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About Dr. Krongrad: Publications

Krongrad A: A method of treating hormone-independent cancer. U.S. patent 5,786,362, July 28, 1998

The present invention relates to the discovery that proliferation of cells of late stage hormone dependent cancers which have become hormone-independent can be selectively inhibited or killed by subjecting cell populations containing such cells to inhibitors of protein kinase C (herein referred to as "PKC"). Applicant has observed that cells in which hormone dependence is lost [eg. prostate cancer] grow aggressively and relatively independently of serum. In particular, hormone-independent cancer cells can be selectively killed by specific PKC inhibitors, such as, for example, chelerythrine.

The present invention relates to a method of treating populations of cells with a PKC inhibitor, such that hormone-independent tumor cells in the cell population are selectively growth inhibited or killed. In addition, the present invention relates to the use of PKC inhibitors as a biological marker of hormone-independence in cancerous cell populations. In particular, the PKC inhibitor, chelerythrine is a useful biological marker for androgen-independent cells.

The present invention further relates to the growth inhibition or killing of androgen independent cells wherein the growth-regulated gene c-fos and the serum response element (referred to as "SRE") genetic sequence are deregulated. Direct activation of PKC in androgen dependent cells can mimic the c-fos or SRE deregulation seen in androgen independence and also cause androgen independent expression of an androgen target promoter, probasin. Direct activation of the serum response factor (referred to as "SRF"), the final effector in the PKC signaling cascade, was found to be sufficient to do the same. These discoveries have led, in the present invention, to a new biochemical model of hormone action. Using the predictions made by this model, the present invention has identified a means to selectively growth inhibit or kill hormone-independent cells. In addition, the present experiments have demonstrated the feasibility of utilizing genetic reagents to target components of the signaling pathway so as to allow gene therapeutic approaches to hormone independent cancers. The present invention allows the growth inhibition or killing of tumor cells in a cell population comprising hormone independent cancer cells as to the design of novel therapeutic strategies in hormone independent cancers.