Projects

The Goals of this project are to identify proteins differentially expressed in oral cavity squamous cell carcinoma:

1. from subjects with different stages including normal (healthy), squamous mucosa dysplasia and invasive carcinoma
2. from the above subjects who are either smokers or non-smokers.

Accomplishing these goals will:

1. help identify those proteins that may be important for disease progression
2. contribute to identifying proteins associated with (and thus may underlie mechanisms of) the effect of smoking in these subjects.

This research project has been selected by the Board of Directors for the Thomas J. Dobleman Head & Neck Cancer Institute for funding and support. This specific project will be conducted by a superbly qualified and internationally recognized team at the Boys Town National Research Hospital.

Development and preliminary testing of Multistatin: a novel therapeutic agent for the treatment of solid tumors in the head and neck.

Sudhakar Akulapalli, Ph.D., Principal Investigator
Dominic Cosgrove, Ph.D., Co-Investigator

For solid tumors to grow beyond 2mm in size, they must form and maintain a blood supply. It has therefore long been recognized that drugs targeting the formation of new blood vessels (a process referred to as "angiogenesis") may provide new and useful tool for the treatment of patients with solid tumors. World renowned scientist. Dr. Judah Folkman of Harvard Medical School, pioneered the discovery of one such agent, angiostatin. Angiostatin is a fragment of collagen XVIII, a component of matrix material that forms outside of cells, and is an important building block of tissues in the body.

This matrix material is constantly being assembled and broken down in as part of the normal cycle of self renewal in tissues. The fragments of matrix resulting from the breakdown process, including angiostatin, are normally found in the blood. Thus, our body is producing agents all the time; however the normal circulating levels are insufficient to inhibit new blood vessel formation in tumors. Dr. Folkman found out many years ago that administration of high doses of angiostatin is effective in reducing tumor growth in animal models.

Since the discovery of angiostatin, a number of new matrix fragments have been identified that have similar or better ability to block the formation of new blood vessels in tumor bearing animal models. Research aimed at how these proteins work was pioneered by Dr. Akulapalli (the principal investigator for this proposal) and published in a series of highly cited peer reviewed papers in some of the worlds most prestigious journals. The most recent paper, which represented research conducted entirely at BTNRH, and appeared in the September 8th 2005 online publication in the Journal of Clinical Investigation, showed for the first time exactly how these molecules block new blood vessel formation in tumors. Surprisingly, there are at least four different protein fragments that each work in distinct ways. These findings provide the rationale for this proposal to the Dobleman Institute.

The concept is quite simple for this exploratory project. The four known proteins will be used to engineer a fused protein that contains all four fragments with spacers in between them to allow the proteins to have access to cell surfaces. The new fusion protein will be manufactured using standard laboratory methods, and tested alongside the individual protein components for the ability to reduce the growth of solid tumors in mice. Squamous carcinoma cells isolated from head and neck tumors will be utilized. These are well characterized standard cell lines that can be purchased from commercial sources. If successful, these studies will form the basis for a much broader R01 grant proposal (average award $2M) that will be submitted to the National Cancer Institute.

These studies have a real potential for development of a novel treatment for head and neck cancers. It should be noted that this method of treatment would not likely have side effects, since these proteins are normally found in the body. Such a treatment option would be far superior to surgery, radiation, and chemotherapy which have quite severe side effects. We thank the Board of Directors and respected contributors for the Dobleman Institute for providing funds for this important feasibility study.

We thank the Boad of Directors and respected contributors to the Dobleman Institute for funding this important feasibility study.