11.27.23Prostate cells HE GCN2 stainV680%.jpg

Prostate Cancer and the Stress Response

Prostate Cancer, GCN2 and the Integrated Stress Response

Prostate cancer occurs in about 1 in 8 men and is the second leading cause of cancer death among men. Current therapies target androgen receptor activity: however, eventual resistance to these therapies indicates the need for new therapeutic interventions in the treatment of prostate cancer.

The focus of our research is to understand the role of the Integrated Stress Response (ISR) and GCN2 protein kinase in prostate cancer with an eye toward developing effective prostate cancer therapy.

The Integrated Stress Response (ISR) plays a critical role in cell adaptation and survival and has been suggested to be involved in cancer cell growth and survival.

Model GCN2 reg AA prostate cancer_edited

Model for GCN2 regulation of amino acid homeostasis in prostate cancer

We discovered that the eIF2 kinase GCN2, which is critical for cell maintenance of amino acids, is required for sustained growth of many different models of prostate cancer as well as in patient samples.

Genetic or pharmalogical depletion of GCN2 disrupts the uptake and synthesis of amino acids and other metabolites, blocking proliferation of prostate cancer. By targeting GCN2, prostate cancers are starving for nutrients required for growth, and combination therapies featuring GCN2 inhibition are a promising new strategy for resolving androgen-sensitive and castration-resistant prostating cancers.

This research is being carried out in collaboration with Dr. Kirk Staschke (Indiana University School of Medicine) and Dr. Roberto Pili (University of Buffalo, Department of Medicine).

eLife Fig 7A-D GCN2iB tumor reduction.jpg

Pharmacological inhibition of GCN2 reduces tumor growth in cell line-derived and patient-derived xenograph models

Reference:

Cordova RA, Misra J, Amin PH, Klunk AJ, Damayanti NP, Carlson KR, Elmendorf AJ, Kim HG, Mirek ET, Elzey BD, Miller MJ, Dong XC, Cheng L, Anthony TG, Pili R, Wek RC, Staschke KA (2023)

GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis Elife 15;11:e81083