Breakthroughs in Genomic Cancer Medicine: Striving to Fully Understand Genetic Abnormalities

2023/04/27

The dream of analyzing cancer cell genes and curing cancer with treatments tailored to individual patients is gradually becoming a reality. Various research projects aimed at applying personalized medicine are currently underway at the Keio University School of Medicine’s Division of Hematology, which focuses on hematological malignancies such as leukemia, lymphoma, and multiple myeloma. To learn about this cutting-edge research, we sat down with Professor Keisuke Kataoka, who says, “Those of us working in hematology take pride in being in the field closest to both research and clinical practice.”

Prof. Kataoka says he was naturally drawn to medicine due to his many relatives and family members who were physicians. After graduating from the University of Tokyo, he rotated through various medical departments during his postgraduate residency. It was during this time that he discovered his passion for hematology, the field he found to be the most captivating.

“As a medical student, I noticed that there were significant differences between what I learned in the classroom and the realities of clinical medicine, and I often felt overwhelmed by the disconnect between theory and practice during my residency. However, I was amazed by the results achieved by internal medicine treatments in hematology, especially for patients with serious conditions like leukemia and lymphoma. Witnessing such remarkable recoveries, and seeing the possibility that a tumor could be cured with medication, gave me a great sense of motivation, which led me to pursue a career in hematology.”

One of the deciding factors for Prof. Kataoka in choosing a path in hematology was the feeling that he could realize his medical school dream of becoming a physician who could both conduct medical research and give back to patients through their findings. And as it turns out, he was right.

“As the Division of Hematology website states, we’re standing at a frontier that unites basic science and clinical medicine. Our field is particularly active in basic research and has made significant progress in clinical applications compared to other medical specialties. For example, worldwide, there are more papers on leukemia than any other malignant tumors, and hematology is where new concepts in basic research are frequently born. Hematology has developed numerous new drugs for clinical application, pioneering treatments at the forefront of clinical practice, such as hematopoietic stem cell transplantation and CAR-T cell therapy, which have attracted attention from other medical specialties.

In recent years, genetic analysis has been carried out by cancer research institutions worldwide, including the Keio University Hospital's Division of Hematology. What can we learn from the genetic analysis of cancer, and how will it change diagnosis and treatment?

“The term cancer refers to illnesses caused by changes in genes, which we call ‘genetic abnormalities.’ Genes are made up of four types of bases: A, T, G, and C. These bases can become damaged, which can lead to changes such as substitutions, deletions, abnormal copy numbers, or structural alterations within the gene. These abnormalities can cause cells to lose normal function, leading to autonomous proliferation and infiltration or metastasis of surrounding tissues. This is how cancer develops.”

The analysis of cancer cell genes is essentially the study of the cause of cancer itself. The knowledge gained from this analysis forms the foundation of all cancer-related research and contributes to the development of various diagnostic and treatment methods.

“For instance, cancer treatment was previously considered based on the organ where the cancer was found but is now shifting towards treatment tailored to genetic abnormalities. Let me give a simple example. The same type of lung cancer will be treated using different molecular-targeted drugs depending on whether the cancer was caused by a mutation in the EGFR gene or the ALK gene. However, if an abnormality is found in the common HER2 gene, the same molecular-targeted drug may be used regardless of whether the cancer originated in the lung, breast, or stomach.”

Genetic analysis can reveal the cause and nature of cancer and allow for individualized treatment using “miracle drugs” tailored to each individual cancer. The existence of this treatment may seem like a dream come true, but Prof. Kataoka says that presently, about 10–20 percent of the abnormalities investigated have led to treatment.

“This might feel like a small percentage, but genetic analysis has only been widely used for the past 10–15 years. If we consider how long drug development usually takes, it is clear that personalized medicine tailored to each individual, what we call 'genomic cancer medicine,' is slowly but surely becoming a reality.”

One of Prof. Kataoka's long-term studies involves the genetic analysis of adult T-cell leukemia/lymphoma (ATL).

“ATL is a refractory cancer caused by HTLV-1 virus infection and has a high incidence rate in Japan, especially compared to other developed countries. Considering the limited treatment options available, I believed it would be significant to study the pathology of this disease in Japan. So in 2013, I went to work in the Department of Pathology and Tumor Biology at the Kyoto University Graduate School of Medicine and began genetic analysis research of ATL under the guidance of Dr.Seishi Ogawa, a pioneer in human sample-based genetic analysis.”

Prof. Kataoka and his research group conducted an unprecedented large-scale comprehensive genetic analysis on approximately 400 ATL patients. In 2016, they discovered structural abnormalities in immune checkpoint molecule PD-L1.

“We found that in 27% of ATL patients, there were deletions or inversions in the latter part of the PD-L1 gene. Moreover, despite the gene being broken, PD-L1 was activated rather than losing its function. It was completely new, something we hadn’t envisioned as a genetic mechanism, and at the time, we didn’t fully understand its significance.”

Subsequent analyses revealed that the deletion or reversal of the sequence of the PD-L1 gene causes the loss of the normal 3' untranslated region (UTR), leading to a significant increase in the expression of PD-L1.

“We predicted that the same mechanism might be at work in other cancers, so we searched through genetic analysis data from about 10,000 cases in the United States. We found that abnormalities in the 3'-UTR of the PD-L1 gene exist in 12 types of cancer, including lung, stomach, colon, head and neck, and B-cell lymphoma, and that the PD-L1 gene is constantly activated as a result.”

Further analysis using mouse transplantation models suggested that immunotherapy with immune checkpoint inhibitors may be effective in various cancers with abnormalities in the 3'-UTR of the PD-L1 gene.

Following the genetic analysis of ATL, Prof. Kataoka and his team shed light on the mechanism by which cancer cells evade the immune system and further demonstrated the effectiveness of treatment using immune checkpoint inhibitors. Their research, published in Nature in 2016, garnered attention worldwide. In 2021, they conducted whole-genome sequencing of 150 clinical samples from ATL patients. Prof. Kataoka says now that they have a complete picture of genetic abnormalities in ATL, we can expect the development of even more new diagnostic and treatment methods in the future. ATL represents only the first step in Prof. Kataoka's ongoing efforts to unravel the complexities of cancer.

The Kitasato Award, given by the Keio School of Medicine’s Sanshikai alumni association, is one of the school’s top honors, given in recognition of outstanding achievements in basic and clinical research. The 2022 award was given to Prof. Kataoka and his colleagues for their research using pan-cancer analysis to elucidate the mechanisms of cancer development.

The study was the group's most extensive to date, an analysis of over 60,000 samples of more than 150 types of cancer. With the aim of elucidating the characteristics of cancer genetic abnormalities that have yet to be explained, including those that occur at low frequencies, Prof. Kataoka’s group conducted a large-scale pan-cancer genomic analysis using unprecedented amounts of cancer genome data and supercomputers.

What they found was a new genetic mechanism involved in the development of cancer.

“Traditionally, cancer genes have been thought to mutate and activate independently. However, our analysis revealed that in some cancer genes, such as PIK3CA and EGFR, multiple mutations occur within the same gene at a relatively high frequency of about 10% of cases with mutations. These multiple mutations were clustered in functionally weaker sites where mutations typically do not occur independently. Furthermore, we were able to discover a new mechanism in which a synergistic effect resulting from multiple mutations strongly promotes cancer development.”

Expectations are also high for applying this knowledge to genomic cancer medicine.

“We are already seeing research results that show specific inhibitors are effective only when there are multiple mutations, and it is becoming clear that multiple mutations can be a biomarker for predicting the therapeutic response of molecular-targeted drugs. We believe the insights gained from continuing our research can be utilized in genomic cancer medicine.”

Alongside these studies, Prof. Kataoka and his colleagues are working on laying the foundation needed to promote the use of this medicine.

“Genomic cancer medicine requires the use of a cancer gene panel test that examines abnormalities in dozens or hundreds of cancer-related genes simultaneously. While this panel test has been covered by insurance since 2019 for solid cancers such as stomach and lung cancer, it has not yet been implemented in hematology due to the diversity of genetic abnormalities and relatively small number of patients in the field. And so, we have joined forces with the National Cancer Center and other corporations to develop a panel test for hematological tumors and are working toward clinical application in the near future.”

Prof. Kataoka was appointed as a professor of hematology in the fall of 2020 and has been leading the department ever since. He says that he wants to respect and carry on the philosophy of his predecessor, Professor Shinichiro Okamoto, who strove to create a department that makes patients think, "I'm glad I came to Keio." Prof. Kataoka says, “I want our department to do everything we can to meet the expectations of the patients and families who entrust us with their care as well as the doctors at our partner institutions who send them here. Everyone working here has such a strong sense of mission and responsibility.”

As the leader of the Division of Hematology, Prof. Kataoka considers treating people well as one of his guiding principles.

“I know how hard both clinical work and research in hematology can be, which is why I prioritize making a comfortable work environment that suits each and every one of us. This means respecting people no matter their age, gender, alma mater, specialization, or focus in clinical practice and research. It also means cooperating and maintaining good communication. This kind of welcoming work environment is one where everyone can develop and expand on their abilities, which in turn should lead to better results for our patients. I hope to see more like-minded people working together in our department in the future.”

Prof. Kataoka is not only a professor of hematology at Keio but also serves as the director of the Division of Molecular Oncology at the National Cancer Center Research Institute. You would assume that he has a hectic schedule, but Prof. Kataoka says that he’s not as busy as he could be, thanks to the excellent team that he has in his department. In fact, he says there are significant benefits to holding both positions.

“At the National Cancer Center, we conduct research to uncover the molecular pathogenesis of cancer based on genetic abnormalities and explore clinical applications. As the name suggests, the center specializes in exhaustive research on cancer, so we often gain insights from research into other types of cancer. On the other hand, at Keio, our research scope extends beyond cancer to include various blood disorders. We are actively working on developing cell therapies like hematopoietic stem cell transplantation and CAR-T cell therapy, broadening the range of our research. I hope to contribute to the development of medicine and health care by leveraging the strengths and expertise of both institutions in research and clinical practice.”

It has been less than 20 years since Prof. Kataoka graduated from medical school, yet his research has led to significant findings and numerous awards. Looking back on his journey, he says his eagerness to study and gain experience in different areas has paid off.

“I have conducted both 'wet research,' focusing on molecular biology at The University of Tokyo, and 'dry research,' including big data analysis using informatics at Kyoto University, and I have also been involved in clinical work. I believe that my ability to integrate all of these areas of expertise is one of my strengths.”

He also says that he is driven by an unlimited curiosity for new things.

“Research is something that, the more you do it, the more you encounter things that you don't understand. It's like getting closer to your goal only to suddenly see something new much further ahead. But that's what makes it interesting and why I've been able to continue my work for so long. One area of research that I am currently focusing on, for example, is single-cell analysis. If we can uncover the characteristics of each individual tumor cell, we can reveal aspects that cannot be explained by genetic abnormalities alone, which would help cancer research advance even further.”

Prof. Kataoka was also kind enough to share a message for the next generation of medical students.

“There’s no need to rush to decide which path to take while you're still young. It's the privilege of young people to have many choices, so I want you to be interested in fields beyond medicine and to pursue diverse experiences that may prove useful somewhere down the line. And remember that being a doctor or researcher is a job that requires continuous learning throughout your life. It's important to pace yourself and work steadily—without overdoing it—in ways that can be sustained over the long term. I wish you all good luck.

Keisuke Kataoka

Prof. Kataoka graduated from The University of Tokyo Faculty of Medicine in 2005. After working at Toranomon Hospital and The University of Tokyo Hospital, he completed a doctoral course at The University of Tokyo’s Graduate School of Medicine. In 2012, he was appointed project assistant professor at The University of Tokyo’s Graduate School of Medicine. In 2013, he became a project assistant professor in the Department of Pathology and Tumor Biology at the Kyoto University Graduate School of Medicine. As of 2017, he has served as director of the Division of Molecular Oncology at the National Cancer Center Research Institute. And starting in 2020, he joined the Keio University School of Medicine as a professor in the Department of Hematology. He has received numerous awards, including the Young Scientists’ Award at the 2017 Commendation for Science and Technology by the Minister of Education, Culture, Sports, Science and Technology and the Encouragement Award in Internal Medicine at the 2019 General Assembly of The Japan Medical Congress.