By IU Simon Comprehensive Cancer Center
January 10, 2025
New prostate cancer research aims to ‘starve the tumor’
IU Simon Comprehensive Cancer Center researchers have published new findings on prostate cancer in the journal Science Signaling. Led by Kirk Staschke, PhD, and Ronald C. Wek, PhD, the research could lead to new ways to treat prostate cancer.
Staschke, assistant research professor of biochemistry and molecular biology at the IU School of Medicine and an associate member of the Experimental and Developmental Therapeutics research program at the cancer center, answers questions about the paper, “Coordination between the eIF2 kinase GCN2 and p53 signaling supports purine metabolism and the progression of prostate cancer.”
Q. How would you explain the key findings of this research?
Staschke: Our new research suggests a promising new way to treat prostate cancer – that is, starve the tumor of critical nutrients called amino acids to trigger changes in tumor metabolism. Like other tumors, prostate cancers need a lot of nutrients to support their growth. As nutrients become depleted, a protein called GCN2 is called into action to bring additional nutrients into the cancer cells and make additional fuel. Amino acids are also critical building blocks for tumor metabolites, including purine nucleotides, which are required in abundance for tumor cells to grow. When we blocked the function of GCN2 in prostate cancer tumors, this triggered a depletion in purine nucleotides.
Our original hypothesis that blocking GCN2 function would be an effective strategy against prostate cancer was only partially correct. While inhibiting GCN2 did slow the growth of prostate tumor cells, it did not kill them. Prostate tumors have a backup strategy. Our current study also revealed that a protein called p53 is the cancer's backup plan. The p53 transcription factor is frequently altered or deleted in cancer cells but is retained in early-stage prostate cancer. In more advanced metastatic forms of prostate cancer, p53 function is more commonly lost, which makes treating these more advanced cancers challenging. Our new research revealed that depletion of purine nucleotides following inhibition of GCN2 is not tolerated in p53 mutant tumors, indicating that targeting GCN2 and the ISR may be a way of taking advantage of p53 mutations to kill prostate tumors.
Q. How does this research build on previous prostate cancer work at the cancer center?
Prostate cancer is a leading cause of cancer death in men in Indiana and the United States.
Current treatments work by reducing the levels or activity of the hormone testosterone, which prostate cancer cells need to grow. Unfortunately, prostate tumors often become resistant to these treatments, leaving doctors with few options for treatment. Thus, we need new targeted agents that act differently than hormone therapy.
Our previous work showed that GCN2 is required to maintain the levels of amino acids in prostate cancer cells that are needed to fuel tumor metabolism and growth (Cordova et al. 2022 eLIFE 11:e81083). This current work builds on these findings to show that reduced amino acids in prostate tumors trigger a deficiency in purine nucleotides that are only survivable when p53 is expressed.
Q. What is the significance of these findings for your ongoing prostate cancer research?
We would like to understand in greater detail how the loss of GCN2 alters the metabolism of prostate cancer cells. Also, given that altering the activity of GCN2 affects the ability of prostate tumor cells to acquire critical nutrients for growth, our findings open the possibility of altering a patient’s diet to elicit similar effects. Dietary intervention is an emerging topic in the field of cancer therapy. For example, intermittent fasting is suggested to slow the progression of some prostate cancers and may aid some therapies. Our studies help to provide a mechanistic understanding of these strategies and provide new ideas for effective combination therapies in intractable prostate cancers.
Q. What are the possible implications of this research? Are there clinical applications that could be applied in the next few years?
Compounds that target GCN2 are beginning to enter clinical trials. There is a need to develop better, more potent, and selective inhibitors, which is a focus of our lab. In addition, a clear understanding of the vulnerabilities in GCN2-targeted tumors may allow the repurposing of existing drugs to develop a GCN2-centered combination therapy for prostate cancer.
Q. This article was featured on the cover of Science Signaling. Can you describe the image and what it depicts from the research?
Our current work focuses on the role of GCN2 and the ISR in prostate cancer. The cover depicts a colored scanning electron micrograph of prostate cancer cells. Our research article and cover help to foster awareness of the importance of pursuing new ideas for prostate cancer therapies, especially those targeting later onset metastatic cancers.
Q. Additional authors on this paper include cancer center colleagues, trainees and investigators from other institutions. Can you share more about your collaborative effort?
This research was a team effort that included graduate students Ricardo Cordova and Noah Sommers and investigators with complementary expertise that included Dr. Jeffrey Brault (IU School of Medicine), Dr. Roberto Pili (formerly of IU and now at University at Buffalo), Dr. David Goodrich (Roswell Park Cancer Center), and Dr. Tracy Anthony (Rutgers University).
Q. Are there any specific grants or funders you’d like to acknowledge?
The research was supported by the National Institutes of Health, the Showalter Trust, the Prostate Cancer Foundation, the American Cancer Society, and the IU Simon Comprehensive Cancer Center. This support is essential for our research, and we emphasize that foundational research funded through the National Institute of General Medical Sciences (NIGMS) lays the groundwork for many medical discoveries in the United States.
Q. Anything else you’d like to add?
We are hopeful that with these new results, we can begin to think about new therapeutic strategies for targeting advanced prostate tumors that lack p53 function. There is also emerging research from other laboratories that supports the idea that starving cancer cells and targeting GCN2 may be an effective treatment in other cancer types as well.
