Preventing Metastasis: New Approach at NCI

AMSTERDAM--Innovative strategies for thwarting metastasis arenow at the brink of clinical application, Lance Liotta, MD, ofthe National Cancer Institute, reported at the 9th NCI-EORTC Symposiumon New Drugs in Cancer Therapy.

"Proteins that regulate invasion and metastasis and the processof invasion provide new cellular targets for prevention and newmolecular targets for intervention," Dr. Liotta said.

The thinking behind the new approach is that current anticancertherapy often fails because it begins too late, after metastasishas already occurred. Instead, Dr. Liotta argued, the ideal momentto act would be during the window of opportunity between the timethat the cells become hyperplastic and the time that they acquirethe ability to invade and metastasize.

Analyzing Precursor Lesions

NCI pathologists Drs. Buck and Zhuang have developed a new lasercapture technique for microdissecting and genetically analyzingprecursor lesions, which enables them to determine which cellsare most likely to become invasive.

Applying this method, they found that the same genetic locus wasmissing in 90% of invasive prostate carcinoma samples and in 70%of precursor PIN (prostatic intraepithelial neoplasia) lesionsfrom the same patients. "This implicates a new suppressorgene to be identified at 8p21," he said.

The NCI team has also used the new microdissection technique togetherwith X-chromosome inactivation analysis to prove that carcinomain situ of the breast does develop into invasive carcinoma.

They identified a crucial genetic locus at 11q13 that, when absentin invasive carcinoma, was also always missing in carcinoma insitu in the same patient. "We've narrowed this locus downto three to 10 genes on chromosome 11, and we are now sequencingthese genes to see which might be a predictor of carcinoma insitu of the breast," Dr. Liotta said.

Regulators of Cell Motility

In addition to investigating the genetic determinants of tumorcell proliferation, the NCI group is exploring the processes throughwhich tumor cells move forward and penetrate the extracellularmatrix. "The tumor is not going to invade unless it has theability to migrate, and so motility would seem to be a key ingredientnecessary for invasion," he said.

Dr. Liotta and his colleague Dr. Strache have discovered a newprotein called autotaxin that regulates the motility of both tumorcells and endothelial cells. Autotaxin secreted by tumor cellsnot only acts on neighboring cells but also can potentially modifyand open up extracellular matrix proteins, thereby providing apathway for invasion.

"This protein could be a target for inhibitory treatmentsbecause it's an ecto-enzyme, and any inhibitor would not haveto enter the cell," he said.

Dr. Liotta noted that the metallopro-teinases also have been shownto play a critical role in penetrating the extracellular matrixbarrier and fostering tumor invasion and angiogenesis.

"We can make specific inhibitors of these enzymes and showthat they block invasion and retard tumor growth in animal models,"Dr. Liotta said. These new inhibitors have now reached phase Iclinical testing, he added.

Interference with the signal transduction pathways that regulateinvasion and angiogenesis may offer still another approach tocombating invasion, he said.

A new agent called CAI, developed by Dr. E. Kohn, blocks the influxof calcium through the non-voltage-gated channels. CAI has beenshown to inhibit tumor cell growth, invasion, and angiogenesis.The new agent has undergone phase I clinical testing and is nowbeing studied both alone and in combination with paclitaxel (Taxol).

"If we can gain experience using cytostatic anti-invasionagents in advanced cancer, what we would ultimately like to dois to go back to the premalignant lesion, identify patients athigh risk for progression, and treat them with an agent that willblock progression," he said.