Tag: radiotherapy

Categories : CancerTags :

Drug Enhances Radiotherapy for Lung Cancer Metastases in the Brain

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Lung cancer metastasis. Credit: National Cancer Institute

In new research, a team led by University of Cincinnati researchers has identified a potential new way to make radiation more effective and improve outcomes for patients with lung cancer that has spread to the brain. The study, led by first author Debanjan Bhattacharya, PhD, appears in the journal Cancers, and uses a benzodiazepine analogue.

According to the American Cancer Society, lung cancer is the leading cause of cancer death in the United States, accounting for about one in five cancer deaths. Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, making up approximately 80% to 85% of all lung cancer cases.

Up to 40% of lung cancer patients develop brain metastases during the course of the disease, and these patients on average survive between eight and 10 months following diagnosis.

Current standard of care treatments for lung cancer that spreads to the brain include surgical removal and stereotactic brain radiosurgery (using precisely focused radiation beams to treat tumours) as well as whole brain irradiation in patients with more than 10 metastatic brain lesions.

“Lung cancer brain metastasis is usually incurable, and whole brain radiation treatment is palliative, as radiation limits therapy due to toxicity,” said Bhattacharya, research instructor in the Department of Neurology and Rehabilitation Medicine in UC’s College of Medicine. “Managing potential side effects and overcoming resistance to radiation are major challenges when treating brain metastases from lung cancer. This highlights the importance of new treatments which are less toxic and can improve the efficacy of radiation therapy, are less expensive, and can improve the quality of life in patients.”

Research focus

Bhattacharya and his colleagues at UC focused on AM-101, a synthetic analogue, meaning it has a close resemblance to the original compound, in the class of benzodiazepine drugs. It was first developed by James Cook, a medicinal chemist at the University of Wisconsin-Milwaukee. Prior to this study, AM-101’s effect in non-small cell lung cancer was unknown. 

AM-101 is a particularly useful drug in the context of brain metastases in NSCLC, Bhattacharya said, as benzodiazepines are known to be able to pass through the blood-brain barrier that protects the brain from potential harmful invaders that can also block some drugs from reaching their target in the brain.

Research results

The team found that AM-101 activated GABA(A) receptors located in the NSCLC cells and lung cancer brain metastatic cells. This activation triggers the “self-eating” process of autophagy where the cell recycles and degrades unwanted cellular parts.

Specifically, the study showed that activating GABA(A) receptors increases the expression and clustering of GABARAP and Nix (an autophagy receptor), which boosts the autophagy process in lung cancer cells. This enhanced “self-eating” process of autophagy makes lung cancer cells more sensitive to radiation treatment.

Using animal models of lung cancer brain metastases, the team found AM-101 makes radiation treatment more effective and significantly improves survival. Additionally, the drug was found to slow down the growth of the primary NSCLC cells and brain metastases.

In addition to making radiation more effective, adding AM-101 to radiation treatments could allow for lower radiation doses, which could reduce side effects and toxicity for patients, Bhattacharya said. The team is now working toward opening Phase 1 clinical trials testing the combination of AM-101 and radiation both in lung cancer within the lungs and lung cancer that has spread to the brain.

Source: Aalto University

Categories : Cancer DermatologyTags :

Treating Radiation-induced Skin Injuries with Aspirin Hydrogels

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Photo by National Cancer Institute on Unsplash

Radiation is a powerful tool for treating cancer, but prolonged exposure can damage the skin. Radiation-induced skin injuries are painful and increase a person’s chances of infection and long-term inflammation. Now, researchers in ACS Biomaterials Science & Engineering report an aspirin-containing hydrogel that mimics the nutrient-rich fluid between cells and accelerates healing of skin damaged by radiation in animals. With further development, the new salve could provide effective and rapid wound healing for humans. 

Most people undergoing radiotherapy for cancer will experience radiation-induced skin injury that can include redness, pain, ulcers, necrosis and infection. There are few treatments for these wounds, with the most common methods being debridement and hyperbaric oxygenation. Wound dressings made from hydrogels are gaining popularity because they are easy to apply and provide a wet environment for healing that is similar to the inside of the body. Glycopeptide-based hydrogels are especially promising: In laboratory and animal studies, the nanofibre structures have promoted cellular growth and regulated cell adhesion and migration. A research team led by Jiamin Zhang, Wei Wang, Yumin Zhang and Jianfeng Liu proposed loading aspirin, a common anti-inflammatory drug, into a glycopeptide-based hydrogel to create a multifunctional wound dressing for radiation-induced skin injuries.       

In lab tests with cultured cells, the researchers found that the aspirin-contained hydrogel scavenged reactive oxygen species, repaired DNA double-strand breaks and inhibited inflammation caused by radiation exposure without affecting cellular growth. In mouse models of radiation-induced skin injury, the researchers found that dressing wounds for three weeks with the salve reduced acute injuries and accelerated healing – results that the team says point to its potential as an easy-to-administer, on-demand treatment option for reducing radiation damage and promoting healing in humans.

Source: American Chemical Society

Categories : Cancer Medical IndustryTags :

Life Healthcare Concludes Agreement to Sub-License “RM2”

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Photo by Khwanchai Phanthong on Pexels

Life Healthcare through its wholly owned subsidiary Life Molecular Imaging Limited (LMI), has entered into a contract with Lantheus Holdings Inc. (“Lantheus”), to sub-license one of LMI’s early-stage novel radiotherapeutic and radio diagnostic products (RM2).

“As part of Life Healthcare’s strategy to monetise LMI’s product development portfolio, we are delighted to have found a partner for our RM2 product”, said Pete Wharton-Hood, Life Healthcare, CEO.  “Through this agreement, LMI has secured a partnership for the development of this early-stage diagnostic and therapeutic product through to commercialisation. This exciting opportunity unlocks some of the value in LMI’”, continued Wharton-Hood.

Lantheus will make an upfront payment of $35 million for the sub-licensing rights to RM2, as per the agreement. In addition, several payments will potentially be paid to LMI on the achievement of development and regulatory milestones as well as royalty payments when the product is sold commercially.

The sub-licensing agreement secures Lantheus’ rights to develop the product and complete the early development in collaboration with LMI. “LMI is uniquely positioned to assist in this area, says Wharton -Hood and we are pleased by this development as it showcases and harnesses the specialised, dedicated and focused talent within LMI”. “With Lantheus’ experience in developing and providing access to radiotheranostics in cancer, we are confident in our decision to hand them the reins for this promising theranostic pair and are honored to work with them toward improving the future of people with prostate and breast cancer,” said Ludger Dinkelborg, CEO, Life Molecular Imaging.

Lantheus Holdings, Inc. is listed on NASDAQ in the United States of America and is the leading radiopharmaceutical-focused company committed to delivering life-changing science to enable clinicians to Find, Fight and Follow disease to deliver better patient outcomes. Lantheus has been providing radiopharmaceutical solutions for more than 65 years and has identified value and commercial opportunity in continuing the development of RM2.

LMI is a wholly owned subsidiary in Life Healthcare and is registered in the United Kingdom. The company has a product Neuraceq® which has been approved in many countries and is used to detect amyloid plaque in the brain through a PET-CT Scan and has multiple products in early clinical development. LMI also provides clinical research services for pharmaceutical companies.

Life Healthcare has retained R1bn to provide for funding requirements of LMI as part of the Alliance Medical Group disposal which was concluded earlier this year “This transaction will reduce the quantum required and Life Healthcare will consider distributing a portion of the surplus to shareholders as part of the full year dividend,” stated Wharton-Hood.

About RM2

RM2 is a 9 amino acid peptide that binds to Gastrin Releasing Peptide receptor (GRPr); and can be used to treat multiple malignant tumors like prostate, breast, lung, glioma, and ovarian tumors.

About Life Molecular Imaging

LMI is a wholly owned subsidiary in Life Healthcare and is registered in the United Kingdom. The company has one globally approved product Neuraceq ® that is used to detect amyloid plaque in the brain through a PET-CT scan and has multiple products in early clinical development as well as providing clinical research services for pharmaceutical companies.

Categories : CancerTags :

Activists and Patients March on Gauteng Health Department Demanding Radiation Treatment

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Nearly R800-million set aside for radiation treatment outsourcing has not been spent

Activists and patients marched on Tuesday in Johannesburg demanding radiation treatment for cancer. Photo: Silver Sibiya

By Silver Sibiya for GroundUp

Activists and cancer patients marched to the offices of the Gauteng department of health on Tuesday demanding that millions of rands allocated for radiation treatment for cancer patients be used.

SECTION27, Cancer Alliance and Treatment Action Campaign (TAC) called for the department to use R784-million set aside by the provincial treasury in March 2023 to outsource radiation treatment. They say not a single patient has received treatment through this intervention a year later.

In an open letter to health MEC Nomantu Nkomo-Ralehoko last week, Khanyisa Mapipa from SECTION27, Salomé Meyer from the Cancer Alliance and Ngqabutho Mpofu from TAC said that in March 2022, Cancer Alliance had compiled a detailed list of approximately 3000 patients who were awaiting radiation oncology treatment.

They said there were shortages of staff in the two radiation oncology centres in Gauteng, Steve Biko Academic Hospital and Charlotte Maxeke Johannesburg Academic Hospital. Charlotte Maxeke Hospital had only two operational machines compared to seven in 2020. Tenders for new equipment had been delayed and the backlog of patients was increasing, they said.

As a result, SECTION27 and Cancer Alliance had asked the provincial treasury to set aside R784-million to outsource radiation treatment. The money had been allocated in March 2023, but a year later, no service provider had been appointed.

“It has actually been four years since the matter was brought to the Department of Health,” said Mapipa on Tuesday. She said cancer patients were not getting the treatment they needed.

“We as Cancer Alliance and SECTION27 ran to Gauteng Treasury to ask them to allocate these funds. Gauteng Treasury responded and they gave this money, but this money is still sitting.”

Thato Moncho, who was diagnosed with breast cancer in September 2020, is one of the patients on the waiting list. She said she had faced many delays in her treatment. “I’ve had three recurrences of cancer and I need to have radiation six weeks after my surgery, which they failed to give me. I have pleaded with the MEC of Health and the Chief Executive Officer at Charlotte Maxeke to speed up the process so I can get my radiation but they failed.”

“I’m pleading: help us so we can get radiation to live a normal life with our family.”

Gauteng Department of Health spokesperson Motalatale Modiba said the department had received the memorandum and would respond to it. He acknowledged that there had been delays which he said were caused by tender processes.

“It is in our interest to ensure that we get to address the backlog of those that require treatment, and the department will formally respond to the concerns that have been raised.” He said a tender had been awarded.

“In May the process to treat patients will start in both hospitals.”

“The respective heads of oncology in Charlotte Maxeke and Steve Biko hospitals are busy with that process of onboarding.”

Republished from GroundUp under a Creative Commons Attribution-NoDerivatives 4.0 International License.

Source: GroundUp

Categories : Cancer NeurologyTags :

A New Way to Prevent Cognitive Decline from Radiotherapy

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Photo by National Cancer Institute on Unsplash

Microglia, the brain’s immune cells, can trigger cognitive deficits after radiation exposure and may be a key target for preventing these symptoms, University of Rochester researchers have found. Their work, published in the International Journal of Radiation Oncology Biology Biophysics, builds on previous research showing that after radiation exposure microglia damage synapses, the connections between neurons that are important for cognitive behaviour and memory.

“Cognitive deficits after radiation treatment are a major problem for cancer survivors,” M. Kerry O’Banion, MD, PhD, professor of Neuroscience, member of the Wilmot Cancer Institute, and senior author of the study said.

“This research gives us a possible target to develop therapies to prevent or mitigate against such deficits in people who need brain radiotherapy.”

Using several behavioural tests, researchers investigated the cognitive function of mice before and after radiation exposure.

Female mice performed the same throughout, indicating a resistance to radiation injury but Male mice could not remember or perform certain tasks after radiation exposure.

This cognitive decline correlates with the loss of synapses and evidence of potentially damaging microglial over-reactivity following the treatment.

Researchers then targeted the pathway in microglia important to synapse removal. Mice with these mutant microglia had no cognitive decline following radiation. And others that were given the drug, Leukadherin-1, which is known to block this same pathway, during radiation treatment, also had no cognitive decline.

“This could be the first step in substantially improving a patient’s quality of life and need for greater care,” said O’Banion. “Moving forward, we are particularly interested in understanding the signals that target synapses for removal and the fundamental signaling mechanisms that drive microglia to remove these synapses. We believe that both avenues of research offer additional targets for developing therapies to help individuals receiving brain radiotherapy.”

O’Banion also believes this work may have broader implications because some of these mechanisms are connected to Alzheimer’s and other neurodegenerative diseases.

Source: University of Rochester Medical Center

Categories : CancerTags :

Combining Diagnosis and Treatment into One to Treat Pancreatic Cancer

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Pancreatic cancer cells. Credit: NIH

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide, with a 5-year survival rate of less than 10%. Many PDAC tumours go undetected in early stages since they go undetected by conventional imaging methods such as fluorodeoxyglucose positron emission tomography (PET) scans. To tackle this problem, researchers in Japan are combining diagnostic and therapeutic procedures into a single integrated process: ‘theranostics’.

In an article recently published in the Journal of Nuclear Medicine, the Osaka University-led team has developed a ‘radio-theranostics’ strategy that uses a new radioactive antibody to target glypican-1 (GPC1), a protein highly expressed in PDAC tumours. Theranostics, particularly radio-theranostics, has been receiving increasing attention because, by radio-labelling the compounds used to target certain molecules in cancer cells, diagnosis and treatment can be carried out sequentially.

“We decided to target GPC1 because it is overexpressed in PDAC but is only present in low levels in normal tissues,” explains Tadashi Watabe, lead author of the study.

The team used a monoclonal antibody (mAb) designed to target GPC1. The mAb could be labelled with isotopes of zirconium (89Zr) or astatine (211At). First, they injected the 89Zr-GPC1 mAb into a xenograft mouse model, which has a human pancreatic cancer tumour.

“We monitored 89Zr-GPC1 mAb internalisation over seven days with PET scanning,” explains Kazuya Kabayama, the second author of the article. “There was strong uptake of the mAb into the tumours, suggesting that this method could support tumour visualisation. We confirmed that this was mediated by its binding to GPC1, as the xenograft model that had GPC1 expression knocked out showed significantly less uptake.”

The researchers next tested this model with alpha therapy using 211At-GPC1 mAb, a method that could support radioactive label-based delivery of a therapeutic molecule to its target. Administration of 211At-GPC1 mAb resulted in DNA double-strand break induction in the cancer cells, as well as significantly reduced tumour growth. Control experiments showed that these antitumor effects did not occur when mAb internalisation was blocked. Additionally, non-radiolabelled GPC1 mAb did not induce these effects.

“Both radiolabeled versions of the GPC1 mAb we examined showed promising results in PDAC,” says Watabe. “89Zr-GPC1 mAb showed high humoral uptake, while 211At-GPC1 mAb could be used for targeted alpha therapy to support suppression of PDAC tumour growth.”

These highly impactful data demonstrate the potential for using a theranostics approach in PDAC, a disease in dire need of new diagnostic and therapeutic options. In the future, this could lead to early detection of PDAC with PET imaging and systemic treatment with alpha therapy.

Source: Osaka University

Categories : CancerTags :

High-accuracy, High-dose Radiotherapy Proves Effective against Prostate Cancer

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Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health

Patients with intermediate risk, localised prostate cancer can be treated as effectively using fewer and higher doses of radiation therapy delivered over five treatment sessions as they can with lower doses delivered over several weeks, according to researchers from The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.

Significant reduction in treatment time

Results from the PACE B (Prostate Advances in Comparative Evidence) phase III randomised trial showed that stereotactic body radiotherapy (SBRT) performed as well as standard radiotherapy treatment for people whose prostate cancer had not spread, demonstrating a 96% chance of no disease progression within five years, compared to 95% for conventional radiotherapy.

SBRT, which can be delivered on a CyberKnife or standard radiotherapy machines, allows clinicians to target tumours to sub-millimetre precision. This approach uses advanced imaging and treatment planning techniques to deliver radiation with pinpoint accuracy, minimising damage to surrounding healthy tissue. It delivers five high doses of radiation to patients over one to two weeks, compared to standard radiotherapy, which delivers more moderate doses over a much longer period of time – usually around 20 sessions for patients in the UK, which can take up to one month.

Drawing from 38 centres across the UK, Ireland and Canada, researchers enrolled 874 people who preferred radiation treatment or were unsuitable for surgery. Patients were randomly assigned to receive either SBRT, consisting of five doses over one to two weeks, or standard radiation consisting of 20 doses over four weeks or 39 doses over 7.5 weeks. None of the patients received hormonal therapy.

“For something as serious as a cancer diagnosis, the treatment was incredibly easy”

The trial investigated whether SBRT was non-inferior to conventional radiation for treating people with intermediate risk, localised prostate cancer. Non-inferiority was measured by whether patients remained free of biochemical clinical failure (BCF), defined as an increase in prostate-specific antigen (PSA) levels, distant metastases or other evidence the cancer was returning, or death from prostate cancer.

Five years after treatment, people treated with SBRT had a BCF-event free rate of 95.7% compared to 94.6% for those treated with conventional radiotherapy, demonstrating that SBRT was non-inferior to conventional radiation.

Side effects were low in both groups and at five years not significantly different between treatment arms.

One patient who benefited from the treatment was 64-year-old Alistair Kennedy-Rose, who was diagnosed with prostate cancer in 2014 at his local hospital following a blood test which revealed his prostate-specific antigen levels were raised. Alistair was referred to The Royal Marsden and, after being recruited to the PACE-B trial, was treated with SBRT via CyberKnife.

He said: “When I was diagnosed I had no symptoms at all, so it came as quite a shock. There can be a lot of anxiety following a cancer diagnosis, but just ten days after I was referred to the Royal Marsden, I started SBRT. I still find it unbelievable that five days later I finished my treatment, for something as serious as a cancer diagnosis it was incredibly easy. I haven’t had any side effects and I’ve been able to live my life to the full. I can’t thank The Royal Marsden enough for what they have done for me.”

Source: The Royal Marsden

Categories : CancerTags :

MRI-guided Radiation Therapy Reduces Side Effects from Prostate Cancer Radiotherapy

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A technique that uses MRI as a guide can make radiotherapy safer for prostate cancer patients by better aiming beams at the prostate while sparing nearby tissue in the bladder, urethra, and rectum. That is the finding of a thorough analysis of all published clinical trials of the technique, called magnetic resonance–guided daily adaptive stereotactic body radiotherapy (MRg-A-SBRT). The analysis is published in CANCER.

By providing detailed images, MRg-A-SBRT can be used to adjust a patient’s radiation plan every day to account for anatomical changes and to monitor the position of the prostate in real time while the radiation beam is on to ensure that treatment is being directed accurately to the prostate. Although MRg-A-SBRT is becoming more popular and multiple clinical trials have tested it, it is unclear whether the technique, which requires more time and resources than standard procedures, has an impact on clinical outcomes and side effects compared with other ways of delivering radiation.

To investigate, Jonathan E. Leeman, MD, of the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and his colleagues combined data from 29 clinical trials testing MRg-A-SBRT versus conventional CT-guided treatment, with a total of 2457 patients.

MRg-A-SBRT was associated with significantly fewer urinary and bowel side effects in the short term following radiation. Specifically, there was a 44% reduction in urinary side effects and a 60% reduction in bowel side effects.

“The study is the first to directly evaluate the benefits of MR-guided adaptive prostate radiation in comparison to another more standard and conventional form of radiation, and it provides support for use of this treatment in the management of prostate cancer,” said Dr Leeman.

Dr Leeman noted that the study also raises further questions regarding this type of treatment. For example, will the short-term benefits lead to long-term benefits, which are more impactful for patients? Longer follow-up will help answer this question because MRg-A-SBRT is a relatively new treatment. Also, which aspect of the technology is responsible for the improved outcomes seen in clinical trials? “It could potentially be the capability for imaging-based monitoring during the treatment or it could be related to the adaptive planning component. Further studies will be needed to disentangle this,” said Dr Leeman.

An accompanying editorial discusses the analysis’ findings, weighs the potential benefits and shortcomings of adopting this treatment strategy for patients, and questions the value of broad adoption.

Source: Wiley

Categories : CancerTags :

New Radiotherapy Technique Hits The Bullseye on Tumours

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Photo by National Cancer Institute on Unsplash

Researchers in Japan have developed a new radiotherapy technique that has the potential to treat several kinds of cancer, with fewer negative side effects than currently available methods. Published in Chemical Science, the proof-of-concept study showed that tumours in mice grew almost three times less and survival was 100% after just one injection of an alpha-particle emitting radioisotope inside of cancer cells, killing them but sparing healthy tissue.

The side effects of standard chemotherapy and radiation treatment can be devastating, and the eradication of all cancer cells is not guaranteed, especially when the cancer has already metastasised and spread throughout the body. Therefore, the goal of most research these days is to find a way to specifically target cancer cells so that treatments only affect tumours. Some targeted treatments do exist, but they cannot be applied to all cancers. Researchers led by Katsunori Tanaka at the RIKEN Cluster for Pioneering Research (CPR) in Japan and Hiromitsu Haba at the RIKEN Nishina Center for Accelerator-Based Science (RNC) developed this new approach.

“One of the greatest advantages of our new method,” says Tanaka, “is that it can be used to treat many kinds of cancer without any targeting vectors, such as antibodies or peptides.”

The new technique relies on basic chemistry and the fact that a compound called acrolein accumulates in cancer cells. A few years ago, Tanaka’s team used a similar technique to detect individual breast cancer cells. They attached a fluorescent compound to a specific type of azide – an organic molecule with a group of three nitrogen atoms (N3) at the end. When the azide and acrolein meet inside a cancer cell, they react, and the fluorescent compound becomes anchored to structures inside the cancer cell. Because acrolein is almost absent from healthy cells, this technique acted like a probe to light up cancer cells in the body.

In the new study, rather than simply detecting cancer cells, the team targeted those cells for destruction. The logic was fairly simple. Instead of attaching the azide to a fluorescent compound, they attached it to something that can kill a cell without harming surrounding cells. The chose to work with astatine-211, a radionuclide that emits a small amount of radiation in the form of an alpha particle as it decays. Compared to other forms of radiation therapy, alpha particles are a little more deadly, but they can only travel about one twentieth of a millimetre and can be stopped by a piece of paper. In theory, when astatine-211 is anchored to the inside a cancer cell, the emitted alpha particles should damage the cancer cell, but not much beyond.

Once the team figured out the best way to attach astatine-211 to the azide probe, they were able to perform a proof-of-concept experiment to test their theory. They implanted human lung-tumour cells into mice and tested the treatment under three conditions: simply injecting astatine-211 into the tumour, injecting the astatine-211-azide probe into the tumour, and injecting the astatine-211-azide probe into the bloodstream. The found that without targeting, tumours continued to grow, and mice did not survive. As expected, when the azide probe was used, tumours grew almost three times less and many more mice survived – 100% when it was injected into the tumour and 80% when injected into the blood.

“We found that just one tumour injection with only 70kBq of radioactivity was extremely effective at targeting and eliminating tumour cells,” says Tanaka. “Even when injecting the treatment compound into the bloodstream, we were able to achieve similar results. This means we can use this method to treat very early-stage cancer even if we don’t know where the tumour is.” The fluorescent probe version of this technique is already being tested in clinical trials as a way of visualising and diagnosing cancer at the cellular level. The next step is to find a partner and begin clinical trials using this new method to treat cancer in humans.

Source: RIKEN

Categories : CancerTags :

How Cancer DNA Recovers after Heavy Ion Radiation Treatment

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Photo by Jo McNamara

A team of scientists has discovered a new type of DNA repair mechanism that cancer cells use to recover from next-generation heavy ion cancer radiation therapy. Their results are published in the journal Nucleic Acids Research.

Ionising radiation (IR) therapy is frequently used in the treatment of cancer and is believed to destroy cancer cells by inducing DNA breaks. The newest type of radiation therapy harnesses radiation produced by a particle accelerator, which consists of charged heavy particles such as carbon ions. The particle accelerator accelerates the carbon ions to about 70% of the speed of light, which collides with and destroys the DNA of cancer cells.

These ions have a high linear energy transfer (LET) and release most of their energy within a short range, called the Bragg peak. The next-generation cancer radiotherapy works by focusing the Bragg peak on the tumour, which has the added benefit of minimising damage to surrounding normal tissues compared to the commonly used low LET radiation such as gamma or x-rays.

DNA lesions generated by heavy ion bombardment (high LET radiation) are more “complex” than those induced by traditional radiation therapy (low LET radiation). The former carries additional DNA damage such as apurinic/apyrimidinic (AP) site and thymine glycol (Tg) in close proximity to the double-strand breaks (DSB) sites, which is far more difficult to repair than ordinary DNA damage. As a result, the advanced therapy is more cytotoxic per unit dose than low LET radiation.

This makes next-generation radiation therapy a potent weapon against cancer cells. However, it has not been fully investigated how these high LET-induced lesions are processed in mammalian cells, as DNA damage from heavy ion bombardment is a process that seldom occurs on Earth (though astronauts are subject to this in space). Figuring out the complex DSB repair mechanism is an attractive research interest since blocking the cancer cells’ repair mechanism can allow the new radiation therapy to become even more effective.

The researchers visited the QST hospital in Japan to use the synchrotron named HIMAC (Heavy Ion Medical Accelerator in Chiba), which has the ability to produce high LET radiation.

The research team discovered that DNA polymerase θ (POLQ) is an important factor when repairing complex DSBs such as those caused by heavy-ion bombardment. POLQ is a unique DNA polymerase that is able to perform microhomology-mediated end-joining as well as translesion synthesis (TLS) across an abasic (AP) site and thymine glycol (Tg). This TLS activity was found to be the biologically significant factor that allows for complex DSB repair.

Ms SUNG Yubin, one of the joint first authors, explains, “We provided evidence that the TLS activity of POLQ plays a critical role in repairing hiLET-DSBs. We found that POLQ efficiently anneals and extends substrates mimicking complex DSBs” .

The researchers also discovered that preventing the expression of POLQ in cancer cells greatly increased their vulnerability to the new radiation treatment.

“We demonstrated that genetic disruption of POLQ results in an increase of chromatid breaks and enhanced cellular sensitivity following treatment with high LET radiation,” explains Mr. YI Geunil, another joint first author .

The research team used biochemical techniques and Fluorescence Resonance Energy Transfer (FRET) to find out that POLQ protein can effectively repair synthetic DNA molecules that mimic complex DSB. This means that POLQ can be a possible new drug target to increase the cancer cells’ vulnerability against complex radiation damage.

Source: Institute for Basic Science