Researchers have identified a new protein suspected to be involved in prostate cancer metastasis. Their data suggest that the anticancer drug ponatinib, an existing FDA-approved protein inhibitor, reduced prostate cancer growth in mouse models. While there's a lot more research needed before the work can be translated into helping improve outcomes for patients with metastatic prostate cancer, the researchers say the data so far is encouraging.
"Our findings suggest that pharmacological inhibition of RIPK2 is a very promising approach to preventing or delaying prostate cancer metastasis," said study author Wei Yang, PhD, Associate Professor of Surgery and Biomedical Sciences at Cedars-Sinai Cancer. "Targeting RIPK2 will delay the painful symptoms of metastatic prostate cancer and may increase patient survival by years rather than months." The data were published online in Nature Communications (2022; doi.org/10.1038/s41467-022-28340-6). In an interview with Oncology Times, Yang shared more about his work.
1 What are the key findings from this research and what do they add to what was previously known about prostate cancer metastasis?
"The key findings are that receptor-interacting protein kinase 2 (RIPK2) is a novel drug target in prostate cancer metastasis; RIPK2 functions by activating a previously unknown signaling pathway (RIPK2/MKK7/c-Myc phosphorylation cascade) in prostate cancer cells; and RIPK2 inhibition by the FDA-approved ponatinib reduces prostate cancer metastasis in mice by 92 percent. These findings reveal a previously unknown drug target and molecular mechanism in prostate cancer metastasis.
"Despite advances in prostate cancer treatment, distant metastasis remains a major cause of morbidity and mortality from the disease. Most patients diagnosed with metastatic prostate cancer die within 2-3 years. As the proverb goes: 'An ounce of prevention is worth a pound of cure.'
"Thus, an urgent unmet clinical need is to identify new drug targets whose pharmacological inhibition can prevent the formation of radiographically visible metastases. In this study, we discovered RIPK2 as one such drug target. Although RIPK2 has been well-characterized in inflammatory disorders, little is known about its functions and mechanisms in prostate cancer metastasis."
2 How did you land on RIPK2 as a potential target?
"The first question is: Which druggable proteins are involved in prostate cancer progression and metastasis? To answer this question, we analyzed three publicly accessible clinical omics databases to identify potential drug targets in prostate cancer metastasis. Among the seven candidates, RIPK2 has the greatest change in expression levels as prostate cancer progresses. Therefore, we decided to focus on studying the roles and mechanisms of RIPK2 in prostate cancer metastasis.
"Next, is RIPK2 alteration associated with prostate cancer progression and poor prognosis? Indeed, we found that RIPK2 alteration occurs more frequently along with prostate cancer progression and that high RIPK2 expression levels are associated with poor patient survival. Notably, RIPK2 is overexpressed in about half of lethal prostate cancer tumors, suggesting that targeting RIPK2 may benefit a large population of patients with advanced prostate cancer.
"Is RIPK2 required for prostate cancer metastasis? Through in vitro cell assays, we showed that RIPK2 is required for cell invasion and colony formation-two key biological processes in cancer metastasis. Through in vivo studies, we found that RIPK2 is primarily required for prostate cancer metastasis rather than tumor growth.
"How does RIPK2 function in prostate cancer metastasis? Using multidisciplinary techniques, including multi-level proteomics, we discovered that RIPK2 functions primarily by activating MKK7/c-Myc signaling, a novel pathway distinct from the canonical RIPK2/NF- [kappa] B signaling pathway.
"Is it possible to drug the RIPK2/MKK7/c-Myc signaling pathway? Indeed, we found that the signaling pathway can be inhibited by two different RIPK2 inhibitors-ponatinib and GSK583, with the former being more potent than the latter. Importantly, our mouse studies showed that ponatinib can reduce prostate cancer metastasis by up to 92 percent with few side effects."
3 What's the next step of your work and the bottom-line message practicing oncologists should know?
"The next step is to identify molecular biomarkers for selecting right patients for anti-RIPK2 treatment and monitoring drug response. We will also develop small-molecule inhibitors that specifically inhibit the RIPK2/MKK7/c-Myc signaling pathway, minimizing side effects caused by inhibition of other RIPK2 pathways (such as the canonical RIPK2/NF-[kappa]B pathway). Our ultimate goal is to translate the findings into clinical trials to substantially improve cancer patients' survival and quality of life.
"The bottom line is that targeting RIPK2, specifically RIPK2/MKK7/c-Myc signaling, is a very promising approach for preventing prostate cancer metastasis and increasing patient survival by years."