TECHNOLOGY

What is the fifth method for cancer treatment?

The fifth method for cancer treatment involves the use of a “Trojan horse” method. The “horse” molecule, which cancer cells will readily take up, veils the functional molecule; the “weapon“, which will be activated by various physical and chemical means, targeting and eliminating the cancer cells.

第5のがん治療法とは何か

Figure.1: The fifth cancer treatment is shown in the form of a “Trojan Horse”.

A revolution is taking place in cancer treatment. In addition to the conventional standard consisting of three methods of cancer treatment (the first method = “surgery”, the second method = “drug therapy such as anticancer drugs”, the third method = “radiation therapy”), the fourth method = “immunotherapy”(*1) has been dramatically evolved by Dr. Tasuku Honjo (currently a Distinguished Professor at Kyoto University, Nobel Prize winner in 2018). This is a method to activate the immune system by covering the receptors that suppress the immune system, thereby achieving a therapeutic effect.

In recent years, “Photoimmunotherapy”(*2), and “Boron Neutron Capture Therapy (BNCT)”(*3) have also been commercialized by the Japanese. Let’s call them the “fifth cancer treatment method. Its outstanding feature is the use of a binding substance between molecules that selectively bind to, or are taken up by, cancer cells and molecules that cause damage to cancer cells. This is analogous to the “Trojan horse”(*4) strategy that the ancient Greeks used to hide their armed troops to invade the Trojan army in the Trojan War. The “horse” molecules that cancer likes to bind to or take into its cells, lead the “weapon” molecules (Fig. 1). The “horse” molecules and the “weapon” molecules are connected by strong chemical bonds and cannot be easily broken.

In “photoimmunotherapy,” the “horse” is a cancer-selective antibody and the “weapon” is a photosensitive substance. When the antibody binds to the surface of cancer cells and is irradiated with infrared rays, the photosensitive substance explodes like a bomb to destroy the cancer cells. In boron neutron capture therapy (BNCT), a “horse” molecule with a boron atom of mass number 10 is attached to a cancer cell and irradiated with neutrons, the neutrons are intensively captured by the boron atom and destroy the cancer cell. Both of these methods were put to practical use in Japan ahead of any other country in the world.

What is the ORBIO method for cancer treatment?

The ORBIO method uses L-glucose as the “horse” in a “Trojan Horse” strategy. The “horse” carries functional molecules as “weapons” being conjugated by strong chemical bonds. The functional molecules are taken up by cancer cells with much higher selectivity than existing anti-cancer drugs. The cancer cells are then destroyed spontaneously, or otherwise by activating the functional molecules physically and/or chemically.

オルバイオ法とは何か

Figure.2: Chemical structures of D-glucose (right) and L-glucose (left). The structures are mirror images of each other.

In 2010, in Japan, a discovery regarding the nature of cancer occurred quite by accident. D-glucose (see right side; Fig. 2). usually referred to as simply, ‘glucose’, is the most fundamental energy source, that is, the ‘food’ for nearly all cells. In contrast its mirror image molecule, L-glucose (see left side, Fig. 2), is rarely found in nature. Cells do not recognize it as a nutrient. However, Dr. Katsuya Yamada (Professor of Collaborative Research Chair at ORBIO, Hirosaki University) discovered that cancer cells recognize L-glucose as a ‘food’, and selectively take them up. Dr Yamada, and colleagues, achieved this discovery using a green fluorophore attached to L-glucose. Furthermore, when attaching a blue fluorophore they discovered that cancer cells not only readily took it up, but that the cancer cells were damaged by it; it was toxic to them. They proceeded to obtain patents for this discovery. This molecule is one of the newest candidates in the field of ‘theranostics’; a term derived from a combination of the words therapeutics and diagnostics, and can detect and treat cancer cells at the same time. The L-glucose conjugated with such fluorophores selectively taken up by cancer cells, especially in refractory cancers including pancreatic cancer, biliary tract cancer, and ovarian cancer, is also leading to patent-granted proposals for completely new methods of diagnosing cancer.

オルバイオ法とは何か

Figure 3: Specific uptake of L-glucose into cancer cells. Here, glucose transporter (*5) attracts only D-glucose into the cell.

Based on these discoveries, ORBIO Corporation is developing novel techniques that will take the fifth method of cancer treatment a step forward. In our approach L-glucose is used as the ‘horse’ molecule in a “Trojan Horse” strategy. The new molecule which combines L-glucose with a functional “weapon” is referred to as an ORBIO molecule. Use of L-glucose as the “horse” assures unprecedentedly high selectivity for cancer cells. By designing the functional “weapon” adequately, cancer cells take in L-glucose, the “horse”, with the “weapon” molecules. Then, either spontaneously, or by physical and/or chemical means, the weapon is activated and kills the cancer cells. This is the working mechanism of the ORBIO molecule

The ‘ORBIO Method’, which controls cancer using ORBIO molecules, has two remarkable features. The principle feature is its extremely high preference for cancer. As schematically illustrated in Figure.3, L-glucose, which is not taken up by normal cells, is taken up by cancer cells via a channel-like protein(*6) specifically expressed in these cells. The uptake of L-glucose occurs in a highly selective manner in cells of various adenocarcinoma, in particular, refractory cancers such as pancreatic cancer, bile duct cancer, ovarian cancer, as well as uterine body cancer, gastric cancer and so on. The second feature of the ‘ORBIO Method’ is that, unlike surgery, which attempts to remove cancers as they grow, the “Trojan Horse” is effective even on the level of a single cell.Therefore, even at the very early stage, when there are only a few rapidly growing cancer cells, barely detectable by the latest diagnostic methods such as PET, CT, and MRI, the ‘ORBIO Method’ is able to control the progression of the cancer cells.

オルバイオ法とは何か

Figure.4: Of the tumour cell masses a and b, obtained from a mouse pancreas (Figure.A), only a, which exhibits large and small nuclear atypia characteristics of malignant tumours (Figure.B), strongly uptakes fluorescent L-glucose into the cells (Figure.C), while b, which exhibits characteristics of normal cells or benign tumours (Figure.B), does not uptake fluorescent L-glucose (Figure.C).
(Sasaki A. et al., Human Cell 29: 37-45, 2016より)。

Even if the patient has developed metastasis at late stages, and the cancer is too small to be detected by PET, or other diagnostic methods, the cancer cells can be killed as long as they are seeking nutrients to proliferate, no matter where they are hiding.

What is the difference from anti-cancer drugs?

The ORBIO molecule is a conjugate of two or more molecules with clearly defined roles, designed to act specifically on cancer cells without damaging normal cells.

オルバイオ法とは何か

Figure 5: Conceptual diagram showing the effective and adverse effects of conventional and anticancer drugs as a function of dose.

At first glance the ORBIO method, as the fifth method of cancer treatment, is indistinguishable from the second method using anti-cancer drugs because it uses ORBIO molecules to kill cancer by activating some of the molecule groups through physical and chemical methods.

However, the second method using anti-cancer drugs is a therapeutic agent that causes indiscriminate attacks on both cancer cells and normal cells to suppress the growth and metastasis of cancer cells, resulting in serious side effects on normal cells as well. In other words, as shown in Figure.5, the dose amount of anti-cancer drugs that produce expected effects, and the dose amount that produce side effects are generally very close. Among anti-cancer drugs, ‘molecular targeted drugs’ are agents acting on molecules specifically expressed on a subset of cancers, suppressing their growth. Because of their characteristics, the types of cancer they work on are very much limited. In addition, ‘molecular targeted drugs’ can actually affect normal cells and cause unpredictable side effects.

On the other hand, the concept of molecular design of ORBIO molecular drugs is clear because the roles of the molecules are shared within the molecule, which is a combination of molecule groups that is selectively taken up by cancer (‘horse’) and molecules that kill cancer spontaneously, or that are physically or chemically activated to kill cancer (‘weapon’).

Research and development field

The research and development area of ORBIO CORPORATION is focused upon the development of methods for the diagnosis and treatment of cancer using L-glucose as a ‘horse’ molecule. Specifically, we are developing the following three types of methods to combine the ‘weapon’ molecule with the ‘horse’.

(1) Type I: Fluorescence generation effect (visualization and diagnosis)
(2) Type II: Pharmacological action (pharmacological effect)
(3) Type III: Radiofrequency irradiation (Heat generation and cauterization effect)

GLOSSARY

*1 Immunotherapy

This is a method of damaging cancer cells by strengthening the immune system, and is particularly famous for the method discovered by Dr. Tasuku Honjo and others, which led to the Nobel Prize. This is a therapy to fight cancer by boosting one’s own immunity by covering the receptor named PD-1, which suppresses immunity, and Dr. Honjo and his colleagues discovered nivolumab as the protein that plays the role of the cover. Nivolumab was launched in 2014 under the brand name of Opdivo by Ono Pharmaceutical Co.

*2 Photoimmunotherapy

This is a method of cancer treatment invented by Dr. Hisataka Kobayashi and his colleagues at the National Cancer Institute (NCI) of the U.S. National Institutes of Health (NIH), and is exclusively manufactured and sold by Rakuten (Chairman and President Hiroshi Mikitani) under license from NIH. Cetuximab (EGFR antibody) is used as the “Hippocampus” and IRDye® 700DX, a photosensitive substance, is used as the “weapon.

*3 BNCT (Boron Neutron Capture Therapy)

ホウ素中性子捕捉療法(BNCT, Boron Neutron Capture Therapy)

This is a cancer treatment method that selectively damages cancer cells by irradiating neutrons and using alpha and lithium rays generated by nuclear reactions with boron-10, which has a mass of 10. In 2012, Stellar Pharma and Sumitomo Heavy Industries collaborated with the Kyoto University Research Reactor Institute to launch the world’s first accelerator-based clinical trial, and in 2016, the Brain and Nervous System Research Institute in Fukushima Prefecture established the South-Northeast BNCT Research Center and began clinical trials for brain tumors and head and neck cancer using the accelerator- based BNCT system manufactured by Sumitomo Heavy Industries. In 2020, the insurance coverage of BNCT for “unresectable locally advanced or locally recurrent head and neck cancer” started. In April 2021, Stellar Pharma was listed on the Mothers market.

*4 Trojan Horse

Trojan Horse is a device used by the Greeks to bring about the fall of Troy during the Trojan War in Greek mythology. It was made of wood so that people could hide inside. According to the Aeneid by Virgil, after a ten-year siege, the Greeks, under the orders of Odysseus, built a huge wooden horse, hid their troops, including Odysseus himself, inside, and brought them into the city of Troy. Here, the “Trojan Horse” metaphorically refers to the strategy of secretly drawing “weapons” into the target.

*5 Glucose transporter

Glucose (D-glucose) is the most basic source of energy or carbon, and is taken up and used by almost all living organisms in their cells. In the case of mammalian cells, D-glucose must pass through the cell membrane, which consists of a lipid bilayer, to enter the cell, but because D-glucose is a water-soluble molecule of a certain size and shape, it cannot freely pass through the cell membrane. The glucose transporter is a water-soluble molecule of a certain size and shape. Glucose transporters are representative of the transmembrane proteins (also called membrane transport proteins or carrier proteins) that mediate this process, i.e., the transport of D-glucose into the cell (also called membrane transport) in mammalian cells, and the GLUT family is well known.

*6 Channel-like proteins

Channel is a type of transmembrane protein, and ion channels such as sodium ion channels and potassium ion channels are typical examples. The difference between the transporter and the channel is as follows: In the transporter, the binding of a substrate (in the case of a glucose transporter, the substrate is D-glucose) to the transporting protein causes the protein to undergo a conformational change from a state in which the opening and substrate binding sites are directed to the outside of the cell membrane to a state in which the opening and substrate binding sites are directed to the inside of the cell membrane. As a result, the substrate bound to the substrate-binding site from the outside of the cell membrane leaves the protein and moves to the inside of the cell membrane, resulting in the transport of the substrate from the outside to the inside of the cell membrane (carrier). This is similar to a game of musical chairs, where if the chair (i.e., binding site) is occupied, the substrate must wait outside the chair. In contrast, the channel is a protein that does not have a substrate binding site, but instead has a mechanism called a gate that interacts with the substrate and can transport the substrate much faster than a transporter. The term “channel-like protein” refers to proteins that have a transport mode similar to that of channels.