New Therapeutic Target for Clear Cell RCC?

Researchers in North Carolina have reportedly identified a protein called zinc fingers and homeoboxes 2 (ZHX2) as a potential therapeutic target for treating renal cell carcinoma (RCC). In a study published in the journal Science, they report that inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein, a hallmark of clear cell RCC, results in the activation of ZHX2. Furthermore, ZHX2 inhibition impairs tumor growth in vitro and in vivo.

Study investigator William Kim, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, said these new findings are important because current therapies are centered on either immunotherapy or inhibiting targets downstream of the HIFα transcription factor, which is upregulated in the absence of VHL. “The discovery of ZHX2 upregulation will allow for an additional pathway to target either concurrently or sequentially,” Kim told Cancer Network.

Senior study investigator Qing Zhang, PhD, assistant professor of the department of pathology & laboratory medicine and pharmacology in the UNC School of Medicine, said that if VHL is lost, then the ZHX2 protein accumulates, which will turn on signals that promote kidney cancer. “We were just exhilarated by our findings that ZHX2 is a novel oncogenic driver in clear cell RCC. It behaves largely in a HIF2a independent fashion. So, therefore, our studies suggested that a potential cooperative oncogenic event involving ZHX2 and HIF2a leading to clear cell RCC,” Zhang told Cancer Network.

Approximately 90% of patients with clear cell RCC have genetic mutations or alterations that cause them to lose the function of VHL. When the function of VHL is gone, cells can accumulate signals that trigger blood vessels to grow. Zhang said there is now strong evidence showing that VHL plays a central role from initiation, to tumor progression, to metastasis. “Currently, there are no approved drugs against ZHX2 for RCC patients. For current RCC therapies, VEGF inhibitors or multikinase inhibitors, such as sunitinib and sorafenib, are being used for RCC patients, but almost all of these agents demonstrate modest effect,” said Zhang.

Since significant portions of clear cell RCC cell lines don’t respond to a specific HIF2a inhibitor, it is hoped that ZHX2 may be another oncogenic event that can be targeted, said Zhang. He said targeting clear cell RCC with therapeutic agents against ZHX2 alone or in combination with current standard therapies, may achieve synergistic effects in this patient population.

James Brugarolas, MD, PhD, director of the kidney cancer program at the University of Texas Southwestern Medical Center in Dallas, while remarking on the elegant and rigorous nature of the study, also recommends some caution. He said ZHX2 function is complex and while it appears to promote kidney cancer, it suppresses tumor development in other contexts. “In addition, as a transcription factor, the development of inhibitors may be challenging. Furthermore, given its pleiotropic functions, an inhibitory drug may have mixed effects on cell proliferation and tumorigenesis across tissues,” Brugarolas told Cancer Network.