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Aiming for preclinical diagnosis of cancer and dementia from a few drops of blood

Nobel Prize-winning technology revolutionizes early detection efforts

Japan, where approximately a third of the population is 65 or over, has one of the world’s highest levels of population aging. Today, a tenth of the global population is 65 or over, and this percentage is expected to double in 40 years. While average lifespan is on the rise, the gap between average and healthy lifespans is becoming a major social challenge. For people to remain healthy and independent throughout their lives, it is important that even minor indications of disease not be missed, but instead be detected and treated at a preclinical stage. Shimadzu’s goal is to detect disease symptom at the preclinical stage with just a few drops of blood. To realize this objective, the company is actively engaged in technology and device R&D. If medical tests are more easily tolerated by patients, more people will be willing to undergo medical tests, which will lead to early disease detection.

Shimadzu’s protein analysis technology has sparked a revolution in early disease detection. Proteins are not only important structural elements in biology, they are essential in hormones, metabolic enzymes, and immune substances and for the normal functioning of the body. It is also known that when changes occur in protein structures, abnormalities can arise, leading to a wide range of disease. As such, analysis of proteins in the body facilitate disease diagnosis. However, non-destructive macromolecule analysis proved extremely difficult, and for a long time this continued to be an obstacle to progress. The obstacle was overcome when, in the 1970s, Shimadzu’s research team began working on mass spectrometer (MS) technology, eventually developing the soft laser desorption/ionization method to measure the mass of proteins non-destructively. This achievement was met with worldwide acclaim, and Koichi Tanaka, a member of the research team, received the Nobel Prize in Chemistry in 2002. Since then, many researchers have collaborated to build on this research, applying it to the diagnosis of numerous diseases and the development of many pharmaceuticals. It has also proven useful in the discovery of biomarkers (indicators of disease and treatment efficacy) that facilitate early cancer diagnosis.

Developing an analytical method to measure the probability of Alzheimer's disease

As in the case of mass spectrometer research Shimadzu invested many years of effort to develop a PET system capable of imaging cell functions. In first decade of the 21st century, the use of full-body PET systems for diagnosis of cancer became widespread. In 2014, Shimadzu developed a specialized PET system with advanced capabilities to contribute to early detection of breast cancer. Furthermore, in 2020, Shimadzu developed a new PET system capable of also handling head examinations, for early detection of dementia.
In fact, though PET systems are widely used for cancer screening, Shimadzu initially developed them for head imaging. The company collaborated with research institutions to develop devices for diagnosing cerebrovascular disorders, including dementia. However, with the approval and widespread use of drugs for cancer screening, PET systems became widely utilized for that purpose.

Alzheimer’s disease is the most widespread form of dementia. Abnormal accumulations of the protein amyloid beta are observed in Alzheimer’s patients, and it is thought that this is closely associated with disease occurrence. PET system is the most accurate way to assess the degree of amyloid beta accumulation in the brain. For this reason, the use of PET systems to diagnose Alzheimer’s disease was considered from an early stage.

However, this screening was not widely provided by medical institutions. Imaging was lengthy and expensive. Because of this, researchers around the world engaged in intense competition to develop a simple testing method—as simple, for example, as a blood test—to estimate amyloid beta accumulation.

Then Shimadzu sparked a revolution yet again. The Cabinet Office's FIRST Program (Funding Program for World-Leading Innovative R&D on Science and Technology) aims to promote world-class research in a wide range of fields, from basic research to product development. During its participation in this program, Shimadzu developed a groundbreaking method to detect amyloid beta from just a few drops of blood using mass spectrometry, a feat previously considered impossible. Moreover, Shimadzu applied this method to joint research in Japan and overseas, and determined that the amyloid beta detected in the blood was a valid biomarker for estimating the amount accumulated in the brain. Research papers focusing on this analytic technology appeared in 2014 in Proceedings of the Japan Academy Series B, a prestigious international academic journal, as well as in Nature in 2018, and had a galvanizing effect on dementia researchers worldwide. Until then, research relating to detection of amyloid beta accumulation via blood testing had made little progress, but Shimadzu’s achievement opened the way to many additional useful findings.

The treatment of Alzheimer’s disease with new therapeutic agents has progressed in parallel with dementia research. In the wake of governmental approval in the U.S., some of these agents are finally seeing approval in Japan. Clinical drug studies require subjects with evidence of amyloid beta, and verification of this condition requires the use of PET devices or, if PET imaging is not an option, cerebrospinal fluid samples. PET devices are thus indispensable in the development of therapeutic agents. Dementia treatment guidelines are currently in transition, and the contributions that can be expected from the use of mass spectrometry to clinically evaluate the level of amyloid beta in a few drops of blood are just beginning. Detection at the preclinical stage will not only make it possible to delay the deterioration of cognitive functioning by administering therapeutic agents. Measuring their effectiveness will also promote development of even more effective agents, and Shimadzu devices must play a leading role in such efficacy testing.

There is currently no treatment that can restore functioning to non-functioning neurons in the brain. Normal cognitive functioning is critical in preserving the dignity of the individual. Once this is lost, enormous amounts of labor and money are required to care for such individuals, and the loss to society is considerable. If the possibility of dementia can be assessed at an early stage and its progression delayed, healthy lifespan can be extended. Shimadzu’s aim is to contribute technology that will brighten the future of medical treatment.

Supporting development of new, easily tolerated cancer treatment methods

Many types of cancer are now considered curable, if detected at an early stage. Nevertheless, cancer treatment is often physically very stressful. Progress in medicines and medical technology has reduced the degree of this stress, including the stress of side effects, but the effort required for recovery still demands considerable mental and physical toughness on the part of the patient.

In response, photoimmunotherapy was developed as a method to target cancer cells selectively and mitigate the stress of treatment. The method involves injecting patients with a drug that binds selectively to cancer cells. The cells are then exposed to near-infrared light. Photoreaction by the drug destroys the cancer cells and leaves normal cells unaffected, thereby reducing the burden of treatment on cells and internal organs. It has also been found that such treatment helps activate the patient’s immune cells, making the method suitable for practical application in treatment settings.

Photoimmunotherapy was developed by Prof. Hisataka Kobayashi, who was a clinician in the Radiology Department of Kyoto University before moving to America’s National Cancer Institute (NCI), where he is a tenured senior investigator. Photoimmunotherapy is generating significant expectations as a fifth form of cancer treatment, after surgery, anticancer drugs (chemotherapy), radiation therapy, and immunotherapy. Clinical use of photoimmunotherapy in the treatment of late-stage head and neck cancer is under way in Japan.

Shimadzu is conducting clinical research with NCI, Japanese university hospitals, the National Cancer Center Japan, and others. We are using near-infrared camera systems and liquid chromatography-mass spectrometry to assess diagnosis and drug accumulation prior to treatment, progress during treatment, and treatment efficacy and immune acquisition for prognostics management.

A range of clinical trials and studies are currently in progress to expand the range of cancer sites and types suitable for photoimmunotherapy, and to optimize treatment approaches. Such progress is likely to require the resolution of many challenges. Shimadzu will work to achieve this through the application of its devices and technology, support the establishment of safe, reliable, and effective treatment methods, and promote their widespread adoption on the front line of medicine. Our hope is that through development of new, easily tolerated medical treatments, all those who suffer from cancer will be able to approach treatment with a positive outlook.

Shimadzu engages in joint research and development with the foremost institutions and researchers in Japan and abroad. Going forward, we will provide new value through advanced healthcare that integrates medical treatment with analytical technologies. To extend healthy lifespans, we will develop technologies to support the four stages of medical treatment—preclinical diagnosis, clinical diagnosis, treatment, and prognostics—as we enter the era of the 100-year lifespan. We will continue to seek out challenges in firm support of the advancement of medical technology.