Metastatic cancer is a deadly puzzle. Once cancer spreads to more than one part of the body, it is far more likely to result in death. Researchers have struggled for decades to find effective ways to prevent, treat, or reverse metastasis once it begins.
When Yibin Kang was a postdoctoral researcher at Memorial Sloan Kettering Cancer Center in the early 2000s, he thought of metastasis as “the elephant in the room.”
“Nobody knows how cancer cells become metastatic,” he says. Now, after more than 15 years of research on a gene known as metadherin, or MTDH, Kang believes he has made a breakthrough.
Kang hopes his findings will lead to new therapeutic interventions for treating common cancers, including breast, lung, colon, liver, and prostate.
In November 2021, Kang, who is the Warner-Lambert/Parke-Davis Professor of Molecular Biology, and his co-authors published two papers in Nature Cancer demonstrating that in mice, blocking the interaction between MTDH and another protein disables its function and prevents metastasis. Kang hopes his findings will lead to new therapeutic interventions for treating common cancers, including breast, lung, colon, liver, and prostate.
During his time as a postdoctoral researcher, Kang, who arrived at Princeton in 2004, became intrigued by breast cancer, which kills more than 40,000 women annually in the United States. “You could have two breast cancer patients with almost the exact same early-stage cancer and treatment, but they could have very different outcomes,” he recalls. “One would be cured, but the other would experience recurrent metastasis a few years later, treatment would fail, and the patient would die.” Kang wanted to know if there was a way to predict whether a patient’s cancer would return and spread.
Kang began to research MTDH, which had been identified as a factor in metastatic breast cancer in mice. In 2009, he published a human study showing that patients with metastatic breast cancer frequently had a higher DNA copy number and gene expression level of MTDH in their tumors — in other words, the MTDH gene was amplified in patients whose cancer resisted treatment.
In 2014, Kang published another set of studies demonstrating that MTDH plays an essential role in promoting metastasis for breast and prostate cancers (as well as lung and intestinal cancers, according to a follow-up study published in 2020). These studies included two notable results. First, Kang showed that removing the MTDH gene in healthy mice had no discernible effect on their health. This suggested that MTDH is probably not essential for normal growth and development, and that targeting it won’t create adverse side effects.
Second, Kang analyzed the crystal structure of the MTDH protein and found that it interacted with another protein, SND1. Two projections on the surface of MTDH fit precisely into cavities in SND1 like a key into a lock. Kang hypothesized that disrupting the relationship between the two proteins could be a way to neutralize MTDH’s harmful activities.
In search of a way to block the “handshake” between MTDH and SND1, Kang turned to the Small Molecule Screening Center in Princeton’s chemistry department. His team spent over two years testing thousands of molecules in the center’s library before it found a compound that could fill one cavity in SND1, essentially disabling MTDH.
Kang says MTDH plays two key roles in helping cancer flourish: It helps tumors resist stress as they grow, and suppresses the body’s immune response to cancer — which he compares to having “a house on fire, [but the] fire alarm is disabled.” In his most recent papers, Kang demonstrates why disabling MTDH is effective in treating cancer. The first paper shows how the blocking mechanism works. The second shows its therapeutic benefit by demonstrating that blocking MTDH in mice with breast cancer is highly effective when combined with anti-PD1 immune checkpoint therapy, a relatively new treatment that disrupts interactions between proteins that suppress the immune system. This combination works by reactivating the tumor’s alarm system so that it can call for help, and then maintaining the stamina of the “firefighters” that respond to the alarm so that they have enough energy to attack the tumor.
Kang hopes to begin clinical trials on humans in two to three years. He has licensed the technology from his latest studies to Firebrand Therapeutics, a Princeton-based biotech startup, which is continuing to develop the compounds for clinical trials. An important step in the process will be substantially reducing the concentration of the MTDH-blocking compound to prevent unwanted side effects in humans.
Andres Blanco *11, who completed his Ph.D. under Kang and took part in some of Kang’s earliest research on MTDH, notes that metastasis is particularly tricky because cancer cells tend to change with each new region of the body they spread to, which means that treating metastasis is “almost like treating multiple diseases.” He believes that Kang’s latest findings have “very high potential.” The key, Blanco adds, is “to find something that the cancer cells are very vulnerable to [but that] normal cells are minimally vulnerable to.”
Liling Wan *14, who also completed her Ph.D. with Kang and is a co-author on the new papers, is excited by Kang’s results — not only for their potential therapeutic use, but also because they prove how sheer persistence in the lab can yield major insights over time. “It’s really encouraging to see how basic research [might] translate to something that is meaningful in patients,” Wan said.