Tag Archives: #radiotherapy

Pioneering Single-dose Radiotherapy For Breast Cancer Treatment (Medicine)

A breast cancer therapy that requires just one shot of radiotherapy is as effective as traditional radiotherapy, and avoids potential damage to nearby organs, according to a paper by UCL experts.

The results, published in the British Journal of Cancer, mean that eight out of ten patients who receive the treatment, TARGIT-IORT, will not need a long course of post-operative external beam radiotherapy (EBRT). These results strengthen and expand previously published outcomes. 

Patients who received the treatment are less likely to go on to experience fatal cardiovascular disease such as heart attacks, lung problems or other cancers. As well as avoiding scattered radiation from EBRT that can damage nearby vital organs, delivering TARGIT-IORT during the lumpectomy procedure seems to lower the likelihood of death if patients do go on to develop cardiovascular disease, protecting in a drug-like manner. This was the case even when EBRT was also given post-operatively, and is thought to be because the treatment changes the microenvironment in the lumpectomy wound.

The researchers say that delivering radiation immediately to the site where the tumour was can reduce the adverse effects of surgical trauma make the site less conducive for cancer growth and could have an ‘abscopal’ (distant) effect. This is where a treatment such as radiotherapy has a positive effect on tissue away from the operation site, which is increasingly recognised as a beneficial immunological action.

Previous studies have shown that the treatment has fewer radiation-related side effects compared with conventional whole breast radiotherapy, with less pain, a superior cosmetic outcome with fewer changes to the breast as a whole and a better quality of life.

Lead author Professor Jayant Vaidya (UCL Surgery & Interventional Science) said: “With TARGIT-IORT, women can have their surgery and radiation treatment for breast cancer at the same time. This reduces the amount of time spent in hospital and enables women to recover more quickly, meaning they can get back to their lives more quickly.”

TARGIT-IORT is delivered immediately after tumour removal (lumpectomy), and under the same anaesthetic, via a small ball-shaped device placed inside the breast, directly where the cancer had been. The single-dose treatment lasts for around 20-30 minutes and replaces the need for extra hospital visits in eight out of ten cases.

Further tumour subgroup analysis also found that there was a significant overall survival benefit with TARGIT-IORT in patients with grade 1 or 2 cancer.

Professor Vaidya added: “These new results make it clear that the TARGIT-IORT is effective in all tumour subgroups of invasive duct cancer, the most common type of breast cancer. Our new online tool can help clinicians make a decision about additional radiotherapy (recommended in a small proportion of cases) for each individual patient.

“The finding that fewer deaths are from the avoidance of scattered radiation and the possible abscopal effect of TARGIT-IORT is important and should fuel further research, opening doors to new treatments.”

For the clinical trial, which started in March 2000, 2,298 women aged 45 or over with invasive breast cancer and a tumour up to 3.5cm in diameter were randomly assigned to receive either TARGIT-IORT during lumpectomy or post-operative EBRT.

The trial was designed and run from UCL, involved 32 hospitals and medical centres in ten countries: the UK, France, Germany, Italy, Norway, Poland, Switzerland, the USA, Canada and Australia.

Professor Michael Baum (UCL Surgery & Interventional Science) said: These results are the highest level of evidence proving not only the effectiveness of TARGIT-IORT but confirming that it avoids deaths from other causes.

“The new data is biologically very interesting and the new tools will make its application in routine clinical practice much easier. I am pleased that it will benefit thousands of breast cancer patients around the world.”

Professor Jeffrey S Tobias (Professor of Clinical Oncology, UCL and UCLH) said: With “TARGIT-IORT, the majority of patients presenting with early localised breast cancer will never need any further radiotherapy.

“They will avoid all the side effects of whole breast radiotherapy. The chance of remaining free of local recurrence (in the breast itself) is the same as with traditional treatment, but our new analysis shows that even if they do get a local relapse, it will not detract from an excellent prognosis – as good as not having a relapse – a rather different state of affairs from the more serious outlook if this were to happen after EBRT.”

To date, 45,000 patients in 260 centres in 38 countries have received TARGIT-IORT). The clinicians hope that following the latest results, more patients can be offered the treatment both in the UK and around the world instead of EBRT.

Funding for the trial was provided by the National Institute for Health Research (NIHR) Health Technology Assessment Programme, UCL Comprehensive Biomedical Research Centre and Cancer Research UK.

Links

Image

The single-dose radiotherapy delivered with Covid-19 safety protocols in place. The procedure avoids the need for repeat hospital visits, greatly reducing patients’ potential exposure to the virus. © UCL


Provided by UCL

Measuring the Effects Of Radiotherapy On Cancer May Open Up Avenues For Treatment (Medicine)

Radiotherapy works by damaging the DNA of cancer cells. It’s an effective strategy overall, but many cancers have subsets of cells that are able to survive initial radiotherapeutic regimens by using DNA damage repair mechanisms. This often results in resistance to further radiation as cancerous growth recurs. A team led by Roel Verhaak analyzed patient cancers before and after radiotherapy and found a deletion signature in many post-treatment samples. The finding indicates that combining radiotherapy with DNA repair inhibition may improve efficacy.

Ionizing radiation is used for treating nearly half of all cancer patients. Radiotherapy works by damaging the DNA of cancer cells, and cells sustaining so much DNA damage that they cannot sufficiently repair it will soon cease to replicate and die. It’s an effective strategy overall, and radiotherapy is a common frontline cancer treatment option. Unfortunately, many cancers have subsets of cells that are able to survive initial radiotherapeutic regimens by developing mechanisms that are able to repair the DNA damage. This often results in resistance to further radiation as cancerous growth recurs. But until recently, little was known about exactly what happens in the genomes of cancer cells following radiotherapy.

To probe the traits of post-radiotherapy cancer genomics, Jackson Laboratory (JAX) Professor Roel Verhaak, Ph.D., led a team that analyzed gliomas, a brain cancer, both when they first arose and after they recurred in 190 patients. They also looked at data from nearly 3,700 other post-treatment metastatic tumors. In “Radiotherapy is associated with a deletion signature that contributes to poor outcomes in cancer patients,” published in Nature Genetics, the researchers present findings showing that radiotherapy is associated with consistent genomic damage in the form of a large number of DNA deletions. The study also implicates an error-prone DNA damage repair mechanism as being an important contributor to the deletion signature. Targeting this DNA repair mechanism may help maximize the efficacy of radiotherapy. The study was co-led by Floris Barthel, M.D., a senior fellow in the group, and first author Emre Kocakavuk, M.D., a visiting student from University Hospital Essen in Germany.

Analyzing the pre- and post-treatment glioma datasets as well as the post-treatment metastatic tumor dataset, Verhaak and his team identified a significant increase of small (five to 15 base pair) deletions and chromosome or chromosome-arm level deletions in response to radiation. Furthermore, the post-treatment small deletion pattern had distinct characteristics that implicate canonical non-homologous end joining (c-NHEJ) as the preferred repair pathway for radiation-induced DNA damage.

“c-NHEJ is an error-prone mechanism for DNA repair that cancer cells need to use to mitigate the damage done by radiation. We discovered that small deletions commonly happen as a consequence,” says Verhaak.        

The research also reveals that patients who acquire the high small deletion burden have significantly shorter survival than others post-radiotherapy. The finding implies that the deletion signature is associated with a loss of sensitivity to subsequent radiotherapy and suggests that the presence of many small deletions may serve as a biomarker for radiotherapy response. Somewhat paradoxically, tumors that acquire the high deletion burden signature appear to become robust, possessing sufficient, if not precise, DNA repair to survive mutation-inducing treatments. Therefore, even if initial radiotherapy is effective, recurrent tumors that exhibit this genomic trait are unlikely to respond to more.

On the other hand, the study supports the hypothesis that DNA repair inhibitors likely represent an effective therapeutic strategy and could improve cancer cell response to radiotherapy. At this point, research has indeed indicated that drugs known as PARP inhibitors are effective for treating various cancer types, and preliminary work is being done to evaluate other candidate DNA repair mechanism inhibitors. 

“Finding a robust signature of c-NHEJ in post-irradiated tumors is very exciting because it suggests that slowing this repair process during radiotherapy could potentially increase the effectiveness of treatment,” says Barthel.

Featured image: JAX illustration by Karen Davis.


Reference: Kocakavuk, E., Anderson, K.J., Varn, F.S. et al. Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer. Nat Genet (2021). https://doi.org/10.1038/s41588-021-00874-3


Provided by Jackson Laboratory

Hydrogen Peroxide-producing Drug Boosts Cancer-killing Effect of Radiotherapy (Medicine)

A small drug molecule that appears to protect normal tissue from the damaging effects of radiation, may simultaneously be able to boost the cancer-killing effect of radiation therapy, according to a new study led by scientists at University of Iowa, University of Texas Southwestern Medical Center, and Galera Therapeutics, Inc.

The study, published online May 12 in Science Translational Medicine, suggests that the drug’s dual effect is based on a fundamental difference between the ability of cancer cells and healthy cells to withstand the damaging effects of a highly reactive molecule called hydrogen peroxide, which is produced during the dismutation of superoxide.

The drug, known as Avasopasem manganese, is made by Galera Therapeutics. It acts like a natural enzyme called superoxide dismutase and converts superoxide into hydrogen peroxide. Based on its ability to “mop up” damaging superoxide molecules, which are produced by radiation treatment, the drug is currently in clinical trials to test its ability to protect mucosal tissue from the side-effect of radiotherapy.

Since radiation generates large amounts of superoxide, combining the drug with radiation therapy can generate high levels of hydrogen peroxide. This does not harm normal tissue because healthy cells have metabolic systems that remove hydrogen peroxide. In contrast, cancer cells, which are biologically abnormal, can be overwhelmed by high levels of hydrogen peroxide.

Douglas Spitz, portrait
Douglas R. Spitz, PhD

“Cancer cells and healthy cells respond very differently to the increased amount of hydrogen peroxide,” says Douglas Spitz, PhD, UI professor of radiation oncology and co-lead author of the study. “Our study shows that Avasopasem manganese interacts synergistically with high doses of radiation to create hydrogen peroxide that selectively kill cancer cells but is relatively harmless to normal tissue.”

The study showed that in mouse models of lung and pancreatic cancer the drug synergized with radiotherapy to such an extent that the treatment was able to destroy the tumors. The study also showed the greatest synergy occurred with high daily dose radiotherapy, similar to the doses delivered with Stereotactic Body Radiation Therapy (SBRT) currently used to treat some patients with cancer.

The researchers used several experiments to confirm that hydrogen peroxide was the key component in the synergistic effect. They showed the effect was blocked by adding in an enzyme that removes hydrogen peroxide and was enhanced when hydrogen peroxide breakdown was prevented.

“These findings are the result of collaborative efforts over several years by scientists primarily at Iowa, UT Southwestern Medical Center, and Galera, and are already being translated into several ongoing clinical studies,” adds Spitz, who is a member of Holden Comprehensive Cancer Center at the UI. “One of those early phase trials recently reported that Avasopasem manganese in combination with high daily dose radiotherapy appears to nearly double overall survival in patients with pancreatic cancer compared to a placebo plus the same radiotherapy. Our study lays out the novel scientific basis for this potentially ground-breaking therapy for patients.”

In addition to Spitz, the study team included co-lead author Michael Story, PhD, at UT Southwestern Medical Center, and colleagues at UI, UT Southwestern Medical Center, and Galera Therapeutics, Inc.

The research was funded in part by grants from the National  Cancer Institute and a sponsored research agreement with Galera Therapeutics.

All images credit: University of Iowa


Reference: Brock J. Sishc, Lianghao Ding, “Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide”, Science Translational Medicine  12 May 2021: Vol. 13, Issue 593, eabb3768 DOI: 10.1126/scitranslmed.abb3768


Provided by University of Iowa

New Marker Predicts Benefit Of Radiotherapy For Early-stage Breast Cancer (Medicine)

A study involving researchers at Karolinska Institutet and Gothenburg University has found that low levels of a protein called PDGFRb are associated with particularly good results of radiotherapy in women with early-stage breast cancer. The study, which is published in the journal Clinical Cancer Research, also suggests that the efficacy of radiotherapy can be improved with drugs that block this protein.

Fredrik Wärnberg
Fredrik Wärnberg, professor at Sahlgrenska Academy, Gothenburg University. Photo: Lennart Wiman

Some 900 women in Sweden are diagnosed with DCIS (ductalcarcinoma in situ), the earliest possible form of invasive breast cancer. Standard treatment is surgery and subsequent radiotherapy. Although the prognosis is generally good, some ten per cent of patients suffer a recurrence within ten years of diagnosis.

“It is well-known that the benefits of radiotherapy are individual, so we need to find predictive markers that can be used to avoid unnecessary or ineffective radiotherapy,” says the study’s co-last author Fredrik Wärnberg, professor at the Department of Clinical Sciences at Gothenburg University’s Sahlgrenska Academy.

Supporting tissue can influence therapeutic effect

Arne Östman
Arne Östman, professor at Karolinska Institutet. Photo: private

While previous studies have focused mainly on markers in the tumour cells themselves, recent findings show that supporting tissue around the tumour cells can affect the therapeutic effect of DCIS. Studies in cell and animal models have demonstrated that the efficacy of radiotherapy can be influenced by fibroblasts, which are a type of supporting cell in the breast cancer tissue.

Arne Östman’s research group at Karolinska Institutet and Professor Wärnberg’s group have now analysed a large tissue collection from a randomised radiotherapy study (SweDCIS). Their analyses showed that low levels of a particular fibroblast protein, PDGFRb, are associated with especially high radiotherapeutic efficacy for women with DCIS.

Several projects underway

Several new studies have been launched, one a collaboration with the US company PreludeDx on breast cancer diagnostics.

Carina Strell
Carina Strell, researcher at Uppsala University and Karolinska Institutet. Photo: private

“The treatment guidelines of DCIS might need to be changed if these studies confirm our original findings,” says the study’s first author Carina Strell, researcher at the Department of Immunology, Genetics and Pathology, Uppsala University, and the Department of Oncology-Pathology, Karolinska Institutet.

The results of this newly published study also indicate that the efficacy of radiotherapy can be improved if combined with the blocking of PDGFRb. The researchers now plan to interrogate this further in experimental cell and animal models before any studies on patients can begin.

The study was financed by the Swedish Cancer Society, BRECT, the Swedish Research Council, STARGET the Linné grant scheme, the Cancer Research Funds of Radiumhemmet, the EU Caffein ITN network, BRECT at Karolinska Institutet, Region Stockholm and the Research Council of Norway.

Arne Östman receives research grants from Eli Lilly and IPSEN. Co-authors Erik Holmberg and Per Karlsson have a research contract with PFS Genomics. Jonas Bergh receives research grants from Amgen, AstraZeneca, Bayer, Merck, Roche, Pfizer and Sanofi Aventis, all with Karolinska Institutet and/or Karolinska University Hospital as recipient. Fredrik Wärnberg has received financing from PreludeDx for tumour collection with Uppsala University Hospital (Akademiska sjukhuset) as recipient. Troy Bremer is employed and has proprietary interests (including patents) in PreludeDx, receives commercial research grants on behalf of the company from the National Cancer Institute, and is the co-inventor of one or more patents/patent applications licensed to or owned by PreludeDx.

Featured image: Illustration of the DCIS © Illustration: Getty Images


Publication

“High PDGFRb expression predicts resistance to radiotherapy in DCIS within the SweDCIS randomized trial”. Carina Strell, Dick Folkvaljon, Erik Holmberg, Aglaia Schiza, Viktoria Thurfjell, Per Karlsson, Jonas Bergh, Troy Bremer, Lars A. Akslen, Fredrik Wärnberg, Arne Östman. Clinical Cancer Research, online 5 May 2021, doi: 10.1158/1078-0432.CCR-20-4300.


Provided by Karolinska Institute

Study Finds Stereotactic Body Radiotherapy is Safe For Treating Multiple Metastases (Medicine)

A phase 1 clinical trial led by investigators at the University of Chicago Medicine testing the effects of stereotactic body radiotherapy for treating multiple metastases has determined that treatments used for single tumors can also be safely used for treating patients with multiple metastases. The study was run through NRG Oncology and sponsored by the National Cancer Institute. The results were published on April 22 in JAMA Oncology.

Cancer is traditionally treated with a combined approach, with clinicians using surgery, chemotherapy and radiation therapy to kill and remove cancerous tumors. Systemic treatments such as chemotherapy often are not enough to stop the cancer’s growth.

Stereotactic body radiation therapy (SBRT) is a type of radiation therapy that uses precisely targeted beams of very high doses of radiation to destroy tumors. The higher doses are more effective at killing cancer cells than traditional radiation therapy, while the careful targeting of tumors reduces damage to noncancerous tissue.

This approach has been used successfully to treat small, early stage tumors, but until now, it was not clear if such high doses of radiation would be safe in patients with multiple tumors due to metastatic cancer. Because SBRT uses multiple, high-intensity radiation beams, physicians have to be especially careful in locating tumors and targeting the radiation beams to maximize benefits and minimize risks — a challenge that Steven Chmura, MD, PhD, likened to trying to “cross the beams” in the “Ghostbusters” movie.

“Part of the difficulty is working out the logistics for testing this approach in patients across multiple institutions,” said Chmura, Professor of Radiation and Cellular Oncology at UChicago Medicine. “We’ve thought for a long time that you could treat three or four metastases at the same time, but it’s very technically complicated to do so. But before we could test this in something like a large, phase 3 clinical trial, we had to prove that we could get multiple institutions together and come up with a ‘cook book’ for how to do this right, ensuring that treatment was the same across the board. This was really like seven phase 1 clinical trials rolled into one.”

A phase 1 clinical trial, led by Chmura, set out to test the safety of such an approach. In a trial of 39 patients who had breast, prostate or non-small cell lung cancer with at least three metastases or two metastases in close proximity, the investigators determined that there were no treatment-related deaths and that the approach was safe enough to begin phase 2/3 clinical trials in a larger group of patients.

“At the end of the trial, the primary endpoint of six-month dose limiting toxicity was 0%,” Chmura said. “This shows us that treating three or four sites of metastases throughout the body with these high-ablative doses of radiotherapy is safe.”

Radiation therapy is not without risks. While the study found that no patients experienced side effects severe enough to call off the study, several adverse events were linked to the treatment, including gastric ulcers, broken bones and bone pain, and pneumonitis. In many cases during the four-year trial, these side effects appeared months to years following treatment, highlighting the importance of maintaining long-term follow-up contact with these patients. Overall, however, none of these treatments or side effects led to increased risk of death.

“People have been saying for years that if we used SBRT in patients with multiple, limited metastases, we could potentially cure more patients,” said Chmura. “But we needed to conduct these large-scale, phase 2/3 clinical trials to prove that. And before we can do those large trials, we had to set up the infrastructure. The greatest challenge was having a whole team of people come together and figure out how we could define the doses and manage the real-time quality assurance to make sure every single patient had the best treatment possible.”

With this collaborative infrastructure in place, the investigators have launched additional trials to test the efficacy of stereotactic body radiation therapy for treating patients with multiple metastases. The group is currently enrolling patients in a phase 2/3 trial for using SBRT for the treatment of metastatic breast cancer, with the goal of treating up to 450 people.

The study, “Evaluation of Safety of Stereotactic Body Radiotherapy for the Treatment of Patients With Multiple Metastases,” was supported by NRG Oncology (UG1CA189867, U10CA180868, U10CA180822) and the National Cancer Institute (U24CA180803). Additional authors include Hania Al-Hallaq and Yasmin Hasan of the University of Chicago Medicine, Kathryn Winter and Jennifer Moughan of NRG Oncology, Clifford Robinson of Washington University, Thomas Pisansky and Sean Park of the Mayo Clinic, Virginia Borges of the University of Colorado-Anschutz Medical Center, Martha Matuszak of the University of Michigan, Sun Yi of the University of Arizona Medical Center, Jose Bazan and Julia White of the Ohio State University, Philip Wong of the Centre Hospitalier de L’Universite de Montréal, Harold Yoon of the Heartland Cancer Research National Cancer Institute, Janet Horton and Joseph Salama of the Duke University Medical Center, Gregory Gan of the New Mexico Minority Underserved National Cancer Institute Community Oncology Research Program, Michael Milano of the University of Rochester, and Elin Ruth Sigurdson of the Fox Chase Cancer Center.


Reference: Steve Chmura, Kathryn A. Winter et al., “Evaluation of Safety of Stereotactic Body Radiotherapy for the Treatment of Patients With Multiple Metastases”, JAMA Oncol. Published online April 22, 2021. doi:10.1001/jamaoncol.2021.0687


Provided by University of Chicago Medical Center

Dartmouth Researchers Pilot FLASH Radiotherapy Beam Development for Treatment of Cancer (Medicine)

Dartmouth researchers convert a standard linear accelerator used for delivery of radiation therapy cancer treatment, to deliver an ultra-high-dose rate radiation therapy beam to patients “in a flash.”

 A joint team of researchers from Radiation Oncology at Dartmouth’s and Dartmouth-Hitchcock’s Norris Cotton Cancer Center (NCCC), Dartmouth Engineering, and Dartmouth-Hitchcock’s Department of Surgery have developed a method to convert a standard linear accelerator (LINAC), used for delivery of radiation therapy cancer treatment, to a FLASH ultra-high-dose rate radiation therapy beam. The work, entitled “Electron FLASH Delivery at Treatment Room Isocenter for Efficient Reversible Conversion of a Clinical LINAC,” is newly published online in the International Journal of Radiation Oncology, Biology & Physics.

The exceptionally high dose rate of the FLASH Beam is 3,000 times higher than normal therapy treatment (300 Gray per second vs. 0.1 Gray per second, Gray being a standard unit measuring absorbed radiation). Instead of treatment over 20 seconds, an entire treatment is completed in 6 milliseconds, giving the therapy its nickname, “FLASH.” © Brian Pogue, PhD

The exceptionally high dose rate is 3,000 times higher than normal therapy treatment (300 Gray per second vs. 0.1 Gray per second, Gray being a standard unit measuring absorbed radiation). Instead of treatment over 20 seconds, an entire treatment is completed in 6 milliseconds, giving the therapy its nickname, “FLASH.” “These high dose rates have been shown to protect normal tissues from excess damage while still having the same treatment effect on tumor tissues, and may be critically important for limiting radiation damage in patients receiving radiation therapy,” says Brian Pogue, PhD, Co-Director of NCCC’s Translational Engineering in Cancer Research Program and co-author on the project.

While the team awaits news of potential funding from the National Institutes of Health (NIH), early pilot funding from NCCC and Dartmouth’s Thayer School of Engineering allowed for prototyping of the converted LINAC. Pre-clinical testing of the beam began in August and has already provided key data on its potential for different tumor plans. “This is the first such beam in New England and on the east coast, and we believe it is the first reversible FLASH beam on a clinically used LINAC where the beam can be used in the conventional geometry with patients on the treatment couch,” says Pogue.

The FLASH beam is currently being used in preclinical studies on both experimental animal tumors as well as in clinical veterinary treatments, to study the normal tissue-sparing effects and how to maximize the value. The research group has expanded to involve physicians in clinical radiation oncology and dermatology, designing what they hope will be the first human safety trial with FLASH radiotherapy at Dartmouth-Hitchcock, treating patients advanced skin lesions that cannot be removed surgically.

The published project was led by researchers Rongxiao Zhang, PhD, Petr Bruza, PhD, David Gladstone, ScD, and P. Jack Hoopes, DVM, with work done by Dartmouth Engineering PhD students and first authors Ronny Rahman and Ramish Ashraf, and Dartmouth-Hitchcock engineering from Lawrence Thompson and Chad Dexter.

Brian W. Pogue, PhD, is Co-Director of the Translational Engineering in Cancer Research Program at Dartmouth’s and Dartmouth-Hitchcock’s Norris Cotton Cancer Center, MacLean Professor of Engineering at Dartmouth’s Thayer School of Engineering, Professor of Surgery at Geisel School of Medicine at Dartmouth, and President and Co-Founder of DoseOptics, LLC, which develops camera systems and software for radiotherapy imaging of Cherenkov light for dosimetry. His research interests include optics in medicine, biomedical imaging to guide cancer therapy, molecular-guided surgery, dose imaging in radiation therapy, Cherenkov light imaging, image-guided spectroscopy of cancer, photodynamic therapy, and modeling of tumor pathophysiology and contrast.

Reference: https://linkinghub.elsevier.com/retrieve/pii/S0360301621000249

Provided by Dartmouth-Hitchcock Health

About Norris Cotton Cancer Center

Norris Cotton Cancer Center, located on the campus of Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH, combines advanced cancer research at Dartmouth College’s Geisel School of Medicine in Hanover, NH with the highest level of high-quality, innovative, personalized, and compassionate patient-centered cancer care at DHMC, as well as at regional, multi-disciplinary locations and partner hospitals throughout NH and VT. NCCC is one of only 51 centers nationwide to earn the National Cancer Institute’s prestigious “Comprehensive Cancer Center” designation, the result of an outstanding collaboration between DHMC, New Hampshire’s only academic medical center, and Dartmouth College. Now entering its fifth decade, NCCC remains committed to excellence, outreach and education, and strives to prevent and cure cancer, enhance survivorship and to promote cancer health equity through its pioneering interdisciplinary research. Each year the NCCC schedules 61,000 appointments seeing nearly 4,000 newly diagnosed patients, and currently offers its patients more than 100 active clinical trials.

About Dartmouth-Hitchcock Health

Dartmouth-Hitchcock Health (D-HH), New Hampshire’s only academic health system and the state’s largest private employer, serves a population of 1.9 million across northern New England. D-H provides access to more than 2,000 providers in almost every area of medicine, delivering care at its flagship hospital, Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH. DHMC was named again in 2020 as the #1 hospital in New Hampshire by U.S. News & World Report, and recognized for high performance in 9 clinical specialties and procedures. Dartmouth-Hitchcock also includes the Norris Cotton Cancer Center, one of only 51 NCI-designated Comprehensive Cancer Centers in the nation; the Children’s Hospital at Dartmouth-Hitchcock, the state’s only children’s hospital; affiliated member hospitals in Lebanon, Keene, and New London, NH, and Windsor, VT, and Visiting Nurse and Hospice for Vermont and New Hampshire; and 24 Dartmouth-Hitchcock clinics that provide ambulatory services across New Hampshire and Vermont. The D-H system trains nearly 400 residents and fellows annually, and performs world-class research, in partnership with the Geisel School of Medicine at Dartmouth and the White River Junction VA Medical Center in White River Junction, VT.

Study Identifies Distinct Sub-types of Aggressive Tumours to Allow For Targeted Treatment (Medicine)

Study led by Singapore clinician-scientists has found a way to classify angiosarcomas into three subtypes, allowing for more targeted treatment, better outcomes for patients and the development of new therapies.

  • Angiosarcomas are clinically aggressive tumours that are more prevalent in Asian populations.
  • Study led by Singapore clinician-scientists has found a way to classify angiosarcomas into three subtypes, allowing for more targeted treatment, better outcomes for patients and the development of new therapies.
  • Findings were published in The Journal of Clinical Investigation in October this year.

A new study led by clinician-scientists from the National Cancer Centre Singapore (NCCS), with collaborators from research institutions worldwide, has found that angiosarcomas have unique genomic and immune profiles which allow them to be classified into three different subtypes. With this new and improved classification system, patients can be treated using a personalised-medicine approach and it will encourage the development of novel treatments.

© Jason Chan et al.

Angiosarcomas, a type of cancer that forms in the lining of the blood and lymph vessels, are more commonly found in Asia making up 7% of all sarcoma diagnoses. Angiosarcomas are aggressive and can spread to various regions of the body and most often occur on the scalp and face.

For angiosarcomas that have not spread, a combined approach using surgery, radiotherapy and/or chemotherapy is often the course of action for treatment. Once the cancer has metastasised, various chemotherapy treatments are typically administered, which often have poor clinical efficacy and little benefit. As a result, angiosarcomas present a challenge for clinicians and patients because treatment options are limited and prognosis is bleak.

“At NCCS, we treat around 100 patients with sarcomas a year. With a deeper understanding of the tumours, we can better treat these group of patients,” said Clinical Assistant Professor Jason Chan, first author of the study and Consultant Medical Oncologist, Division of Medical Oncology, NCCS.

For the study, 68 patients diagnosed with angiosarcoma at NCCS and Singapore General Hospital between 2000 to 2015 were identified. The research team analysed the tumour samples using multiomic sequencing, NanoString immuno-oncology profiling, and multiplex immunohistochemistry and immunofluorescence.

Multiomic sequencing, which is used to find associations or pinpoint biomarkers in biological entities, like an angiosarcoma, found that 50% of the head and neck angiosarcomas exhibited higher tumour mutation burden (TMB) and UV mutational signatures. This indicated that half of the head and neck angiosarcomas may have developed as a result of UV exposure, and are likely to respond to a type of cancer treatment known as immune checkpoint inhibitors.

NanoString profiling, a technology that profiles gene expression in tumours, revealed that patients with angiosarcomas were grouped into three clusters. Patients in the third cluster had specific enrichment of immune cells and genes involved in immune-related signalling. Tumour inflammation signature (TIS) scores were also highest in this third cluster. Cluster one, like cluster three, was found to be predominantly head and neck angiosarcomas although with a lower inflammation footprint. Cluster two exhibited higher expression of genes that typically promote tumour growth and spread. They were also mainly secondary sarcomas, meaning they had previous exposure to certain environmental or genetic risk factors.

Recent clinical studies have shown that treating tumours with high TMB and TIS scores with immune checkpoint inhibitors showed promising results. By stratifying these 68 angiosarcoma patients, the study results suggest that checkpoint immunotherapy can be used for clusters one and three, while the tumour-promoting genes that are highly expressed in cluster two could be explored as potential treatment targets using targeted therapies.

“Our results are very promising, as they show that we can potentially use existing modes of therapy, like immunotherapy to treat a subset of angiosarcoma patients,” said Clin Asst Prof Chan. “The next step will be to perform further molecular and immunological dissection of angiosarcomas to get more insight into how we can best use precision medicine to target these cancers.”

The findings, published in The Journal of Clinical Investigation in October of this year, is testament that research can directly improve patient care.

“Understanding angiosarcomas will allow oncologists to treat their patients in a more targeted way and it is also a confirmation that NCCS is continuously conducting cutting edge, translational research that has an impact on patients,” said Professor Soo Khee Chee, senior author of the study and Founding Director, NCCS.

The research team plans to further the study by investigating the molecular and genomic profiles of other sarcoma subtypes. This study is part of a plan to investigate rare cancers and establish NCCS as a leading global cancer centre.

Reference: Jason Yongsheng Chan, … , Bin Tean Teh, Khee Chee Soo, “Multiomic analysis and immunoprofiling reveal distinct subtypes of human angiosarcoma”, J Clin Invest. 2020;130(11):5833-5846. https://doi.org/10.1172/JCI139080. https://www.jci.org/articles/view/139080

Provided by Singhealth

About the National Cancer Centre Singapore

National Cancer Centre Singapore (NCCS) provides a holistic and multi-disciplinary approach to cancer treatment and patient care. We see close to 65 per cent of the public sector oncology cases, and they are benefiting from the sub-specialisation of our clinical oncologists.

To deliver among the best in cancer treatment and care, our clinicians work closely with our scientists who conduct robust cutting-edge clinical and translational research programmes which are internationally recognised. NCCS strives to be a global leading cancer centre, and shares its expertise and knowledge by offering training to local and overseas medical professionals.

http://www.nccs.com.sg

Researchers Identify Genomic And Immune Indicators That Predict Lethal Outcomes In Prostate Cancer (Medicine)

Prostate cancer is one of the most common cancers among men in the United States. One in nine men will be diagnosed during his lifetime. When diagnosed, a patient’s disease is graded from 1 to 5 based on how aggressive it is, with 5 being the most aggressive. Those with grades 4/5 disease are at the highest risk of poor outcomes or death from the disease; however, there are no immunologic or genomic indicators that can help physicians determine the best course of treatment for this group of patients.

Moffitt Cancer Center researchers, led by Kosj Yamoah, M.D., Ph.D., associate member and director of cancer disparities research in the departments of Radiation Oncology and Cancer Epidemiology, are hoping to change that. The team conducted studies to determine if genomic heterogeneity in tumors from grade 4/5 prostate cancer patients can be exploited to identify patient subsets that are at higher risk for lethal outcomes and that may benefit from targeted treatment strategies. Their results were published in the journal European Urology.

Their studies focused on transcriptomic interactions between the tumor immune content score and the Decipher score, a 22-gene classifier that provides a score predicting the probability that cancer will spread. The researchers analyzed data from 8,071 prostate cancer patient samples of any disease grade (6,071 prostatectomy and 2,000 treatment naïve) in the Decipher Genomics Resource Information Database (GRID) registry. Each patient sample was also given an immune content score (ICS) that was derived using the mean expression of 264 immune cell-specific genes.

The samples were separated into four distinct immunogenomic subsets based on their results: ICS high/Decipher high, ICS low/Decipher high, ICS high/Decipher low and ICS low/Decipher low. The researchers discovered that approximately 25% of all grade 4/5 patient samples were in the ICS high/Decipher high subset.

The ICS high/Decipher high patient samples were further evaluated for the association between immunogenomic subtypes and radiation response signatures. They found that the ICS high/Decipher high subset were genomically more radiosensitive, meaning these tumors would respond well to radiation therapy. This subset also had a higher abundance of T cells and monocyte/macrophages. However, the research team says further research is needed to unravel the biologic mechanisms of this association.

“Our results will aid in the subtyping of aggressive prostate cancer patients who may benefit from combined immune-radiotherapy modalities,” said Yamoah.

Although the findings may not be applicable to other tumor genomic platforms at this time, he said the Decipher GRID platform is used routinely in clinical care throughout the country and the results can be readily validated in various ongoing clinical trials and promises to be practice changing in the near future.

References: Kosj Yamoah et al, Novel Transcriptomic Interactions Between Immune Content and Genomic Classifier Predict Lethal Outcomes in High-grade Prostate Cancer, European Urology (2020). DOI: 10.1016/j.eururo.2020.11.038

Provided by H. Lee Moffitt Cancer Center & Research Institute

New Cancer-fighting Method Leverages The Mechanical Force of T Cells (Medicine / Oncology)

EPFL scientists have developed a cancer treatment method that destroys tumor cells using the mechanical force of our bodies’ own T cells. They have just completed a proof of concept for their novel immunotherapy approach.

Mechanical force of T cell automatically breaks the DNA – thereby releasing the drug. Credit: my SCImage / 2020 EPFL

Immunotherapy is a promising weapon in the fight against cancer. It has proven to be much more effective than chemotherapy and radiotherapy in treatment of some cancers. The drawback is that it manages to cure only about 20% of patients; the remaining 80% do not respond to this kind of treatment. “But if doctors use a stronger form of immunotherapy in order to treat more people, it could become toxic for patients and lead to side effects,” says Li Tang, the head of EPFL’s Laboratory of Biomaterials for Immunoengineering within the School of Engineering. His team of scientists is developing a method that focuses immunotherapy only on tumor cells, so that the treatments are more effective and less harmful to the body as a whole. Their approach has just been published in Materials Horizons as a cover story.

A T-cell booster

T cells are the cells in our immune system that destroy cancer cells. Immunotherapy involves administering drugs to make those cells more powerful. “When T cells come into contact with cancer cells, they destroy the cells by releasing chemical compounds as well as applying mechanical force,” explains Tang. For immunotherapy to work with limited patient toxicity, the drugs have to be delivered precisely during this step. Existing immunotherapy treatments use biochemical signals to control the drug-release process. “But that’s a blunt tool because doctors have no control over how a drug diffuses within the body,” says Tang. To get around this problem, his team developed a method that uses a biomechanical signal, which means that drugs are released only when T cells come into contact with cancer cells. “The T cells’ mechanical force is only triggered when they are touching their target cells,” he says.

Releasing drugs by breaking DNA

Tang’s method involves using a silica microparticle that contains lots of tiny holes. The drug is placed inside the holes, which are then capped with double-strand DNA. “We chose DNA because T cells are able to break the double-helix strands,” says Tang. When a T cell comes into contact with the microparticle, its mechanical force automatically breaks the DNA – thereby releasing the drug. “For now we’ve only just completed the proof of concept stage. We’ve shown that our idea works, but we need to develop the technology further before we can start conducting clinical trials,” says Tang. More specifically, his team will work on improving the system’s sensitivity, shrinking the microparticle down to the nanometric scale, and trying it out with different drugs. Tang eventually hopes to develop a dual-agent process whereby the T cell attaches to a nanoparticle that in turn comes into contact with the cancer cell. That means the drug would be released by the T cell, making it more effective in destroying tumors.

Tang’s lab is the first to use the mechanical force of T cells in immunotherapy applications. “If our discovery increases the percentage of patients who respond to immunotherapy by even one percentage point, then we’ll have met the challenge,” he says.

Li Tang receives the Emerging Investigator Award

The scientific journal Materials Horizons awarded its Emerging Investigator Award to Professor Li Tang for his publication entitled: “T cell force-responsive delivery of anticancer drugs using mesoporous silica microparticle ». The Editorial Board select every month, from a list of eligible articles, an early-career researcher in materials science who is identified as having the potential to influence future directions in the field. “My lab is doing innovative research at the interface of cancer immunotherapy and material engineering. This award is a great recognition for the work done by my team”, says the professor.

Funding

The Swiss National Science Foundation and European Research Council.

References: Kewen Lei a and Li Tang, “T cell force-responsive delivery of anticancer drugs using mesoporous silica microparticles”, Material Horizons, 2020. https://pubs.rsc.org/en/content/articlelanding/2020/MH/D0MH01285H#!divAbstract

Provided by EPFL