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Study of novel metastasis inhibitors in lung cancer

Institution: University of California, San Diego
Investigator(s): Mark Fuster, M.D.
Award Cycle: 1999 (Cycle 8) Grant #: 8FT-0118 Award: $69,208
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Lung cancer is a particularly aggressive form of cancer: It is the leading cause of cancer death in the United States, and the majority of patients present with advanced disease for which surgery is not an option. Metastasis, the process whereby tumor cells spread to distant organs via the bloodstream, contributes a large part of the morbidity and mortality of lung cancer. Metastasis is also associated with the vast majority of lung cancer treatment allures, and drugs aimed at inhibiting this process have great potential in both halting disease progression and modifying response to current therapy.

This project targets important steps in lung cancer metastasis. There are certain adhesion molecules (those that contain sugar, a.k.a. "glycosides") which assist metastatic cells in binding to blood vessels of distant organs, once they are free from the primary tumor. A class of adhesion molecules which may serve a vital role in this process is known as selectins. Their presence on the inner lining of blood vessels throughout the body may facilitate lung tumor cells (bearing the corresponding "ligand" molecules, much like a "lock and key") in attaching to blood vessels in the brain, liver, bones, or to other parts of the lungs – common organs to which lung cancer spreads. Research has also shown that platelets, which are normal clotting elements of blood, may facilitate this process by using the same molecules to mediate platelet-tumor cell adhesion. In distant blood vessels, such tumor cell-bound platelets may assist in tumor cell attachment and eventual uptake.

The proposed research is aimed at the above tumor ligand molecules, and specifically at disrupting their sugar-molecule structure by treating tumor cells with a new class of drugs that impair the cell's sugar-making machinery. Tumor cells treated with such compounds lack the ability to bind platelets or blood vessel inner-lining cells; and thus these inhibitors have potential as anti-metastatic drugs. To date, no studies have examined lung cancer cells treated with such agents. We are initially examining if these agents affect the ability of lung tumor cells to bind donated human platelets and to cultured blood vessel-lining cells. Subsequent animal studies will include simulated metastasis models under humane treatment conditions; and as pharmacology develops, techniques to examine tumor growth /metastasis in inhibitor-treated mice are planned. Ultimately, such agents have potential as anti-metastatic agents in human lung cancer.

Final Report
The goal of this TRDRP-funded research project has been to develop novel, potent inhibitors of lung cancer metastasis – the process by which lung tumor cells (TCs) ultimately defeat the cancer victim by spreading to other parts of the body. We have developed a class of modified carbohydrate-based compounds which appear to have a significant role in modifying specific adhesion molecules on the cancer cell’s surface, and this in turn appears to inhibit the binding of treated cultured human cancer cell lines to their natural adhesion “receptor” target molecules (selectins). We have extended these observations to mouse metastasis models, and thus validate such agents as potential anti-metastasis agents for use in human cancer. Our specific research goals remain unchanged: (1) Examine the effect of the candidate inhibitors on specific TC adhesion molecules expressed on the cell surface, including assessment of effects on binding to immobilized selectin receptors, cultured human endothelial cells, and human platelets – which normally express such “selectins” when stimulated. (2) Study the efficacy of such compounds on inhibiting artificial metastasis patterns in humane mouse TC injection studies. (3) Determine if a therapeutic effect exists in models of spontaneous mouse carcinoma/ metastasis, with special focus on any inhibition of tumor angiogenesis – the process necessary for metastatic cells to gain a blood supply and survive. The third aim is still in progress.

The novel carbohydrate inhibitors appear to potently reduce the TC’s ability to adhere to immobilized selectins. Initial studies on TCs from human lung, colon, lymphoma, and breast cancers showed approximately 10 – 20 fold increased potency over an historical monosaccharide carbohydrate inhibitor. Our studies on binding to human platelets have revealed a variable effect of inhibitors on platelet binding to TCs in culture. However, particularly strong inhibition was noted in two of three cell lines examined. Furthermore, we have demonstrated reduced TC adhesion to immobilized endothelial cells following treatment of TCs with these inhibitors. The latter demonstrates the ability of the inhibitors to alter the TC’s ability to latch onto the inner-lining cells of blood vessels – a step which may be crucial for TCs to leave the bloodstream and establish metastases. We have now completed the mouse tail-vein injection studies, using a colon TC line for short-term metastasis studies as well as both colon- and lung- tumor cell lines in long-term tumor metastasis/ growth studies. In comparison with control TCs, a significant reduction in TC metastasis (measured at 4 weeks post-injection) was noted following injection of inhibitor-treated TCs into the tail-veins of laboratory mice. This was noted using both a colon-tumor cell line as well as a lung-tumor cell line. Current studies are focused on introducing the inhibitors into the bloodstream of mice to allow for continuous dosing during tumor growth in more “typical” models of tumor growth and metastasis. These pharmacology experiments are planned over the next several months; and ultimately, we wish to examine tumor growth/ metastasis in murine spontaneous-tumor models under pharmacologic dosing of inhibitors. Such studies will further validate the possible application of such compounds as anti-metastasis drugs for treating lung cancer.

We ultimately plan to extend these or related compounds toward use in human lung cancer trials. Provided a strong anti-metastasis effect continues to emerge in the remaining experiments, such inhibitors may eventually have a significant impact on this high-mortality tobacco-related disease.