Renal cell carcinoma (RCC) is the most common form of kidney cancer. Nearly 15,000 people in the United States succumb to RCC each year, and the incidence is rising. The best treatment options today are surgery and radiation, but this type of cancer has proven to be particularly resistant to drugs, creating an urgent need for more effective interventions.
In the last twenty years, one strategy generated widespread excitement among cancer researchers, only to show disappointing results in clinical trials. That approach involves the use of drugs to activate TRAIL pathway – a network of protein molecules that triggers programmed cell death when it binds to receptors of tumor cells. TRAIL is especially attractive to physicians because it kills cancer cells while sparing healthy cells.
While TRAIL drugs did not improve survival rates in past studies, advances in biology, disease modeling, and protein design have led to renewed hope that more precise regulation of the signaling pathway could lead to better outcomes for patients. Julie Mathieu, PhD, an Assistant Professor of Comparative Medicine and a faculty member in the Institute for Stem Cell and Regenerative Medicine (ISCRM), is partnering with colleagues at the Institute for Protein Design (IPD) and Fred Hutchinson Cancer Research Center to test this hunch.
The research Mathieu is conducting is funded in part by a New Investigator Award through the Cancer Center Support Grant program administered by the Fred Hutch/University of Washington Cancer Consortium. This support is allowing Mathieu to design new activators of TRAIL receptors and to assess their functionality using tumor-on-chip technology.
There are several possible explanations for the failure of TRAIL to live up to its promise as a cancer fighter. Mice may have developed a resistance to TRAIL. The problem may have had to do with the receptors. Or, the TRAIL signals were not strong enough to induce the death of the cancer cells. Mathieu believes developing a new TRAIL therapy means finding a new way to increase the apoptotic signal.
Mathieu has a longstanding interest in TRAIL. As a PhD, in France, she studied how the TRAIL pathway (in conjunction with inhibition of the NF-kB pathway) drives apoptosis in leukemia and sarcoma cancers. After joining the Ruohola-Baker Lab as a postdoc, she focused on the role of hypoxia on cell reprogramming – an important mechanism by which cancer cells divide and multiply and sometimes acquire resistance to chemotherapy.
Along the way, Mathieu and her colleagues gained insights on the relationship between molecules known as HIF1 and HIF2 and the activation of TRAIL, findings that were detailed in the journal Cell Stem Cell. “Both HIF1 and HIF2 are important for cellular metabolism,” says Mathieu. “We found that if we overexpressed HIF1, it led to increase in cell reprogramming and that if we overexpressed HIF2, there was no cell reprogramming. We found that this happens because HIF2 increases the expression of TRAIL.”
Now these revelations are being paired with breakthroughs in synthetic protein technology. Mathieu is part of a collaborative team of ISCRM and IPD researchers working together to turn advances in cell biology and protein design into treatments for cancer, COVID-19, and other urgent health challenges. One joint effort between ISCRM and IPD centers on the application of nanocage technology.
Nanocages are spherical structures that are assembled by computer designed proteins. These cutting-edge tools, designed by IPD scientists, supercharge antibodies by clustering them on cell surfaces, increasing their potency, and making them more effective at combating many deadly diseases and disorders, including cancer and COVID-19, that have proven difficult to treat or cure. Mathieu sees nanocages as a way to unlock the potential of TRAIL to treat cancer.
According to Mathieu, clustering specific cancer-targeting antibodies on the surface of the nanocages could give scientists unprecedented control over TRAIL signaling and open up new avenues of cancer treatment. “Using these designed proteins for the next generation of cancer therapy is very exciting,” says Mathieu. “I believe we can develop new ways to activate cell death and overcome drug resistance by binding more antibodies to TRAIL receptors. This could be a big step forward for cancer research.”
To test the ability of TRAIL-boosting nanocages to induce cell death, Mathieu and Shally Saini, a visiting scientist in the Ruohola-Baker Lab, have conducted experiments with a renal carcinoma cell line that have previously shown resistance to TRAIL. Now, the researchers see that TRAIL is triggering apoptosis and doing so without harming healthy cells. This work is described in the April 2021 issue of Science.
IPD investigator Robby Divine, a graduate student in the Department of Biochemistry, is the study’s lead author. Among the listed authors are Mathieu and Hannele Ruohola-Baker, along with the following members of the Ruohola-Baker lab: Yan Ting (Blair) Zhao, a graduate student in the Department of Oral Health Sciences in the UW School of Dentistry, and visiting scientists Shally Saini and Infencia Xavier Raj.
Currently, Mathieu and her colleagues are exploring exactly why the nanocages work, looking at the role of other pathways, and using CRISPR gene-editing technology to examine the behavior of the receptors that help the antibodies recognize cancer cells. In a related effort, Mathieu is partnering with Dr. Chris Miller, PhD, a staff scientist in the Warren Lab at Fred Hutch and Shreeram Akilesh, PhD an Assistant Professor of Laboratory Medicine and Pathology. Their goal is to test how kidney cells react to the TRAIL drugs using tumor-on-a-chip devices; soon, they plan to use cells from actual patients.
IPD investigators George Ueda, PhD and James Lazarovitz, PhD are also contributing to this research.
“We’re seeing promising results already from our chip studies,” says Mathieu. “Overall the data points to a hopeful future for cancer patients, especially those suffering from renal cell carcinoma. The progress in the last few years is a testament to the spirit of collaboration between ISCRM, IPD, and Fred Hutch. We all want the same thing, which is to find new ways to beat cancer.”