National Prostate Cancer Awareness Month
Dr Reddy reported novel targeted therapeutic agents against ERG-Positive Prostate Cancers at DOD conference IMPACT 2011 (March 2011).
Abstract presented at DOD Grant Funded investigator's conference IMPACT 2011 (March 10th 2011)
PC074077-2060
RED 037F8 AND RED 046H6 ARE POTENT ANTICANCEROUS AGENTS AGAINST PROSTATE CANCERS
E. Shyam P Reddy1, Shubhalaxmi Kayarthodi,1 Yasuo Fujimura,1 Huali Xu,1 Chunshu Yang,1 Jinbo Fang,1Wendell Fortson,1 Roland Matthews,1 Viplove Senadhi,2 Ganapathy Bhat,1 William E. Grizzle,3 Edward Partridge,4 and Veena N. Rao1
1Morehouse School of Medicine, Atlanta, 2Johns Hopkins University School of Medicine, 3University of Alabama at Birmingham, and 4University of Alabama at Birmingham Comprehensive Cancer Center
Background and Objectives: Previously, we have identified several ETS oncogenes that play a major role in human cancers. The most notable genes discovered include ERG-1 and ERG-2 genes. We have named the gene as ERG (ETS Related Gene). This gene is involved in Ewing sarcoma and also leukemias (acute myeloid leukemia). Recently, it was shown that ERG gene is also involved in a majority of human prostate cancers, resulting in the overexpression of ERG in prostate cancer cells. We have shown that ERG gene codes for sequence specific transcriptional activator. We have previously demonstrated that ERG and aberrant ERG proteins inhibit apoptosis, and this may be one of the reasons for the activation of the ERG gene in leukemias and human solid tumors. Loss or reduction of nuclear receptor activity was shown to lead to prostate tumorigenesis in humans. We have found that both ERG and its highly related protein, Fli-1, inhibit nuclear receptor activity, which pays a major role in apoptosis of cells. These results suggest that the transcriptional inhibitory properties of ERG may play a role in the anti-apoptotic function of ERG in prostate cancer cells. We hypothesized that small molecule-based agents that reverse the inhibitory properties of ERG proteins can be used as a targeted therapeutic agents to prostate cancer. We have screened a library of random compounds using a cell-based assay that measures the inhibitory activity of ERG proteins. Using this assay, we have identified two potent novel therapeutic agents (RED 037F8 and RED 046H6) that reverse the ERG inhibition of nuclear receptor activity (patent pending). We also hypothesized that these therapeutic agents may function as targeted agents that kill prostate cancer cells but not normal cells.
Brief Description of Methodologies: (1) A cell-based assay that measures the inhibitory activity of ERG proteins. (2) In vivo assays to study the regulation of nuclear receptors.
Results to Date: (1) RED 037F8 and RED 046H6 inhibit strongly the growth of prostate cancer cells carrying TMPRSS2-erg translocation. (2) RED 037F8 and RED 046H6 induce significantly apoptosis in prostate cancer cells. (3) These therapeutic agents appear to have no major effect on the growth of normal cells. (4) Experiments are in progress to test their effect on prostate cancer cells in mice (xenograft models) (preclinical trials).
Conclusions: Previously, we identified a novel ETS family member and named it ERG and showed that it functions as a sequence specific transcriptional activator. ERG gene is shown to be overexpressed and also involved in a majority of prostate cancers. We identified two novel therapeutic agents (RED 037F8 and RED 046H6) that reverse the ERG inhibition of nuclear receptor activity (patent pending). RED 037F8 and RED 046H6 inhibit strongly the growth of ERG-positive prostate cancer cells by inducing apoptosis (cell death program). Preclinical trials are in progress.
Impact Statement Describing the Potential Impact on Research, Patient Care, or Quality of Life: Using a cell-based assay, we have identified two novel prototype therapeutic agents that reverse ERG regulatory functions. These agents may serve as anti-cancerous drugs against prostate cancer cells. They may also serve as targeted therapeutic agents because of their lack of significant harmful effects on normal cells. Study of the mechanism of action of these agents may lead to development of an improved cell-based assay, which in turn could lead to the discovery of better therapeutic agents.
This work was supported by the U.S. Army Medical Research and Materiel Command under W81XWH-08-1-0628 and the Georgia Cancer Coalition Distinguished Cancer Scholar award, U54/56 Morehouse School of Medicine/University of Alabama at Birmingham/Tuskegee University Partnership Grant, and the Research Centers in Minority Institutions.
http://www.gofundme.com/6x6kn4
PC081329-2311
IDENTIFICATION OF NOVEL THERAPEUTIC AGENT THAT TARGET ERG-POSITIVE PROSTATE CANCER CELLS
E. Shyam Reddy, Shubhalaxmi Kayarthodi,1 Huali Xu,1 Yasuo Fujimura,1 Chunshu Yang,1 Jinbo Fang,1 Ganapathy Bhat,1William E. Grizzle,2 and Veena N. Rao1
1Morehouse School of Medicine, Atlanta and 2University of Alabama at Birmingham
Background and Objectives: We have discovered an important member of the ETS family and named this gene as ERG (Ets Related Gene), which has been shown to be involved in many human cancers (Ewing sarcoma and leukemias). Recently, the ERG gene was found to be involved in a majority of human prostate cancers, resulting in the overexpression of ERG in prostate cancer cells. We have shown that ERG protein functions as a sequence specific transcriptional activator.We have previously demonstrated that ERG and aberrant ERG (EWS-ERG and TLS-ERG) proteins inhibit apoptosis, and this may be one of the reasons for the activation of the ERG gene in leukemias and human solid tumors. Loss or reduction of nuclear receptor activity may be one of the critical factors that lead to prostate tumorigenesis in humans. Recently, we have observed that ERG and its related Fli-1 proteins inhibit nuclear receptor activity, which plays a major role in apoptosis of cells. These results suggest that these transcriptional inhibitory properties of ERG may play a role in the anti-apoptotic properties of ERG in prostate cancer cells. If inhibition of nuclear receptor activity by ERG plays an important role in prostate cancer tumorigenesis, we thought this assay could be used to search for small molecular weight compounds that can relieve the ERG inhibition of nuclear receptor activity and these candidate compounds may have the potential to function as anti-cancerous agents on prostate cancer. Based on this hypothesis, we have screened a library of compounds for their ability to relieve ERG inhibition of nuclear receptor activity and obtained one compound (RED027B11) that showed relatively high activity in relieving the ERG inhibition (to be patented). We hypothesized that this agent may target prostate cancer cells but not normal cells.
Brief Description of Methodologies: (1) Development of cell-based assay for ERG function. (2) In vivo assays to study the regulation of nuclear receptors.
Results to Date: (1) RED027B11 inhibits the viability of prostate cancer cells carrying TMPRSS2-ERG translocation. (2) RED027B11 has no major effect on the growth of normal cells. (3) RED027B11 induces apoptosis (cell death program) in prostate cancer cells. (4) Experiments are in progress to test whether RED027B11 show in vivo efficacy in mice xenograft models (preclinical trials).
Conclusions: Previously, we discovered ERG gene and have shown that it functions as a sequence specific transcriptional activator. This ERG gene is shown to be involved in the majority of prostate cancers. Now we have identified a novel therapeutic agent, RED027B11, that targets ERG function and inhibits growth of prostate cancer cells by inducing cell death program. Preclinical trials are in progress.
Impact Statement Describing the Potential Impact on Research, Patient Care, or Quality of Life: We have identified a potential prototype drug/agent that not only relieves ERG inhibition but also functions as anticancerous agent against prostate cancer cells. Since this small molecule has no major effect on normal cells, this agent can be used as a safe, targeted therapeutic agent. Understanding the mechanism of action of this prototype therapeutic agent may lead to the development of an improved assay, which in turn could lead to identification of better therapeutic agents.
This work was supported by the U.S. Army Medical Research and Materiel Command under W81XWH-09-1-0236 and the Georgia Cancer Coalition Distinguished Cancer Scholar award, U54/56 Morehouse School of Medicine/University of Alabama at Birmingham/Tuskegee University Partnership Grant, and the Research Centers in Minority Institutions.
http://www.gofundme.com/6x6kn4
LINK: Anti-epilepsy drug Valproic acid targets ERG-positive Prostate cancers
Facts about prostate cancer*:
• Prostate cancer is the most common non-skin cancer and the second leading cause of cancer death in men in the United States.
• One in six men in the U.S. will receive the diagnosis in his lifetime.
• The median age of death from prostate cancer from 2000 through 2004 was 80 years, and 71 percent of deaths occurred in men older than 75 years.
• Prostate cancer is a clinically heterogeneous disease. A substantial proportion of prostate cancer cases detected with current screening methods will never cause symptoms during the patients’ lifetime.
• For the first time, cancer rates and cancer deaths both dropped in the U.S., according to the American Cancer Society’s 2008 Annual Report. Declines in the three most common cancers in men: lung cancer, colon cancer, and prostate cancer.
• Although age is a risk factor for prostate cancer, the disease is more dangerous in men in their 50s and early 60s than in older men. Th is is why it is so important for men to begin screening before the age of 60. Prostate cancer in older men is often a slower growing and less dangerous variety.
• A family history of prostate cancer on either the father’s or mother’s side increases the risk of developing the disease.
• African-American men have twice the risk of developing prostate cancer as Caucasian men. The disease is most common in North America and northern Europe.
• Prostate cancer is more common in regions with lower exposure to sunlight, such as Michigan, and in regions where diets are high in fat.
*Sources: The American Cancer Society 2008 Annual Report; U.S. Preventive Services Task Force (USPSTF) recommendation statement, August 2008; University of Michigan Comprehensive Cancer Center.
LINK: Anti-epilepsy drug Valproic acid targets ERG-positive Prostate cancers
http://www.gofundme.com/6x6kn4