third year in a laboratory, although it is during these subsequent years in the laboratory that post-doctoral fellows have the independence, confidence, skills, and knowledge to make their own critical contributions to TSC research.

I will use the Rothberg Award to retain these outstanding individuals, allowing them to continue to focus on TSC research beyond the timeframe allowed by other types of fellowship support.

The Rothberg funds will allow us to continue to use both genetic and cell culture approaches to dissecting the molecular pathways leading to pulmonary and renal disease in TSC. There appears to be substantial overlap between the biology of cancer and the biology of TSC. For example, pathways involving cell proliferation, differentiation, and signaling that are aberrant in TSC are also frequently involved in human cancer. My bias is that certain biologic therapies being developed for cancer patients will be efficacious for TSC patients. Biologic therapies currently under development and/or testing for cancer patients include angiogenesis inhibitors, farnesylation inhibitors, specific tyrosine kinase inhibitors, and inhibitors of the Rho pathway.

As a medical oncologist, I am fortunate to be a Member of Fox Chase Cancer Center. Fox Chase is an NCI-designated Comprehensive Cancer Center with an active pharmacology department and an ongoing interest in Phase I clinical trials. The Rothberg funds will provide us with flexibility to develop in vitro models and test specific compounds in our models; this type of work is often quite difficult to fund through other mechanisms such as NIH RO1's. These models can also be applied to high throughput screening of libraries of potential therapeutic agents.

The personal satisfaction I derive from TSC research stems in part from my strong desire to identify new therapeutic strategies for TSC and LAM patients. This "translation" of laboratory research into clinical initiatives drives many of the projects in the laboratory. Developments in the last three years in the TSC field, including the identification of Rho activation by TSC1, suggest that targeted therapeutics for TSC can be a reality within the next five years. Developing these therapies demands that we understand the normal cellular functions of tuberin and hamartin, and that in vitro and in vivo systems be developed for the testing of potential therapies.

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