Saturday, May 18, 2024
5/18/2024
DESCRIPTION (provided by applicant): Prostate cancer is a prevalent disease among men in the United Sates. Current therapies are limited, and there is no successful treatment once tumor cells have spread to other tissues. Discovery of successful therapies is still a truly important challenge. However, identification of new targets for cancer therapy requires a thorough understanding of the molecular processes that lead to cell transformation. Recent studies have shown that transcription factor Egr-1 (Early Growth Response-l) is present at much higher levels in human prostate tumors as opposed to normal cells. An important result from J. Milbrandt's laboratory was that lack of Egr-1 expression significantly delayed the progression of prostate carcinoma in mouse models. However, there has been no study to directly assess the role of Egr-1 in tumor initiation or to measure the effect of specifically blocking Egr-1 expression in prostate cancer cells. These issues are critical and need to be tested before designing Egr-based therapies. Our approach is based on the rationale that blocking Egr-1 expression in prostate cancer cells will inhibit cell proliferation and eventually stop tumor growth. We describe the design and obtaining of specific antisense oligonucleotides that block Egr-1 function. Preliminary results show that inhibition of Egr-1 expression in prostate cancer cell lines actually hampered cell proliferation and inhibited the capacity of these cells to form colonies in culture dishes and in soft agar, two hallmarks of transformed cells. Conversely, we observed that ectopic expression of Egr-1 in 267B prostate cells induced transformation. These data point to Egr-1 as a potential participant in prostate cancer progression and therefore, as a potential molecular target for prostate cancer therapy. The objectives of the present proposal are to: validate Egr-1 as a target for prostate cancer therapy in human systems and test the efficacy of the antisense oligonucleotide in animal models for prostate cancer (Specific Aim 1); identify Egr-1 functions in prostate cells and investigate the molecular mechanisms that contribute to Egr-1 oncogenic properties (Specific Aim 2). Demonstration that Egr-1 acts as an oncogene in prostate cancer challenges an existing paradigm given that this transcription factor is most often believed to have tumor suppressor effects in other cell types. The proposed study should lead to a novel understanding of the molecular mechanisms underlying prostate cancer progression, validate a target for prostate cancer treatment and design a novel therapeutic approach.
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