Prostate cancer is diagnosed in about 200,000 men and castrate resistant prostate cancer (CRPC) accounts for about 30,000 deaths annually in the USA. Now, scientists have identified a key gene - eIF4G1 - that shows grade and stage specific upregulation in prostate cancer and is overexpressed and/or amplified in the majority of cases of CRPC. The study revealed that silencing eIF4G1 or disrupting eIF4G1 function using a chemical inhibitor sensitized CRPC to current therapies.
Almost all the deaths from prostate cancer are a result of emergence of CRPC. Now, scientists from the Department of Biochemistry and Molecular Biology and the Feist-Weiller Cancer Center at LSU Health Shreveport have identified a key gene - eIF4G1- that is overexpressed in the majority of cases of CRPC, allowing these cancer cells to rapidly respond to androgen deprivation therapies. The new findings, “Eukaryotic Translation Initiation Factor 4 Gamma 1 (eIF4G1) is upregulated during prostate cancer progression and modulates cell growth and metastasis” (SREP-18-09172) were published online in Scientific Reports in May 2018, and could lead to the identification of new approaches, therapies and a new class of drugs to target and treat CRPC. This would be a critical development in the fight against CRPC, which does not respond to any other current treatments, according to the study’s lead authors Dr. Hari K. Koul, Associate Director for Basic and Translational Research at the Feist Weiller Cancer Center, Director of Hormone Related Malignancies research program, and the Carroll W. Feist Endowed Chair in Cancer and Professor in the Department of Biochemistry and Molecular Biology.
“Conventional therapies produce a high rate of cure for patients with localized prostate cancer, but there is no cure once the disease has spread beyond the prostate primarily due to emergence of CRPC,” says Dr. Koul, noting that resistance to androgen receptor targeted therapies accounts for almost all of the prostate cancer deaths.
Dr. Koul opines that, “There has been little progress in developing curative therapies for CRPC despite discovery of the second generation AR targeted therapies over the past two decades, and there are no curative drugs specifically for this form of cancer.”
Dr. Koul and his colleagues found that the gene eIF4G1 is amplified and overexpressed in a majority of CRPC patients that allows prostate cancer cells to overcome current treatments. They also found that the silencing of this gene (using SiRNA technology) and or inhibition of function of the eIF4G1 protein made by this gene sensitized CRPC cells to antiandrogens, as well as second generation AR targeted therapies, in experimental settings. “This is quite exciting that eIF4G1 would serve as an excellent target for combination therapy with current first and/or second generation AR targeted therapies,” says Dr. Koul.
Dr. Koul cautions that additional work is required for translating these laboratory findings into therapies and we plan to further explore this pathway, develop small molecular inhibitors that target eIF4G1 and conduct preclinical tests.
The members of Dr. Koul’s research team that participated in this study includes Dr. Praveen Jaiswal, Sweaty Koul, and Prakash ST Shanmugam.