Tag: pancreatic cancer

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Preventing Unnecessary Pancreatic Cancer Surgery

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Pancreatic cancer. Credit: Scientific Animations CC BY-SA 4.0

Pancreatic cysts are fluid-filled sacs that can form in the pancreas. Some remain benign, while others have the potential to develop into pancreatic cancer. A recent study, which followed 257 patients in Japan for an average of five years, showed that the presence or absence of invasive nodules in pancreatic cysts is key to assessing whether these cysts are benign or cancerous.

The findings, published in the journal Annals of Surgery, may help patients diagnosed with a high risk of pancreatic cancer to avoid unnecessary surgery.

Pancreatic cancer is one of the most life-threatening and rapidly growing cancers. Pancreatic cysts, known as pancreatic intraductal papillary mucinous neoplasms (IPMNs), are gaining attention as one of the precursors of the cancer that can be identified by radiological imaging. In this context, patients diagnosed with pancreatic cysts are referred for further evaluation, and if they meet the criteria for being at particularly high risk of developing cancer, called high-risk stigmata, they are often recommended for surgery.

However, it was not clear whether all patients who met the criteria would need to undergo surgery. “In fact, among patients who underwent surgery, there were a number of cases where pathological examination results showed that their IPMNs were still benign and had not progressed to cancer,” explained Ryohei Kumano from Nagoya University, the first author of the study. “Pancreatic surgery is a significant burden for patients, so we wanted to find a more accurate way to diagnose whether their IPMNs are benign or cancerous in order to avoid unnecessary surgery.”

A research group consisting of Professor Hiroki Kawashima and Dr Kumano from Nagoya University Graduate School of Medicine, Professor Eizaburo Ohno from Fujita Health University, and their colleagues focused on the presence or absence of invasive nodules in 257 IPMN patients with high-risk stigmata. The researchers evaluated the prognosis of the patients with and without these nodules.

Invasive nodules, solid growths within cysts that have begun to invade surrounding tissues, are difficult to detect with a conventional method that uses a CAT scan. Therefore, the researchers instead used contrast-enhanced endoscopic ultrasound, which is thought to detect invasive nodules more accurately.

To track the prognosis of patients with and without invasive nodules between surgical and non-surgical groups, the researchers followed them for an average of about five years (ranging from 6 months to 24 years, depending on the patient).

The results showed that the presence or absence of invasive nodules had a significant impact on their survival. For patients with invasive nodules, undergoing surgery had a positive effect on improving their survival. On the other hand, most patients without invasive nodules had a favorable outcome even without surgery. 

Endoscopic ultrasound (EUS) enables differentiation between non-invasive and invasive nodules within IPMN, providing crucial information for surgical decision making. (Credit: Ryohei Kumano) 

In this study, a total of 21 patients who did not have invasive nodules opted for clinical monitoring instead of surgery. Notably, their five-year survival rates were 84.7% for overall survival and 100% for disease-specific survival.

In addition, in patients at higher risk for surgery, such as the elderly, there was little difference in survival rates between patients who underwent surgery and those who did not, if they had no invasive nodules. “Avoiding surgery, especially in such patients, seems to be a reasonable treatment strategy, given the fact that pancreatic surgery is highly invasive, carries a high risk of complications, and requires a long recovery period,” Kumano said.  

“We expect that our findings will contribute to future clinical guidelines for IPMNs, leading to more accurate cancer diagnosis and optimised treatment selection.”

Source: Nagoya University

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Research Identifies the Key to Pancreatic Cancer’s Extreme Aggressiveness

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Pancreatic cancer. Credit: Scientific Animations CC BY-SA 4.0

Pancreatic cancer is one of the most aggressive cancers and has one of the lowest survival rates: only 10% after five years. One of the factors contributing to its aggressiveness is its tumour microenvironment, known as the stroma, which makes up the bulk of the tumour mass and consists of a network of proteins and different non-tumour cells. Among these, fibroblasts play a key role, helping tumour cells to grow and increasing their drug resistance.

Now, a study led by researchers from the Hospital del Mar Research Institute and other institutions has identified a new key factor contributing to this feature of pancreatic cancer: a previously unknown function of Galectin-1 protein inside the nuclei of fibroblasts. This discovery, published in the journal PNAS, offers new insights into the role of these cells in the progression of pancreatic cancer.

“The stroma is considered a key component in the aggressive nature of pancreatic cancer, as it interacts with tumour cells, protects them, and hinders the action of drugs. Moreover, stromal cells, particularly fibroblasts, produce substances that support tumour growth and dissemination,” explains Dr Pilar Navarro, coordinator of the Cancer Molecular Targets Research Group at the Hospital del Mar Research Institute and IIBB-CSIC-IDIBAPS. Until now, fibroblasts were known to secrete Galectin-1, a protein with pro-tumour properties. This study, however, shows that the molecule is also located inside fibroblasts-specifically in their nuclei-where it plays a key role in gene expression regulation.

The presence of this molecule activates fibroblasts, making them support tumour cell development. The researchers also discovered that “Galectin-1 can regulate gene expression in these cells at a highly specific level without altering the DNA sequence, through epigenetic control. One of the genes it regulates is KRAS, which plays a critical role in pancreatic tumours,” explains Dr Navarro. This gene is also present in tumour cells in 90% of patients, though in this case it is mutated. It is considered one of the main drivers of uncontrolled growth and tumour aggressiveness.

Designing new strategies

The team behind the study had previously identified the prominent role of Galectin-1 in pancreatic cancer. The newly discovered functions now pave the way for developing new strategies to tackle this type of tumour. “Until now, efforts have focused on inhibiting Galectin-1 secreted by the stroma surrounding the tumour. Now, we see that we also need to block the protein inside the fibroblast nuclei,” says Dr Neus Martínez-Bosch, researcher at the Hospital del Mar Research Institute. “We need to find new inhibitors that work inside fibroblasts, not just on the protein they secrete,” she adds.

To carry out the study, researchers worked with tissue samples from pancreatic cancer patients, allowing them to analyse the presence and function of Galectin-1 in fibroblast nuclei. They also performed in vitro experiments with human fibroblast cell lines, investigating the effects of inhibiting both the protein and the KRAS gene, and observed deactivation of these cells-effectively halting their cooperation with tumour cells.

Dr. Judith Vinaixa, also a researcher at the Hospital del Mar Research Institute and first author of the study, highlights the importance of these results: “We have confirmed the key role of Galectin-1 in the fibroblast cell nucleus, where it regulates the expression of multiple genes critical for cell behaviour.”. Dr. Gabriel Rabinovich, researcher at IBYME (CONICET) and the CaixaResearch Institute, adds: “The next steps will involve exploring therapeutic combinations that inhibit both extracellular and intracellular Galectin-1. This protein also participates in key processes such as blood vessel formation and resistance to immunotherapy. Therefore, this strategy becomes particularly relevant given the multiple antitumoral effects of Galectin-1 inhibition.”

Source: IMIM (Hospital del Mar Medical Research Institute)

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New Blood Test for Pancreatic Cancer Exceeds Gold Standard

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Pancreatic cancer. Credit: Scientific Animations CC BY-SA 4.0

A recent double-blinded, peer-reviewed analysis published in Cancer Letters revealed that an experimental test for pancreatic cancer correctly identified 71% of lab samples compared to only 44% correctly identified by the current gold-standard test.

An experimental blood test for pancreatic cancer that was developed by teams led by VAI Professor Brian Haab, PhD, and Randall E. Brand, MD, a physician-scientist and professor of medicine at the University of Pittsburgh, created the test. This evaluation by a commercial laboratory is an important milestone toward making the test available for patients.

Before the new test can be used by doctors to diagnose cancer, it must undergo clinical validation. During this process, a CLIA-accredited diagnostics laboratory adapts the experimental test into a version that reliably works under the strict conditions in a clinical lab. CLIA is a rigorous federal standard that ensures lab quality.

“Validation studies are essential for transforming a test developed in an academic lab into one that is used to diagnose real people,” Haab said. “For a person being evaluated for pancreatic cancer, the stakes are high. Validation studies ensure that new tests work as intended.”

The new test works by detecting two sugars — CA199.STRA and CA19-9 — that are produced by pancreatic cancer cells and escape into the bloodstream. CA19-9 is the current gold-standard biomarker for pancreatic cancer. Haab’s lab identified CA199.STRA as a cancer biomarker and developed the technology to detect it.

The new test also greatly reduced the number of false negatives while maintaining a low false positive rate, according to the recent analysis. Low rates of false positives and false negatives are important because they reflect the test’s ability to correctly identify the presence or absence of cancer.

Clinical validation of the test will be conducted by ReligenDx, a CLIA-accredited diagnostics lab based in Pennsylvania. The process is expected to take two years.  

If successful in clinical validation, Haab envisions the test being used in two main ways: 1. Catching pancreatic cancer more quickly in people at high risk of the disease, which would enable earlier treatment and 2. Monitoring progression and treatment response in people diagnosed with pancreatic cancer.

Source: Van Andel Research Institute

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Adding Vitamin C to Chemotherapy Doubles Pancreatic Cancer Survival Time

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Pancreatic cancer. Credit: Scientific Animations CC BY-SA 4.0

Results from a randomised, phase 2 clinical trial show that adding high-dose, intravenous (IV) vitamin C to chemotherapy doubles the overall survival of patients with late-stage metastatic pancreatic cancer from eight months to 16 months. 

“This is a deadly disease with very poor outcomes for patients. The median survival is eight months with treatment, probably less without treatment, and the five-year survival is tiny,” says Joe Cullen, MD, University of Iowa professor of surgery, and radiation oncology, and senior author of the study. “When we started the trial, we thought it would be a success if we got to 12 months survival, but we doubled overall survival to 16 months. The results were so strong in showing the benefit of this therapy for patient survival that we were able to stop the trial early.” 

The findings, published in Redox Biology, mark another success for high-dose, intravenous vitamin C, which has overcome many hurdles in the almost 20 years UI researchers have persevered to demonstrate its benefit for cancer patients. 

“We’ve had ups and downs of course, but this is a culmination of a lot of people’s hard work,” says Cullen who also is a member of UI Health Care Holden Comprehensive Cancer Center. “It’s really a positive thing for patients and for the University of Iowa.”

Increased survival, improved quality of life

In the study, 34 patients with stage 4 metastatic pancreatic cancer were randomized to receive either standard chemotherapy (gemcitabine and nab-paclitaxel), or the chemotherapy plus infusions of high-dose vitamin C. The results showed that average overall survival was 16 months for the patients receiving the chemotherapy plus vitamin C, compared to eight months for the patients getting just chemotherapy. In addition, progression free survival was extended from four months to six months. 

“Not only does it increase overall survival, but the patients seem to feel better with the treatment,” Cullen says. “They have less side effects, and appear to be able to tolerate more treatment, and we’ve seen that in other trials, too.” 

The new study is not the only evidence of the benefit of including IV vitamin C as part of cancer treatment. Earlier this year, the results of another UI phase 2 clinical trial in patients with glioblastoma, a deadly form of brain cancer, were published. That study also showed a significant increase in survival when high-dose, IV vitamin C was added to standard of care chemotherapy and radiation. Cullen was also part of that trial along with his colleague Bryan Allen, MD, PhD, UI professor and head of radiation oncology. 

A third phase 2 trial in non-small cell lung cancer is still underway, with results expected within the year. All three trials were funded by a 2018 grant from the National Cancer Institute (NCI). 

“This NCI funding was incredibly important for us to conduct these phase 2 trials and obtain these really encouraging results. Our aim is to show that adding high-dose, IV vitamin C, which is very inexpensive and very well tolerated, can improve treatment for these cancers that are among the deadliest affecting the U.S. population,” Cullen adds. 

A long journey to clinical trials

Cullen, Allen, and their colleagues at UI Health Care have been researching the anti-cancer effect of high-dose, IV vitamin C for decades. Their work revealed a critical difference between intravenous and oral vitamin C. Intravenous vitamin C administration produces very high levels in the blood, which cannot be achieved with oral delivery. These high concentrations result in unique chemical reactions within cancer cells that render the cell more vulnerable to chemo- and radiation therapies. 

Cullen notes that despite scepticism towards vitamin C as a cancer therapy, the results he and his colleagues have obtained, from basic science findings to understand the biological mechanisms at work, through the various clinical trials, have been highly encouraging and robust. 

“Through every step of the process, it continued to improve. We did it in cells, it worked great. We did it in mice, it worked great. Then our phase one trials looked very promising. So, the progression has just been phenomenal, really,” Cullen says. “For example, in one of our phase 1 trials for pancreatic cancer, where we combine high-dose, IV vitamin C with radiation, we still have three long-term survivors. They’re out nine years at this point, which is far beyond the typical survival range.” 

Source: University of Iowa Health Care

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Can Metabolic-bariatric Surgery help Prevent Pancreatic Cancer in Obesity?

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Sleeve gastrectomy. Credit: Scientific Animations CC4.0

Obesity and type 2 diabetes are risk factors for various malignancies, including pancreatic cancer, which has a high death rate. A new analysis in Diabetes/Metabolism Research and Reviews suggests that metabolic-bariatric surgery may lower the risk of developing pancreatic cancer in people with obesity, especially in those who also have type 2 diabetes.

In the systematic review and meta-analysis, investigators identified 12 relevant studies that explored the effects of metabolic-bariatric surgery on pancreatic cancer incidence, with a total of 3 711 243 adults with obesity. Surgery was associated with a 44% reduction in pancreatic cancer risk among individuals with obesity but without type 2 diabetes and a 79% risk reduction in those with both obesity and type 2 diabetes.

“Metabolic-bariatric surgery not only has beneficial effects on obesity and type 2 diabetes but also may play a crucial role in reducing the risk of pancreatic cancer in these individuals,” said corresponding author Angeliki M. Angelidi, PhD, of the Broad Institute of MIT and Harvard. “These findings underscore the need for further research to elucidate the underlying mechanisms and understand the full spectrum of health benefits of metabolic-bariatric surgery beyond weight loss.”

Source: Wiley

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How Cancer Reprograms Immune Cells to Join the Enemy

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Squamous cancer cell being attacked by cytotoxic T cells. Image by National Cancer Institute on Unsplash

Cancer has been described as “a wound that does not heal,” implying that the immune system is unable to wipe out invading tumour cells. A new discovery reported in PNAS confirms that a key molecule can reprogram immune cells into turncoats that promote cancer growth.

Studying the behaviour of these “pro-tumour” immune cells is important because they could be targets for therapies that block their harmful activity, said Minsoo Kim, PhD, corresponding author of the study and a research leader at the Wilmot Cancer Institute.

Kim led a team of scientists investigating the dynamic interactions that occur between cells in the tumor environment, and the underlying factors that cause the harmful transformation of immune cells from good to bad.

They found that PAF (platelet-activating factor) is the key molecule that controls the destiny of the immune cells. PAF not only recruits cancer-promoting cells, but it also suppresses the immune system’s ability to fight back. In addition, they found that multiple cancers rely on the same PAF signals.

“This is what could be most significant,” said Kim. “Because if we find a treatment that could interfere with PAF, it could potentially apply to many types of cancer.”

Much of the team’s work focused on pancreatic cancer cells. It is one of the most deadly cancers, with a five-year survival rate of about 12%, and is notoriously hard to treat because pancreatic tumours are surrounded by a toxic stew of proteins and other tissues that protect the cancer from the immune system’s natural role to attack invaders. They also studied breast, ovarian, colorectal, and lung cancer cells, using advanced 3D imaging technology to watch the behaviour of immune cells as they swarmed to the cancerous region.

Source: University of Rochester Medical Center

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Faster Detection of Pancreatic Cancer

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Glycopeptide probes detect tumour-associated antibodies in blood samples

Pancreatic cancer. Credit: Scientific Animations CC BY-SA 4.0

Pancreatic cancer is one of the most lethal forms of cancer, primarily because it is usually diagnosed very late. Current markers are too insensitive and unspecific for early detection screenings. In the journal Angewandte Chemie, a research team has now introduced a new method that could lead to a significantly more precise and reliable diagnosis. It is based on the selective detection of specific antibodies in blood samples.

Tumours produce certain proteins (tumour-associated antigens) that draw the attention of our constantly “patrolling” immune system and trigger an immune response. As a consequence, antibodies directed against the tumours (tumour-associated autoantibodies) are formed, circulating in the blood at very early stages of the disease – which makes them useful for early detection. An international team led by Roberto Fiammengo and Giovanni Malerba at the University of Verona (Italy) as well as Alfredo Martínez at the Center for Biomedical Research of La Rioja (Logroño, Spain) and Francisco Corzana at the Universidad de La Rioja, has now developed an approach to diagnostic testing for pancreatic cancer that is based on the detection of such special tumour-associated autoantibodies.

They chose to use autoantibodies directed against the tumour-associated form of mucin-1 (TA-MUC1). Mucin-1 is a heavily glycosylated protein (a protein with sugar components) that occurs, for example, in glandular tissue. In many types of tumours, including pancreatic cancer, it is found in significantly elevated concentrations. In addition, the pattern of glycosylation is different from the normal form. The team’s goal was to detect autoantibodies that are directed specifically against TA-MUC1 and are a clear indicator of pancreatic cancer.

Based on structural analyses and computer simulations of known antibodies against TA-MUC1 (SM3 and 5E5), the team designed a collection of synthetic glycopeptides that mimic different segments (epitopes) of TA-MUC1. They also made unnatural modifications to increase the chances of identifying autoantibody subgroups indicative of the disease. The team immobilised these model antigens on gold nanoparticles achieving probes suitable for a serological assay (dot-blot assay). The diagnostic assay was validated with real samples from patients with pancreatic cancer and a healthy control group. Some of the nanoparticle probes could differentiate very well between samples from diseased and healthy individuals demonstrating they detected tumour associated autoantibodies. Notably, these specific autoantibodies displayed significantly better correct positive/false positive ratios than current clinical biomarkers for pancreatic cancer.

Probes with smaller glycopeptide antigens that correspond to only a single epitope, gave better results than larger probes that mimic multiple epitopes – an advantage for easier synthetic production. A short glycopeptide with an unnatural modification to its sugar component was found to be particularly effective for the detection of discriminating autoantibodies. This new structure-based approach could help in the selection of autoantibody subgroups with higher tumour specificity.

Source: Wiley

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Pancreatic Cancer Drug is Promising Against Most Aggressive Medulloblastoma Subtype

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Pancreatic cancer. Credit: Scientific Animations CC BY-SA 4.0

A drug that was developed to treat pancreatic cancer has now been shown to increase symptom-free survival in preclinical medulloblastoma models – all without showing signs of toxicity. Survival rates for medulloblastoma vary according to which one of the four subtypes a patient has, but the worst survival rates of about 40%, are for Group 3. The research, published in the Journal of Clinical Investigation, focused on this most aggressive subtype.

Jezabel Rodriguez Blanco, PhD, an assistant professor at Medical University of South Carolina, led the research. Her work focused on the drug triptolide, which is extracted from a vine used in traditional Chinese medicine, and its water-soluble prodrug version, Minnelide. A prodrug is an inactive medication that the body converts into an active drug through enzymatic or chemical reactions.

MYC is an oncogene, or gene that has the potential to cause cancer. MYC is dysregulated, or out of control, in about 70% of human cancers, and it shows up in much higher levels in Group 3 medulloblastoma than in the other medulloblastoma subgroups. Despite its well-known role in cancer, this oncogene historically has been considered impossible to target with drugs.

Despite its poor druggability, previous research in other cancers had shown that triptolide and its derivatives had the ability to target MYC. When Blanco was still a postdoctoral fellow at the University of Miami, her mentor, David Robbins, PhD, attended a presentation by the research team that showed that the more copies of MYC that a tumour has, the better that triptolide works.

“He came to me, and he told me, ‘You know, as Group 3 medulloblastoma has many MYC copies, you should get some research models and try the drug,” Blanco recalled. She started the project from scratch. “I started talking to people, getting cell lines and animal models, learning how to propagate them, getting the drug, using it.” 

Blanco received initially received grants to on the Group 3 research, and continued it as a side project. She knew how well triptolide was working in these hard-to-treat tumours, and she did not want her initial results to fall through the cracks.

Determining the mechanism of action has been the most challenging part of the project, she noted, due to the drug’s multiple effects, and there could still be additional mechanisms beyond those that Blanco identified.

“It was affecting MYC gene expression by affecting the RNA pol II activity, and then it was affecting how long the protein lasts. So, the fact that it’s working through two different mechanisms on this oncogene may explain why it’s so effective in tumours that have extra copies of MYC,” she said, explaining that RNA polymerase II is a protein that helps to make copies of DNA instructions, which are used to produce proteins in the cell.

Despite the challenges of narrowing down the mechanism of action specific to the cancer, it was quite clear that however it worked, it did work, she said.

The efficacy was 100 times higher in the Group 3 tumours with extra MYC copies than in the Sonic Hedgehog tumours with normal levels of MYC, she said. She found that Minnelide reduced tumour growth and the spread of cancer cells to the thin tissues that cover the brain and spinal cord, called leptomeninges. It also increased the efficacy of the chemotherapy drug cyclophosphamide, which is currently used in treatment.

Blanco decided to move forward with publication rather than waiting to write a manuscript that answered all possible questions. Knowing that most parents whose children receive a Group 3 medulloblastoma diagnosis will lose their child in less than two years was the incentive she needed to push this work out.

“There was a point at which I could not hold these data anymore because it was working so well that it needed to go out,” she said. “The preclinical models were showing such a nice efficacy that it was like, ‘OK, I cannot keep on holding this work, digging deeper into the mechanism of action because the kids that have Group 3 medulloblastoma are dying while we are doing those experiments.”

Minnelide has been tested or is currently in testing in phase I and phase II clinical trials of adults with different types of cancer, including pancreatic cancer, where it showed some efficacy.

Blanco is hopeful that, with this new research on Group 3 medulloblastoma, a clinical trial for children with this disease can be launched.

Her paper is dedicated to the memory of Insley Horn, a 9-year-old Charleston girl who succumbed to one of these aggressive brain tumours. Research, Blanco said, is the only tool we have to prevent the loss of lives like Insley’s.

Source: Medical University of South Carolina

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Chemotherapy Before Surgery Extends Survival in Pancreatic Cancer

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Pancreatic cancer. Credit: Scientific Animations CC BY-SA 4.0

Patients with pancreatic cancer who received chemotherapy both before and after surgery experienced longer survival rates than would be expected from surgery followed by chemotherapy, according to a new study from researchers at Yale School of Medicine.

The study, published June 20 in JAMA Oncology, included patients with pancreatic ductal adenocarcinoma (PDAC), an aggressive cancer with a high mortality rate which accounts for 90% of pancreatic cancers. The researchers say these findings are encouraging for the 15 to 20% of patients with operable pancreatic cancer.

The single-arm Phase II trial evaluated a modified form of the chemotherapy treatment FOLFIRINOX. This combination treatment consisting of leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin received US Food and Drug Administration approval in 2011 as a first-line treatment for patients with metastatic pancreatic cancer. Patients in the trial received six cycles of the modified FOLFIRINOX before surgery, followed by an additional six cycles of the chemotherapy treatment after surgery. The modified regimen consisted of slightly lower doses of FOLFIRINOX to improve tolerability, which was previously shown in a 2016 publication not to impact outcomes negatively.

Of the 46 patients who started the modified treatment, 37 completed all six cycles of chemotherapy before surgery and 27 had successful tumour removal operations. For all enrolled patients, the 12-month progression-free survival rate was 67%, indicating significant progress in controlling the disease. Furthermore, 59% of all patients lived at least two years after completing the full chemotherapy treatment plan and surgery.

The study was the first of its kind for patients with PDAC when senior author and Yale Cancer Center member Jill Lacy, MD, started it in 2014. The study goal had been a 12-month progression-free survival rate of at least 50% of patients.

“When the study launched, even with operable pancreatic cancers, 90% of patients were still relapsing and dying from their cancer eventually,” said Michael Cecchini, MD, the first author of the study. “We sought to move chemotherapy up in their treatment regimen and give it before surgery to see if we could improve the outcome for our patients.”

The study used advanced techniques to monitor the progress of treatment, including analysing circulating tumour DNA (ctDNA) and using the cancer biomarker keratin 17 to help predict outcomes. For example, patients with detectable ctDNA four weeks post-surgery had significantly worse progression-free survival than those who had no detectable ctDNA.

Cecchini said larger randomised clinical trials are needed to continue to investigate the role of FOLFIRINOX before surgery for patients with operable PDAC.

“I think even though there have been changes in standard of care for patients with this aggressive pancreatic cancer type, we have here very promising data to justify a larger study,” said Cecchini.

Source: Yale School of Medicine

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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