DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Targeting Angiogenesis and Lymphangiogenesis in Tuberous Sclerosis Complex

Principal Investigator: DARLING, THOMAS N
Institution Receiving Award: HENRY M. JACKSON FOUNDATION
Program: TSCRP
Proposal Number: TS080064
Award Number: W81XWH-09-2-0002
Funding Mechanism: Idea Development Award
Partnering Awards:
Award Amount: $683,086.91


PUBLIC ABSTRACT

Patients with tuberous sclerosis complex (TSC) develop tumors in many different organs. TSC skin tumors bleed with minor trauma, and they can be disfiguring. There are no effective oral or topical treatments for TSC skin tumors. Thus, patients must undergo repeated surgical procedures that can leave scarring. The goal of our studies is to improve the treatment of these skin tumors by studying how drugs inhibit their formation.

TSC skin tumors have abundant blood and lymphatic vessels. Little is known about the origin of these vessels in TSC. Angiogenesis, the formation of blood vessels, and lymphangiogenesis, the formation of lymphatic vessels, are important in the growth and spread of cancers. Blood vessels increase the growth of cancers by providing nourishment to the tumor. Both blood vessels and lymphatic vessels are important routes for cancer cells to spread from one location to another in the body. Drugs blocking angiogenesis or lymphangiogenesis can decrease the size and spread of cancers in experimental models, and work in this area has led to new treatments for cancer.

Our studies will determine what stimulates angiogenesis and lymphangiogenesis in TSC tumors and will test whether drugs block the formation of blood and lymphatic vessels in our experimental models of TSC skin tumors. In preliminary studies, we found that cells grown from skin tumors in TSC patients produce more than the usual amounts of proteins that stimulate angiogenesis and lymphangiogenesis. These abnormalities may be due to the loss of a TSC gene. Rapamycin is a drug that is being used experimentally to treat TSC tumors since it inhibits the growth pathway that is stimulated by loss of the TSC gene. We will test whether rapamycin inhibits the overproduction of proteins involved in angiogenesis and lymphangiogenesis. If it does, this may explain how rapamycin decreases the size of the tumors. However, it is possible that rapamycin suppresses some proteins but not others. This may be part of the reason why rapamycin does not completely eradicate the tumors. Therefore, we will also test another drug called tranilast. Tranilast works in a different way than rapamycin, and we will test how effective it is in blocking angiogenesis and lymphangiogenesis.

This research has several potential clinical applications. Information learned about the skin tumors is likely to apply to at least some of the internal tumors in TSC, since they share the same genetic and signaling abnormalities. The studies will give us a better idea of how rapamycin and tranilast inhibit tumor growth in TSC. It will reveal their weak points and will help us decide whether to test rapamycin and tranilast in combination or whether other drugs may be needed for better inhibition of vessels and tumor growth. We may be able to identify proteins that are useful in a blood test to determine whether tumors are growing or responding to treatment. The results from these studies can be readily used to help design clinical trials using these drugs. Clinical trials with improved ways of monitoring tumor responses could begin at the completion of these preclinical studies.