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Discovery of serum markers of lung cancer

Institution: Cedars-Sinai Medical Center
Investigator(s): Phillip Koeffler, M.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7IT-0066 Award: $120,300
Subject Area: Cancer
Award Type: Inno Dev & Exp Awards (IDEAS)

Initial Award Abstract
The detection of cancer markers in serum can provide early diagnosis, monitoring of the effectiveness of therapy, and detection of early recurrence. The prostate-specific antigen (PSA) is a prime example of the power of serum tumor markers. The PSA has markedly enhanced our abilities to screen and monitor patients with prostate cancer. The principals concerning PSA can also apply to lung cancers where a critical lack of serum markers decreases the ability of physicians to manage these patients. Our research will provide a novel and rapid method to look for new proteins which can be used as serum markers of lung cancer. These markers will enable early cancer detection or early relapse, and guidance in choosing effective therapy for lung cancer.

Our allows us to screen for genes that produce lung cancer-specific proteins which are secreted out of the cell. Once we have assured ourselves that we have indeed isolated lung cancer-specific, secreted proteins, we will determine if individuals with lung cancer have these proteins circulating in their bloodstream. If indeed they do, we will test a large collection of sera from individuals with early and late lung cancer to determine how specific and sensitive our newly identified proteins are as serum markers of lung cancer. Also, as a by-product of this research, we may find that these newly discovered proteins, in addition to being markers for lung cancer, may have unique functions that teach us fundamentals of lung cancer.

Final Report
We identified a secreted protein known as Cyr61 whose expression in lung cancer was associated with decreased growth of these cancer cells both in vitro and in vivo, in nude mice. We studied how this protein decreased growth and identified a series of proteins that were regulated by Cyr61. These proteins are known to slow the growth of cells. Furthermore, we identified the pathway by which Cyr61 is probably secreted. We then provided data to show that in an autocrine or paracrine fashion, Cyr61 bound to proteins on its surface of the lung cancer cells which stimulated a cascade of events eventually associated with slowing of cell division. This slowing of cell division was dependent on a protein brake known as p53. In cells that had mutant p53, the Cyr61 protein did not inhibit growth, but in those cells that had wild-type p53, growth was inhibited. Therefore, we believe that Cyr61 in lung cancer cells can act as a tumor suppressor gene, but if the p53 becomes mutated, Cyr61 no longer behaves as a tumor suppressor. Taken together, our data suggest that the mechanism by which lung cancer cells can progress towards a more malignant character is either by turning-off of Cyr61 or mutating the p53 gene.

Cyr61, a member of CCN family, is a tumor suppressor in non-small cell lung cancer.
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Tong X, Xie D, O'Kelly J, Miller CW, Muller-Tidow C, and Koeffler HP ART
Yr: 0 Vol: Nbr: Abs: Pg: