Most cancer deaths occur from metastatic tumors rather than from the primary tumor alone. Although many of the new drugs in the past decade are directed against tumors , changes in overall cancer survival have only been modest. Most cures of cancer are still through surgery and early detection, with chemotherapeutic agents simply delaying the inevitable and buying the patient some number of months or years of life of varying quality. Yet, the drug screening \and clinical trial paradigms are aimed at identifying drugs that shrink primary tumors with efficacy against metastatic disease emerging only fortuitously. The overall hypothesis of this project is that a novel drug screening approach using metastatic cancer cells suppressed by a local microenvironment would yield drugs that are preferentially active against dormant micrometastases, leading ultimately to drugs active against metastases. We used a medium throughput screening system and a chemical library to identify three candidate compounds - Bordeaux Red (BDR), Wool Violet 2R (WV) and 3,4,5,6-tetrabromofluorescein (TBF) which have significant anti-proliferative selectivity against suppressed bladder, prostate, breast, glioma and gastric tumor cells grown on a normal suppressive matrix called SISgel as compared to their actively growing counterparts on Matrigel. Further, in a human bladder cancer flank xenograft implant model, we have shown that metronomic dosing of all three candidate agents as monotherapy is capable of decreasing the size of suppressed tumors and that one of these compounds, TBF, is also capable of significantly reducing the growth rate and perhaps the vascularity of an actively growing colon xenograft. In the first specific aim, we seek to determine whether our three candidate compounds are active against two additional tumor xenograft models, MDA-MB-435 metastatic breast and DU145 metastatic prostate cells, injected into the flank of athymic mice either in the suppressive matrix SISgel or on the permissive matrix Matrigel, with primary tumor growth and tumor vascularity assessed. In the second specific aim the effect of our three candidate compounds on the formation lung metastases, primary tumor growth, and tumor vascularity in the orthotopically implanted MDA-MB-435 breast model will be assessed. Together these studies will give proof of principle that our candidate compounds are active against suppressed as compared to activated metastatic tumors in vivo and whether our agents can be used to prevent metastases, which currently often end up leading to patient death. This proof of principle represents an essential element in our business plan by connecting cell culture studies with animal models of human cancer. PUBLIC HEALTH RELEVANCE: Most cancer deaths are not due to the primary tumor but are due to metastatic tumors, many of which lie dormant for years while remaining resistant to chemotherapy. We believe that many of these recurrences are due to cancer cells that have been suppressed by a normal extracellular matrix, the "floor" that cells grow on. Research in our laboratories have developed a novel screening system that identifies drugs that potentially can kill dormant cancer cells. This study is seeking to prove that the killing activity seen in cell culture occurs in animal models of cancer, which will establish proof for our business model.

R43CA135867

2008-09-01

2009-11-30