Ingredient in Children’s Glue Helps Tumors Retain Cancer Drug
By Deborah Borfitz
December 13, 2024 | Japan has long taken a leadership role in the pursuit of boron neutron capture therapy (BNCT) as a treatment for cancer. The approach involves injecting patients with a boron-containing compound that accumulates in tumor cells and acts as an exclusive target for neutrons to kill and was the research focus of a pair of Harvard scientists throughout the 1950s, according to Takahiro Nomoto, Ph.D., associate professor at the University of Tokyo.
Two problems emerged to dampen their enthusiasm, and halted BNCT research in the U.S. for decades, he says. One was inadequate selective tumor accumulation of the boron drug, and the other was the low purity of the neutral beam and the high rate of γ-ray contamination. “These factors prevented the tumor-selective irradiation that is the hallmark of BNCT.”
Nomoto helped find a way to fix the first problem in using BNCT as a therapy for difficult-to-treat head and neck cancers—simply add polyvinyl alcohol (PVA), the primary ingredient in most children’s glue. The discovery was reported recently in the Journal of Controlled Release (DOI: 10.1016/j.jconrel.2024.11.017).
The second problem found a solution with the 1974 opening of a heavy water neutron irradiation facility attached to the Kyoto University Research Reactor (KUR), modified in 1995 for the use of epithermal neutrons, continues Nomoto. This enabled brain tumor BNCT to be performed without craniotomy, and clinical studies rapidly progressed and confirmed “excellent efficacy” of the method for recurrent cases with and without prior radiation therapy as well as for recurrent cases of malignant meningiomas. “To date, more than 400 cases of brain tumors, 30 cases of malignant melanoma, and 130 cases of head and neck cancer have been treated,” he reports.
In 2020, the first two BNCT treatments—a L-BPA and accelerator-based BNCT systems—were approved by the Ministry of Health, Labor and Welfare (MHLW) in Japan for the indication of “unresectable locally advanced or locally recurrent head and neck cancer,” respectively, Nomoto says. Three months post-approval, the drugs were listed on the National Health Insurance drug price list, making them medical devices covered under the country’s universal healthcare system.
“Subsequent clinical results for head and neck cancer have shown a high response rate, attracting increased attention,” says Nomoto. “As of November 2024, clinical trials are underway for angiosarcoma, recurrent high-grade meningiomas, and solid malignancies of the thoracic region to further expand indications.”
‘Useless’ No More
In the latest preclinical study using KUR’s neutron irradiation capabilities, Nomoto and his team combined PVA with a boron-containing compound known as D-BPA to dramatically improve its tumor-selective accumulation beyond what could be achieved by currently approved drugs. The result was more effective BNCT, helping to spare healthy cells from unnecessary radiation damage.
D-BPA, he notes, is a “mirror-image isomer of L-BPA” and thought to be possibly more selective for a tumor-associated amino acid transporter (LAT1), but was considered a “useless” compound—and therefore removed from the composition of L-BPA—because it doesn’t amass in tumors when administered. “The addition of PVA to this seemingly useless D-BPA resulted in better tumor-selective accumulation and retention than the clinically used drugs.”
In a previous study, combining PVA and L-BPA was found to result in the formation of complexes that significantly improved retention of boron inside cells during radiotherapy (Science Advances, DOI: 10.1126/sciadv.aaz1722). “Since the irradiation time of thermal neutrons is 30-60 minutes, which is longer than the irradiation time of general radiation therapy, it was thought that the therapeutic effect of BNCT could be further improved if the retention of BPA in cancer cells could be prolonged,” Nomoto explains.
However, L-BPA can enter cells through amino acid transporters other than LAT1—i.e. ATB0,+ and LAT2, which are highly expressed in normal cells. “Depending on the location of the cancer, cancer cells and surrounding normal cells take up a considerable amount of L-BPA,” Nomoto says, making some cancers ineligible for BNCT. “This is also true for PVA-L-BPA.”
This is what made D-BPA an attractive alternative, he says. When mixed with PVA, the resulting complex (PVA-D-BPA) showed tumor-selective accumulation and retention that “exceeded our expectations... [and] those of L-BPA and PVA-L-BPA.”
Since the utility of D-BPA as a BNCT agent was demonstrated “by the extremely simple method of mixing PVA and D-BPA in aqueous solution,” Nomoto says, “we hope to commercialize PVA-D-BPA or its derivatives for cancer types that cannot be treated with L-BPA or PVA-L-BPA.”
He and his team are currently exploring practical applications of the technology with Stellar Pharma and Osaka Medical and Pharmaceutical University, with support from the Japan Agency for Medical Research and Development. They will also be working with Stellar Pharma and Mitsubishi Chemical Corporation over the next few years to optimize the PVA formulation and hope to achieve proof of concept at the animal testing level by 2030 before moving on to non-clinical and clinical trials.
Lengthy History
BNCT has a long history that began shortly after the 1932 discovery of “fast” neutrons, which differ from the thermal neutrons being used therapeutically, says Nomoto. The principle behind the neutron capture reaction, the foundation for BNCT, was proposed four years later and its strong effect was then confirmed by biological experiments. The idea remained unrealized in the absence of a research reactor providing a neutron source with “high neutron flux density,” meaning a very intense stream of thermal neurons more likely to interact with boron atoms by physical collision.
It was another few decades before Harvard University professors W.H. Sweet and L.E. Farr first promoted the application of BNCT to cancer therapy, he says. Between 1951 and 1961, they attempted to use it as a treatment for malignant gliomas using the research reactors at Brookhaven National Laboratory and the Massachusetts Institute of Technology. But patients experienced severe adverse reactions, and survival was shorter than with conventional treatment.
After that failure, BNCT research—especially clinical research—was taken over by Japanese investigators with the focus being on neutron sources as well as drugs that selectively accumulate in tumor cells, says Nomoto. A new boron drug, known as BSH, resulted from these efforts and was used by famed Japanese neurosurgeon Hiroshi Hatanaka to perform BNCT for malignant gliomas. BSH can reach a high concentration ratio between brain tumor tissue, where the blood-brain barrier is malfunctioning, and normal brain tissue.
Hatanaka achieved good results with BSH for many years using multiple research reactors, but the selective effects were not tied to the drug’s function to target tumor cells, he continues. L-BPA, on the other hand, focuses on the melanin synthesis pathway that is significantly enhanced in melanoma and selectively accumulates in tumor cells where it showed strong cell-killing effects.
With the advent of L-BPA, BNCT was recognized for the first time as a tumor cell-selective therapy with a high-quality curative effect, says Nomoto. More recently, researchers have found that the amino acid transporters LAT1, LAT2, and ATB0+ are involved in the tumor accumulation mechanism of L-BPA, expanding its clinical utility to the treatment of other tumor types.
All the progress made in Japan helped U.S.-based clinical treatment research using BNCT resume in 1994, he points out. EU countries, notably the Netherlands and Finland where research reactors are located, quickly followed suit. Other countries—Sweden, the Czech Republic, Argentina, Italy, and Taiwan among them, have since taken up BNCT research but Japan remains the global leader.
Accelerator BNCT
The world saw its first accelerator for BNCT in 2010, the consequence of a collaboration between Sumitomo Heavy Industries, Ltd. and Kyoto University, which enabled the capture of neutrons without a nuclear reactor, Nomoto says. Researchers globally came together two years later for a conference in Japan to propose use cases for the clinical application of accelerator-based BNCT. Stellar Pharma Corporation, which was developing a formulation of L-BPA, also teamed up with Sumitomo for a phase 1 clinical trial of the approach for brain tumors.
A phase 1 clinical trial for head and neck cancer and a phase 2 trial for brain tumors and head and neck cancer were subsequently initiated, he adds. Meanwhile, results of the reactor-based studies prompted the start of trials for an expanded list of indications.
In 2019 at the National Cancer Center, Stellar Pharma launched a first-in-human BNCT study for malignant melanoma and angiosarcoma with the CICS Corporation that had developed an accelerator for BNCT, reports Nomoto. The phase 2 trial of accelerator BNCT for angiosarcoma was initiated in November 2022.
The MHLW formed the so-called Strategy of SAKIGAKE and Stellar Pharma’s L-BPA and Sumitomo Heavy Industries' accelerator for BNCT are two of the designees in 2017, giving them a “development boost,” he says. These were the first two BNCT treatments to be approved in Japan in 2020.
Progress... and Obstacles
“An important aspect of drug development in BNCT is that boron drugs should accumulate selectively in tumor cells and do not cause side effects unless they are irradiated with neutrons,” says Nomoto. “The dose of boron drugs is much higher than that of common anticancer drugs because the concentration of boron in the tumor must be at the mM [millimoles per liter] level... for a sufficient nuclear reaction to occur in the tumor to be therapeutic. Therefore, it is required that such compounds have little or no toxicity unless irradiated by thermal neutrons.”
Those compounds are not easy to synthesize, he adds. BSH and L-BPA both have “extremely low” toxicity, and L-BPA has the added advantage of cellular uptake of the amino acid transporters that enable tumor-selective accumulation of the drug. Of all such compounds under development, L-BPA has had the best clinical results so far.
That said, Nomoto quickly adds, no drug reported to date is “selectively taken up by cancer cells without [some] uptake by normal cells.” Depending on the type of cancer, L-BPA sometimes shows little difference in uptake between tumor and normal cells. Given that thermal neutrons are scattered in the body and irradiate both types of cells, “BNCT cannot be applied for such cases... [and] the development of drugs other than L-BPA is required.”
Improvements in nuclear reactors have made to possible to deliver “extra-thermal” neutrons and thus treat up to 7 centimeters (cm) from the surface layer of the body, versus about 1 cm previously. While craniotomy is no longer necessary, even for irradiating brain tumors, “it is difficult to set up a hospital next to a nuclear reactor,” necessitating equipment to irradiate epithermal neutrons inside the hospital, he says, referencing back to the first accelerator-based neutron source for BNCT developed by Kyoto University and Sumitomo Heavy Industries.
“In Japan, the development of a new accelerator-based neutron source generating neutrons by irradiating proton beam to lithium is also in progress,” Nomoto adds. That project is being jointly undertaken by CICS Corporation and the National Cancer Center.
The clinical usefulness of BNCT where thermal and epithermal neutrons can reach tumors within 7 cm from the surface are many, says Nomoto. In addition to head and neck cancer, which is now covered by insurance, “clinical trials are underway for other diseases such as meningioma and hemangiosarcoma, and further expansion of indications is expected in the future.”
One of the biggest obstacles in making progress may well be low awareness of BNCT, indicates Nomoto. “We are working day and night to promote BNCT by integrating various fields such as medicine, physics, and chemistry, but we are concerned about the lack of researchers involved in this field.”