Cancer affects about half of the Japanese population and accounts for about one-third of the country’s deaths. In particular, recurrence and metastasis are the biggest barriers to treating cancer and are the source of many patients’ suffering. We spoke with Professor Hideyuki Saya of the Keio University School of Medicine’s Institute for Advanced Medical Research, who is studying cancer stem cells, which can cause cancer recurrence and metastasis, with the aim of finding a cure for otherwise intractable cancers.
“I became a neurosurgeon because I wanted to be a great doctor like the manga character Black Jack, who I idolized growing up. But at one point in my career, I felt like I’d hit a wall with treating malignant brain tumors. Even after tumors are surgically removed, they can return in a matter of months. I’ve seen them claim the lives of many patients. I felt like we’d reached the limits of surgical treatment. I wanted to find a way to save those patients, so I pause my career as a surgeon and chose a career of basic research.”
Prof. Saya wanted to establish a new kind of treatment that would cure otherwise intractable cancers. A turning point came in the late 1990s with the discovery of “cancer stem cells.”
“Cancer cells were traditionally thought to be a collection of cells of a similar nature that proliferate uncontrollably. However, cancers were found to have founder cells, cancer stem cells, which self-replicate and differentiate to form cancer tissue. Cancer stem cells can be thought of as ‘queen bees,’ who create and proliferate many ‘worker bees,’ or non-cancer stem cells.
Scientists also discovered that cancer stem cells grow at a slower rate than non-cancer stem cells and are much more resistant to cancer treatments.
“Even if a tumor appeared to have shrunk due to radiation therapy or chemotherapy, it was often just the death of those ‘worker bee’ non-cancer stem cells. The ‘queen bee’ cancer stem cells, which are resistant to different stresses, survive and eventually resume self-replication and differentiation. Put simply, cancer stem cells were the main cause of recurrence and metastasis. I believe that this discovery proved to be the turning point that fundamentally changed the landscape of cancer treatment.”
To develop a treatment method that would target these cancer stem cells, Prof. Saya focused his research efforts on a molecule known as CD44v. Next, we hear about the results of his research, which he describes as “years of work combined with a pinch of luck.”
“I first encountered CD44 as a graduate student. At the time, I was working with antibodies that would detect cancer cells, and for a certain molecule, the antibodies would make the cancer cells clearly stand out from the normal cells around them. That molecule was CD44. I had a hunch that this CD44 molecule would prove to have an important relationship to cancer. But at the time, I didn't know anything more than that.”
In 1988, Prof. Saya transferred to the MD Anderson Cancer Center at the University of Texas, one of the world's leading cancer research centers, to further devote himself to research.
“That was when we discovered the CD44v molecule, a modified version of CD44. We found that CD44v, which is rarely detected in normal tissue, is expressed in highly malignant cancers. Yet we still did not know why CD44v was associated with malignancy. I kept coming back to the mystery of why it might be present in malignant tumors.”
Fast forward ten years, and one day, Prof. Saya happens to come across a paper by a research team at Stanford with data showing that CD44 is expressed in cancer stem cells.
“’Ah, that's it!’ I thought. I felt so frustrated. Why hadn’t I realized that CD44 was a cancer stem cell marker during all my years of research? It soon became clear that CD44, particularly CD44v, must be more than just a biomarker, and we decided that the next step would be to figure out its function on our own.”
In 2010, true to his word, Prof. Saya and his team discovered that CD44v is expressed in cancer stem cells and that it is involved in drug resistance. They found that the CD44v-xCT complex formed by CD44v in the cell membrane promotes the uptake of cystine, an amino acid, and synthesizes glutathione, a powerful antioxidant, and that these large amounts of glutathione lowered reactive oxygen species (ROS), thus weakening the effects of chemo- and radiotherapy.
“We were finally able to prove that CD44v was the key to the drug resistance of cancer stem cells. That was a huge step forward for us.”
It was a world first and a discovery 30 years in the making. It also marked the beginning of a new struggle to develop a means of controlling CD44v and pushing research forward into clinical trials.
Prof. Saya thought that if CD44v could not promote cystine uptake, then it would not be able to produce glutathione, resulting in a regression of cancer stem cells. Having identified the function of the cells, he conducted a thorough search of existing drugs that could inhibit the uptake of cystine, which is how he happened upon “sulfasalazine.” Developed in the 1940s, the drug was used for ulcerative colitis and rheumatism.
And as early as 2013, it was being used in clinical trials conducted together with the National Cancer Center Hospital East. “When patients with gastric cancer were treated with sulfasalazine for two weeks, there was a dramatic decrease in the number of CD44v cells in cancer tissue, which is exactly what we hoped would happen.”
However, the trial did not show any early tumor shrinkage, making it clear that treatment of cancer stem cells with sulfasalazine must be combined with treatment of non-cancer stem cells that have the potential to proliferate rapidly. So, in 2017, the team conducted a clinical trial for lung cancer patients, this time in collaboration with Kyushu University.
“Patients with inoperable advanced lung cancer were given sulfasalazine in addition to conventional anticancer treatments. This time, the effect was undeniable. While cancer came back within an average of 4.3 months when using conventional anticancer treatments, that time increased to an average of 11.7 months with the use of sulfasalazine. These results were very good for advanced lung cancer, which normally has a poor prognosis.”
Drug discovery research that investigates how to repurpose conventional drugs, such as Prof. Saya’s research into sulfasalazine, is known as “drug repositioning.” It is a common technique today, and the repurposing of drugs for Ebola and rheumatoid arthritis is now being considered for the treatment of COVID-19. Prof. Saya has been considering this kind of drug repositioning for more than 20 years, but back then, it didn’t yet have a name.
“Developing a cure for cancer has long been a goal of mine, but I knew from personal experience just how difficult it had been for doctors to conduct drug discovery research in university laboratories. And that is why I came up with the idea of trying to achieve the desired result using drugs that were already available for use. Existing drugs can move quickly into clinical trials because there is already data on their safety and pharmacokinetics. And while this approach may not be the best, it is certainly the fastest. I thought it would be the best way to get treatments to patients quickly.”
Prof. Saya, who was at Kumamoto University at the time, collected all available drugs by himself to create a “conventional drug library.” Of the approximately 3,000 drugs on the market, he was able to prepare approximately 1,600 of them for his laboratory.
“Collecting all of them was quite the undertaking. But I am happy to say that since creating the library 20 years ago, it has been used by many researchers all over Japan. Here at Keio, Prof. Hideyuki Okano is using our library to identify drugs for intractable neural diseases.”
Even today, 20 years after the library was established, Prof. Saya's desire to “deliver treatments from bench to bedside as soon as possible” is being realized across many research fields.
Prof. Saya says that he is “just one step away” from translating his many years of research findings into clinical application. That gap between basic research and clinical application can be so wide, however, that it is often called the “valley of death.”
“First of all, in order to proceed to clinical research, basic research has to meet very high standards in terms of safety and efficacy. But the issue is that research at the university level, including appropriate response to adverse events, has not met those standards so far those standards. And it requires a huge financial investment in order to ensure such a high level of research and development. What’s more is that even if quality results are obtained in basic research, most researchers don’t know the processes or procedures needed to translate those results into clinical application. In other words, we need a bridge that will span the gap between basic and clinical research.”
In 2014, Keio University established the Keio University Hospital Clinical and Translational Research Center. Prof. Saya, who is well versed in both basic research and clinical practice, has led the center as director since 2015.
“The Clinical and Translational Research Center provides all the support necessary for the success of translational research, which bridges the gap between excellent basic research findings and clinical application. For example, we formulate intellectual property strategies, provide support for acquiring research funding, negotiate with ministries and agencies, prepare and conduct clinical trials, carry out market research, and negotiate partnerships and alliances with companies and organizations. We provide this support not only for Keio but also for the early-stage research of other universities and research organizations.”
In 2017, the Clinical and Translational Research Center expanded into a secretariat office and the Metropolitan Academic Research Consortium (MARC) was established, creating a system of collaboration and cooperation among clinical research institutions in the Tokyo metropolitan area, including private medical and dental schools.
“Organizations that support translational research are gradually forming across Japan. The Clinical and Translational Research Center is still in its infancy, but we plan to continue working hard to develop new treatments needed both in Japan and around the world.”
Sulfasalazine had been proven to suppress CD44v-xCT, which increases the drug resistance of cancer stem cells, but several issues still needed to be dealt with to bring it into clinical practice.
“Cells will eventually develop resistance to any drug with prolonged administration. To cure otherwise intractable cancers, we realized that we had to use a combination therapy that would preemptively intercept resistant cells.”
Wondering if there was a drug that could be used to treat cells that have developed resistance to sulfasalazine, Prof. Saya and his team once again screened existing drugs and discovered a more effective treatment by combining it with oxyfedrine, which was once used to treat chest pain.
“At this stage, we are still experimenting on mice, but we have found that the combination of sulfasalazine and oxyfedrine almost completely prevents tumor growth. After conducting cancer research for many years, I am very confident in these findings. By combining drugs, known as compounding, we are resolving disadvantages inherent in drug repositioning, such as the challenge of obtaining cooperation from pharmaceutical companies due to patent expiration. It's a lengthy process, but we are committed to carrying this research to the clinical trial stage and creating something that will have clinical application.”
When asked to share a message with young doctors and researchers, Prof. Saya shared a memory from his younger days.
“I think my experience at the MD Anderson Cancer Center, where I worked for six years starting in 1988, has shaped who I am as a researcher. At the time, the center was defining its mission and vision, gathering insights from staff.
Over the course of several months, MD Anderson formulated its mission: “to eliminate cancer in Texas, the nation, and the world through outstanding programs that integrate patient care, research and prevention, and through education for undergraduate and graduate students, trainees, professionals, employees and the public.” The vision: “We shall be the premier cancer center in the world, based on the excellence of our people, our research-driven patient care and our science.”
“The process of thinking about my role in society and what I wanted to achieve was something that had a profound impact on me. It was also at this time that all staff members were ordered to write their own mission and vision on the back of their name tags so that it would always be close to their hearts, literally.”
On the back of his name tag, Prof. Saya wrote:
Mission: Use knowledge gained from basic research to treat cancer and prevent recurrence and metastasis
Vision: Establish the world’s most advanced research group for basic and applied cancer research
"It's been 30 years since I first laid out my mission and vision, and I still have a long way to go. But the further you strive, the better. I always keep these words close at heart while working on my research.”
Prof. Saya added one last thing: “core values.”
“A core value could be respecting patients who cooperate in clinical trials, obtaining consent when receiving samples, or valuing teamwork. These are basic human and ethical values. I equate doing medical work to climbing a steep mountain with these “heavy stones” on your back. Mission, vision, and core values. My wish is that young researchers will always remember these three things as they devote themselves to their studies.”
Prof. Saya graduated from the Kobe University School of Medicine in 1981 and conducted his graduate work as a resident at the school’s Department of Neurosurgery. He studied as a postdoctoral fellow at the UCSF Brain Tumor Research Center until 1988 before being appointed as an Assistant Professor at the Neuro-Oncology Department of the MD Anderson Cancer Center. He served as a professor at the Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, before assuming his current position as professor at the Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, in 2007.