Tag Archives: #pancreaticcancer

MasSpec Pen Shows Promise in Pancreatic Cancer Surgery (Medicine)

A diagnostic tool called the MasSpec Pen has been tested for the first time in pancreatic cancer patients during surgery. The device is shown to accurately identify tissues and surgical margins directly in patients and differentiate healthy and cancerous tissue from banked pancreas samples. At about 15 seconds per analysis, the method is more than 100 times as fast as the current gold standard diagnostic, Frozen Section Analysis. The ability to accurately identify margins between healthy and cancerous tissue in pancreatic cancer surgeries can give patients the greatest chance of survival.

The results, by a team from The University of Texas at Austin and Baylor College of Medicine, are published this week in the Proceedings of the National Academy of Sciences.

“These results show the technology works in the clinic for surgical guidance,” said Livia Schiavinato Eberlin, an assistant professor of chemistry at UT Austin who leads the team that invented the pen, in collaboration with James Suliburk, head of endocrine surgery at Baylor. “Surgeons can easily integrate the MasSpec Pen into their workflow, and the initial data really supports the diagnostic accuracy we were expecting to achieve.”

The most common type of pancreatic cancer, pancreatic ductal adenocarcinoma, spreads rapidly and is highly lethal, with a five-year survival rate of 9% for all stages. The most effective treatment option is surgical removal of the tumor.

Cancer surgeons face a dilemma: It’s often difficult to tell good tissue from bad. If any cancerous tissue is left behind, there’s a risk the tumor will regrow, potentially requiring the patient to undergo additional rounds of surgery, radiation or chemotherapy, and decreasing the chances of survival. On the other hand, removing too much healthy tissue, especially from vital organs, can also compromise a patient’s health. Determining the margin between healthy and cancerous tissue is critical to a successful surgery.

MasSpec Pen in the Operating Room
Dr. James Suliburk, head of endocrine surgery at Baylor College of Medicine, using the MasSpec Pen during a thyroid surgery. Credit: James Suliburk/Baylor College of Medicine

For this study, the investigators first used the MasSpec Pen to analyze 157 banked human pancreatic tissues to develop and evaluate the technology in the laboratory for pancreatic cancer. Then, the investigators moved the system to the operating room at Baylor St. Luke’s Medical Center in Houston, which is affiliated with Baylor College of Medicine, where the surgeons tested the technology in 18 pancreatic surgeries. The pen has been tested in more than 150 human surgeries to date, including for breast and thyroid, and results of those additional tests will be submitted for publication soon.

Mary King, a graduate student and the study’s first author, and other members of the Eberlin research group operated the mass spectrometer during surgery.

A typical surgery to remove a pancreatic tumor can take from 6 to 12 hours.

“Surgery of the pancreas is a very complex and detailed surgery that requires numerous intraoperative decisions over several hours that can have long-lasting effects on oncologic outcomes for patients with pancreas cancer,” said George Van Buren, M.D., associate professor of surgery at Baylor and one of the surgeons who performed operations during the experiment. “The MasSpec Pen technology opens the door for real-time, precision medicine to be performed in the operating room at a level that has never been seen before.”

These are the first published results of intraoperative use of the MasSpec Pen, in other words, on intact or just-removed tissue from patients during surgery. Preclinical research published about the technology in 2017 led to widespread enthusiasm and interest, including from writers in Hollywood who adapted the idea for a segment on the television program “Grey’s Anatomy.”

The researchers plan eventually to submit the design to the U.S. Food and Drug Administration for approval as a medical device.

Banked tissue samples were provided by the Cooperative Human Tissue Network and Baylor.

This work was supported in part by the National Cancer Institute of the National Institutes of Health, and by the Gordon and Betty Moore Foundation. Livia Eberlin receives support for research in her lab from the Cancer Prevention and Research Institute of Texas.

King, Suliburk, Eberlin, Jialing Zhang and others are inventors in US Patent No. 10,643,832 and/or in other patent applications related to the MasSpec Pen technology licensed by The University of Texas to MS Pen Technologies Inc. and its subsidiary Genio Technologies. Zhang, Suliburk and Eberlin are shareholders in MS Pen Technologies Inc.

The University of Texas at Austin is committed to transparency and disclosure of all potential conflicts of interest. The university investigator who led this research, Livia Schiavinato Eberlin, has submitted required financial disclosure forms with the university. Eberlin is a co-founder with an equity stake in MSP Technologies, an inventor-led startup formed to commercialize the MasSpec Pen technology, owned by the university.

Featured image: Jialing Zhang demonstrates using the MasSpec Pen on a human tissue sample. Photo credit: Vivian Abagiu/Univ. of Texas at Austin.


NOTES TO REPORTERS:

1) When the study publishes, it will be available at: https://doi.org/10.1073/pnas.2104411118

2) Images and videos associated with this news release are here: https://utexas.box.com/s/977b13ex0stdsovi7cgud6z5561a2556


Provided by University of Texas at Austin

Scientists Reveal a New Therapeutic Vulnerability in Pancreatic Cancer (Medicine)

Lowering levels of a hormone called PTHrP can prevent metastases and improve survival in mice with pancreatic cancer and could lead to a new way to treat patients, according to a study(link is external and opens in a new window) from cancer researchers at Columbia University Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center and with collaborators at the University of Pennsylvania.

When patients are first diagnosed with pancreatic cancer, the cancer usually has spread to other organs. Because of these metastases, nearly all patients will succumb to their cancer within one year of diagnosis, but no drugs exist to prevent metastasis.

In an effort to find treatments, cancer researchers at Columbia—led by Anil K. Rustgi, MD, and Jason R. Pitarresi, PhD—investigated a hormone called PTHrP. Although PTHrP (parathyroid hormone-related protein) is often highly active in patients with pancreatic cancer, its role in metastasis was unclear.

Loss of PTHrP dramatically improves survival in mice

The researchers first manipulated the levels of PTHrP in mice with pancreatic cancer. Elimination of PTHrP from mice—with genetic engineering or with an antibody that targets the hormone—not only eliminated metastasis and enhanced overall survival, but also dramatically reduced the size of the initial tumors in the pancreas.

Even in mice with a highly aggressive form of pancreatic cancer, the increase in survival was dramatic, increasing from a median of 111 days to 192 days, with near complete elimination of metastases. The 73% increase in survival, the researchers say, is one of the largest observed in mice with this type of pancreatic cancer, which closely resembles human cancers.

The striking results with mice led the researchers to test the anti-PTHrP antibodies in human pancreatic cancer cells. The results from these experiments were also encouraging: Among 3D organoids derived from pancreatic cancer patients under an IRB-approved protocol, anti-PTHrP antibodies greatly reduced growth and viability of the cells.

Organoids of human pancreatic cancer treated with anti-PTHrP antibodies (right) vs untreated (left). Image from Jason Pitarresi, PhD. © CUIMC

Two-pronged attack on cell growth and metastasis

Targeting PTHrP attacks pancreatic cancer in two ways, the researchers say. It reduces the ability of the tumor cells to transition from an epithelial state to a mesenchymal state, which is necessary for the creation of new metastases. And targeting PTHrP also prevents the growth of primary and secondary tumors.

“We think these findings provide a strong rationale for further developing anti-PTHrP therapy towards clinical trials,” says Rustgi, who adds that the antibody used in the study has the potential to be used in people and credits Richard Kremer, MD, PhD, of McGill University for developing the antibodies. 

“We are hopeful that a drug targeting PTHrP could be used to treat most patients with pancreatic cancer,” he says, “because the vast majority have tumors with high levels of PTHrP. There is the potential application to other cancers as well.”

Potential with other cancers

The researchers originally began investigating PTHrP because its gene is often amplified when another nearby gene, KRAS, is amplified. KRAS has long been recognized as a cancer-promoting gene in pancreatic and other cancers. 

For patients, that may mean anti-PTHrP therapies may have potential in other cancers that are known to harbor KRAS amplifications.

For researchers, the finding also suggests a wider search for cancer-causing genes is needed.

“We feel that PTHrP may have been previously overlooked as a mere passenger gene co-amplified with KRAS, but our study shows that PTHrP has its own tumor-promoting functions,” Pitarresi says. “It suggests other so-called ‘passenger’ genes may have bigger roles in cancer than we initially thought and should be examined more closely.”  Rustgi notes “it might open up for combinatorial therapies of targeting the KRAS pathway with an antibody to PTHrP.”


Provided by Columbia University Irving Medical Center

Study Identifies Biomarker That Could Help to Diagnose Pancreatic Cancer (Medicine)

Researchers from Queen Mary University of London have identified a protein that could be used to aid in the diagnosis of pancreatic cancer

Researchers from Queen Mary University of London have identified a protein that could be used to aid in the diagnosis of pancreatic cancer.

Findings from the new study suggest that a protein called pentraxin 3 (PTX3) may be a specific diagnostic biomarker – or biological measure – for pancreatic cancer, with the ability to differentiate pancreatic cancer from other non-cancerous conditions of the pancreas.

The research was published today in npj Precision Oncology, and primarily funded by the Pancreatic Cancer Research Fund, Barts Charity and Cancer Research UK.

PTX3 levels elevated in patients with pancreatic cancer

In the study, researchers measured PTX3 levels in serum blood samples from patients with pancreatic ductal adenocarcinoma (PDAC) – the most common type of pancreatic cancer – and from healthy volunteers or patients with other non-cancerous conditions of the pancreas, and found levels of the protein to be significantly higher in the serum samples of those with PDAC.

Patients with PDAC had notably higher serum PTX3 levels than those with intra-ductal papillary mucinous neoplasm or chronic pancreatitis – two non-cancerous conditions that often present with similar symptoms to PDAC, making a definitive diagnosis more difficult.

Hemant Kocher, Professor of Liver and Pancreas surgery at Queen Mary University of London and consultant at Barts Health NHS Trust, who led the study, said: “In the clinic, computerised tomography (CT) scanning is usually used in the diagnosis of pancreatic cancer. Although CT can detect the presence of a pancreatic mass, it cannot distinguish pancreatic cancer from other non-cancerous pancreatic diseases. This poses frequent diagnostic dilemmas in clinical practice, and there are currently no clinically applicable biomarkers for the early detection of PDAC.”

“The findings from our study suggest that PTX3 could be used as a biomarker to improve PDAC diagnosis, and warrants further testing to determine whether it could aid early detection of PDAC in the clinic.”

“Thanks to the generous donation of samples from patients in London, Verona and Milan, our study represents a clinically relevant cohort with translational significance. This research has been made possible by an international collaboration of cancer biologists, surgeons, oncologists, clinical triallists, statisticians and bio-banking specialists, with funding from a number of sources.”

Blood samples from 267 donors were analysed, including 140 samples from patients with PDAC, which had been donated to tissue banks in London, Verona and Milan. Samples in London were from the Pancreatic Cancer Research Fund Tissue Bank – the national tissue bank for pancreatic cancer.

The research was performed in collaboration with researchers from Humanitas Research Hospital and Humanitas University (Milan, Italy), including Dr Paola Allavena and Professor Alberto Mantovani (who also holds the Chair of Inflammation and Therapeutic Innovation at Queen Mary’s William Harvey Research Institute), and ARC-NET Research Centre for Applied Research on Cancer (Verona, Italy), including Dr Aldo Scarpa. The Humanitas team is supported by the Italian Association for Cancer Research (AIRC).

A cancer biomarker released from non-cancerous cells

Most cancer biomarkers used in clinical practice are proteins released from the cancer cells themselves. One of the defining features of PDAC is that there are very few cancer cells; pancreatic cancer is surprisingly made up of mostly non-cancer cells, which have been co-opted by cancer to build a huge amount of scar tissue or stroma around the cancer, providing a strong defence for the cancer cells.

The unique feature of PTX3 is that this biomarker is released from non-cancerous cells such as stellate cells (star shaped cells) that surround the pancreatic tumour. Further analyses conducted by the team in human PDAC samples, pancreatic cancer cell lines and a mouse model of pancreatic cancer confirmed that PTX3 is, indeed, released predominantly from pancreatic stellate cells when they have been activated in response to signals from cancer cells.

By looking at data from clinical trials, the team found that when pancreatic cancer alone is targeted, PTX3 does not seem to change upon administration of chemotherapy; however, when medications targeting both cancer and stroma are administered, changes are seen in PTX3 levels. This change in PTX3 can be easily measured in blood to monitor how the drug is working. Thus, PTX3 may help in monitoring the effectiveness of treatment much earlier than scans may be able to indicate treatment response.

Stellate cells have an important role in normal tissue formation, and normal stellate cells do not seem to release PTX3. Stellate cells release PTX3 when they are ‘activated,’ which can occur in cancer or in response to other conditions. Therefore, further investigations are necessary to determine whether the PTX3 levels detected in this study are specific to stellate cell activation in PDAC.

Direction for future clinical trials

Pancreatic cancer is the deadliest of the common cancers and claims the lives of approximately 9,400 people each year in the UK. The majority of pancreatic cancer cases are diagnosed when the cancer is at an advanced stage due to a lack of specific symptoms at the early stages of the disease and the absence of specific biomarkers that can aid early detection.

This study suggests that PTX3 may be a sensitive and specific biomarker able to distinguish cancerous from non-cancerous conditions of the pancreas. The team hope the findings will provide direction for future prospective clinical trials to determine whether PTX3 could be effective in the clinic as a biomarker for early detection and, perhaps, used in conjunction with other biomarkers to monitor response to treatment of pancreatic cancer.

Maggie Blanks, CEO of Pancreatic Cancer Research Fund, said: “We’re extremely pleased that the Pancreatic Cancer Research Fund Tissue Bank has been a valuable resource for this research. It’s also exciting to learn that the project has found a new potential biomarker for both earlier detection and treatment monitoring and we look forward to hearing more about the team’s progress.”


Reference: Goulart, M.R., Watt, J., Siddiqui, I. et al. Pentraxin 3 is a stromally-derived biomarker for detection of pancreatic ductal adenocarcinoma. npj Precis. Onc. 5, 61 (2021). https://doi.org/10.1038/s41698-021-00192-1


Provided by Queenmary University of London

Finding the Weak Points in Radiation-Resistant Pancreatic Cancer Cells (Medicine)

Scientists clarify interrelated cellular processes that help pancreatic cancer cells survive radiotherapy, paving the way to more effective treatment strategies 

Pancreatic cancer is one of the deadliest cancer subtypes not just because it is difficult to diagnose early, but because it is inherently resistant to chemotherapy and radiotherapy. In a recent study, scientists from Japan investigated the relationship that exists between the radiation resistance of pancreatic cancer cells, the natural cell cycle, and a cellular mechanism called autophagy, or “self-digestion.” Their results pave the way for novel radiosensitizers and improved therapeutic strategies for resistant cancers. 

Of all the different types of cancer known, a subtype of pancreatic cancer called pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive and deadly. This disease begins in the cells that make up certain small ducts in the pancreas and progresses silently, usually causing no symptoms until advanced tumors actually obstruct these ducts or spread to other places. PDAC is not only difficult to diagnose, but also very unresponsive to available treatments. In particular, researchers have noted that PDAC cells can usually survive radiotherapy through mechanisms that remain largely unknown.

Part of the Radiation and Cancer Biology Group of the National Institutes for Quantum and Radiological Science and Technology, Japan, Dr. Sumitaka Hasegawa and colleagues Motofumi Suzuki and Mayuka Anko are currently studying what makes PDAC cells so radiation-resistant, and if there’s a way to break through their defenses. In their latest study, published in the International Journal of Radiation Oncology, Biology, Physics, they’ve managed to uncover some of the mysteries underlying the curious relationship between treatment resistance in PDAC, the cell cycle, and a process called autophagy—or “self-digestion.”

Every cell in our body is the result of the completion of countless cell cycles, from one cellular division to the next. Each cell cycle, shown schematically in Figure 1, is a chemically orchestrated sequence of phases in which a multitude of proteins actively control the growth of the cell and ensure it divides safely. When DNA damage is encountered, the cell cycle is halted at what’s called the G2 checkpoint and division is postponed until the problem is fixed. In many types of cancers including PDAC, the G2 checkpoint is strongly activated after irradiation, which has been shown to increase resistance to therapy.

On the other hand, autophagy is a natural mechanism by which a cell digests some of its own organelles and proteins, especially damaged or unnecessary ones, to reclaim nutrients and maintain proper internal conditions, among other functions. While essential for healthy cells, researchers have found that autophagy increases in cancer cells right after radiation treatment and that it actually helps them endure and survive therapy.

Most interestingly, because autophagy and the G2 checkpoint share some of the same chemical signals, it has been suggested that these two processes are interrelated. “Although a relationship had been proposed, the mechanistic details of the interactions between autophagy and the G2 checkpoint after irradiation were unclear. Thus, in our recent study, we sought to understand more about the link between these processes, especially in PDAC cells,” explains Dr. Hasegawa.

After numerous experiments in PDAC cell cultures, the team of scientists led by Dr. Hasegawa determined that irradiation-induced autophagy is dependent on the G2 checkpoint being activated. Moreover, they showed that autophagy helped the irradiated PDAC cells generate more energy (in the form of a molecule called ATP), which in turned led to their survival. Thus, the team proceeded to analyze what happened to irradiated PDAC cells when the G2 checkpoint was chemically inhibited. These irradiated cells, which could not activate the G2 checkpoint, did not undergo autophagy, and thus were much more likely to die post-radiation (Figure 2).

These promising results were then tested in mice onto which PDAC cells were transplanted to produce tumors. By treating these mice with both radiation and the G2 checkpoint inhibitor, the scientists managed to greatly suppress tumor growth compared to when irradiation was administered alone (Figure 3). In essence, this means that suppressors of the G2 checkpoint, which also mitigate autophagy, could be effectively used as tools to lower the radiation resistance of PDAC cells. “Our research,” concludes Dr. Hasegawa, “should facilitate the development of radiosensitizers or new radiotherapeutic strategies for PDAC. In turn, this could largely improve the survival rate of patients with this type of cancer.

Further studies will be needed to better understand the connection between the G2 checkpoint and autophagy and how these processes make cancer cells more resistant. Let us hope scientists eventually find ways to effectively combat particularly difficult cancer types, such as PDAC, and give more years of life to affected people. ​

Cell cycle and autophagy induction after X-ray irradiation in human pancreatic cancer cells (MIA PaCa-2)
Figure 1. Cell cycle and autophagy induction after X-ray irradiation in human pancreatic cancer cells (MIA PaCa-2): (Left) Cell cycle indicating the G2 checkpoint right before the M phase, which denotes cell division. (Right) MIA PaCa-2 cells were autophagy-positive (LC3-positive) 12 hours after X-ray irradiation. In contrast, no autophagy was found in non-irradiated cells. © QST
Cell survival after combination of X-ray irradiation with a G2 checkpoint inhibitor
Figure 2. Cell survival after combination of X-ray irradiation with a G2 checkpoint inhibitor : MIA PaCa-2 cells were either irradiated with X-rays (IR) only or irradiated with X-rays and administered a G2 checkpoint inhibitor (MK). The combined therapy killed cells much more effectively than irradiation alone. © QST
Tumor challenge study in combination with X-ray and G2 checkpoint inhibitor
Figure 3. Tumor challenge study in combination with X-ray and G2 checkpoint inhibitor: Combined therapy (IR+MK) suppressed tumor growth much better than either treatment alone in MIA PaCa-2 tumors grown on mice. © QST

About Dr. Sumitaka Hasegawa from National Institutes for Quantum and Radiological Science and Technology, Japan:

Sumitaka Hasegawa is a physician-scientist and currently a group leader of the Radiation and Cancer Biology Group at the National Institutes for Quantum and Radiological Science and Technology, Japan. He graduated from Nagasaki University Graduate School of Biomedical Sciences after graduating from the medical school of Nagasaki University. He spent as a postdoc at UCLA and the Stanford University. He has many publications in the field of cancer research, radiation oncology, and nuclear medicine, including prestigious journals such as Nature, Science, Journal of the American Chemical Society, and the Proceedings of the National Academy of Sciences of the United States of America.

Funding information:

This study was supported by the Japanese Society for the Promotion of Science KAKENHI (Grant number 18K15653 [MS]) and research grants from the National Institutes for Quantum and Radiological Science and Technology.

Research Article

Motofumi Suzuki, Mayuka Anko, Maki Ohara, Ken-ichiro Matsumoto and Sumitaka Hasegawa, “Radiation-induced autophagy in human pancreatic cancer cells is critically dependent on G2 checkpoint activation: a mechanism of radioresistance in pancreatic cancer”, International Journal of Radiation Oncology, Biology, Physics “: June 7, 2021. DOI: https://doi.org/10.1016/j.ijrobp.2021.04.001


Provided by QST

Scientists Show How to Attack the ‘Fortress’ Surrounding Pancreatic Cancer Tumours (Medicine)

Tackling the scar tissue that shields pancreatic tumours from effective drug access is a promising advance in a notoriously hard-to-treat cancer.

UNSW medical researchers have found a way to starve pancreatic cancer cells and ‘disable’ the cells that block treatment from working effectively. Their findings in mice and human lab models – which have been 10 years in the making and are about to be put to the test in a human clinical trial – are published today in Cancer Research, a journal of the American Association for Cancer Research.

“Pancreatic cancer has seen minimal improvement in survival for the last four decades – and without immediate action, it is predicted to be the world’s second biggest cancer killer by 2025,” says senior author Associate Professor Phoebe Phillips from UNSW Medicine & Health.

“But our latest advance means today I am the most optimistic and hopeful I have been in my career.”

Pancreatic cancer is notoriously difficult to treat because of the dense scar tissue surrounding tumours – the tissue acts like a fortress that blocks chemotherapy delivery.

“This scar tissue is produced by critical ‘helper cells’ – also called cancer-associated fibroblasts – which cancer cells recruit to support their growth and spread. Yet, these helper cells have been ignored in current treatment strategies,” A/Prof. Phillips says.

“Our approach hits both the tumour cells and the helper cells, so it’s ideal for overcoming the aggressiveness and drug resistance of the disease.”

In today’s paper, the team demonstrates their novel way to metabolically rewire helper cells by targeting one particular protein called SLC7A11, which in turn shuts off the cells’ tumour-promoting activity and reduces the scar tissue they produce.

“We found that switching off SLC7A11 in mice with pancreatic tumours directly killed pancreatic cancer cells, reduced the spread of tumour cells throughout their body and decreased the scar tissue fortress,” says Dr George Sharbeen, a postdoc researcher in A/Prof. Phillips’ lab who led the experimental work.

pancreatic cancer tumour
A human pancreatic tumour section showing SLC7A11 in helper cells (yellow). Image: UNSW Sydney

Comprehensive models, in-depth study

SLC7A11 has been studied in pancreatic cancer cells before, but this is the first piece of research to show that it plays a critical role in non-tumour helper cells, too.

“In other words, we have identified a novel ‘dual cell’ therapeutic target – tackling both the tumour cells and their helpers – which overcomes the current limitations of standard chemotherapy.”

The team used several complementary models to improve the clinical translatability of their findings, including patient-derived pancreatic cancer cell lines and helper cells, 3D at-the-bench models including an explant model that maintains pieces of human pancreatic tumour tissue, and multiple mouse models of pancreatic cancer.

“We also used our cutting-edge nanomedicine we developed in a multi-disciplinary collaboration with engineers – UNSW Professor Cyrille Boyer and University of Queensland Professor Thomas Davis – to deliver a gene therapy to inhibit SLC7A11. This therapy is advantageous because our nano-drug is tiny and able to penetrate the scar tissue in pancreatic cancer,” co-first author Associate Professor Joshua McCarroll from the Children’s Cancer Institute says.

Clinical trial about to commence

The team’s findings have formed the foundation for a clinical trial led by A/Prof. Phillips and UNSW Medicine collaborator Professor David Goldstein, which was funded by a recently awarded Cancer Institute NSW Translational Program Grant.

“In this trial, we will repurpose an anti-arthritis drug called sulfasalazine – which we know potently inhibits SLC7A11 – for the treatment of pancreatic cancer patients with tumours that have high SLC7A11 levels, which we’ve shown to be the case in more than half of patients. It has the potential to improve treatment response and ultimately survival of these patients,” A/Prof. Phillips says.

The researchers say the opportunity to repurpose an existing drug that’s already in the clinic will help them make progress more quickly.

“Using an approved drug has allowed us to get this piece into the clinic much faster than what would be the case if we started from scratch with drug development, too,” says A/Prof. Phillips.

“We are taking this exciting development all the way from the lab bench through to the clinic with the sole purpose of improving outcomes for patients with pancreatic cancer.”

The research team hopes to analyse and publish the first set of results of the trial within three years.

Improving outcomes that haven’t changed in decades

In addition to the clinical trial, the team now hopes to assess how their approach interferes with the exchange of nutrients between tumour cells and helper cells. They also want to identify the ideal drugs to combine with their therapeutic approach to enhance anti-tumour effects.  

Pancreatic cancer is a highly lethal disease, with only one in 10 patients surviving beyond five years. In 2020, an estimated 4000 Australians were diagnosed with pancreatic cancer – about 90 per cent of them will die, often within a few months of diagnosis.

“We clearly need improved treatments to turn these dismal statistics around, and we hope clinical translation of our findings will ultimately increase the number of pancreatic cancer survivors,” says A/Prof. Phillips.

“We will not give up until we improve the quality of life of patients and provide them with an effective treatment.”

This work was funded NHMRC, Cancer Institute NSW and PanKind (The Australian Pancreatic Cancer Foundation).

Featured image: Dr George Sharbeen and Associate Professor Phoebe Phillips in their lab. Photo: Richard Freeman / UNSW


Provided by University of New South Wales

Prototype Shows Promise in Countering Pancreatic Cancer (Medicine)

A research team has designed a molecule with potential to interfere in a new way with altered proteins that cause abnormal growth in 35 percent of pancreatic cancers.

Published online in Nature Communications on May 11, a new study from NYU Grossman School of Medicine found that a molecule called a monobody clings to cancer-causing versions of the KRAS protein and keeps them from transmitting their signals. Changes in the DNA of the KRAS gene—which encodes a molecular switch that toggles between active and inactive states to regulate growth—cause the related protein to become “stuck in the on mode.” Cells with such mutations continually multiply and give rise to cancer. 

Called 12VC1, the monobody is part of a class of compounds originally invented by lead study author Shohei Koide, PhD, in 1998. Formed from a simple protein framework, a parental monobody can be turned by automated technologies into trillions of slightly different versions. The study authors screened such a “library” to find 12VC1, which happened to have the right shape and properties to interrupt signals passed on by certain abnormal KRAS proteins. In this way, the study monobody slowed tumor growth by 90 percent over 6 weeks in mice with a model of pancreatic cancer. 

“These results answer a major question in drug discovery, showing that a monobody can block KRAS mutant signals as a potentially new type of protein therapy,” says Dr. Koide, a professor in the Department of Biochemistry and Molecular Pharmacology at NYU Langone, and a senior researcher at NYU Langone Health’s Perlmutter Cancer Center

While the research team first described the potential for a KRAS-targeting monobody in a 2016 paper, the current study went further to demonstrate that it could selectively target abnormal KRAS proteins. It also showed the value of attaching it to an enzyme fragment called VHL, which can send the abnormal KRAS proteins to degradation machines in cells called proteasomes, resulting in sustained inhibition of abnormal KRAS activity. 

No Longer “Undruggable”?

KRAS is a member of one of the most frequently mutated protein families in human cancers, but investigators have failed to find effective inhibitors to it for more than three decades, researchers say. A major obstacle has been that KRAS does not have a suitable pocket to which typical drugs can tightly latch on.

The only successful drugs against mutant KRAS to date, which are in the late-stages of development, act by forming a chemical (covalent) bond with a unique chemically reactive group in one specific KRAS mutant protein, says Dr. Koide. Such drugs only work when the mutant KRAS protein has a reactive group in the “right” position to be attacked by the drug. 

For this reason, there is only one covalent drug type that can interfere with just one cancer-causing KRAS mutant protein called G12C. While present in 20 to 25 percent of lung cancers, this mutant is there in just 1 to 3 percent of pancreatic cancers, the researchers say, with other mutants more common. 

Given these challenges, the field has long sought to interfere KRAS mutants in another way. When KRAS is in the active state, its surfaces can interact based on shape and charge (non-covalently) with proteins like RAF that pass on the message that cells should multiply. Many attempts to block such non-covalent interactions have not advanced past the early stages because they either shut down both normal and mutant KRAS because these proteins differ only slightly, or because they did not bind to mutant KRAS tightly enough. 

The monobody generated in the current study, 12VC1, represents the first agent that selectively prevents two KRAS mutants, G12C and G12V, from binding RAF. Together, these mutants cause 35 percent of pancreatic cancers. Remarkably, 12VC1 binds to the KRAS mutants 400 times more tightly than normal KRAS, leaving the latter free to perform its many cellular functions. The study authors also used an approach called X-ray crystallography to reveal at the level of atomic structure why 12CV1 has this unique capability.

In the current study, the monobody was delivered by a harmless virus carrying the monobody gene. The virus invaded cells to deposit genetic instructions, which were then followed by the target cell to produce the desired monobody. Of note, this experimental delivery method would need further development before it could potentially serve as a platform for drug design. 

Moving forward, Dr. Koide says the team will be looking at whether combinations of monobodies and other delivery technologies could increase the strength of inhibition. 

Along with Dr. Koide, study authors from NYU Langone’s Perlmutter Cancer Center were Kai Wen Teng, Steven Tsai, Takamitsu Hattori, Carmine Fedele, Akiko Koide, and Benjamin G. Neel. Also study authors were Chao Yang, Xuben Hou, and Yingkai Zhang of the Department of Chemistry at New York University; as well as John O’Bryan of the Department of Cell and Molecular Pharmacology at Medical University of South Carolina.

Dr. Shohei Koide, Dr. Akiko Koide, Dr. Teng, and Dr. Hattori are listed as inventors on a patent application on RAS-targeting monobodies filed by New York University (application No. 63/121,903). Dr. Shohei Koide also receives consulting fees from Black Diamond Therapeutics and research funding from Puretech Health and Argenx BVBA. Dr. Neel is a co-founder, and holds equity in, Navire Pharmaceuticals, as well as in Northern Biologics, Arvinas, Recursion Pharma, and Jengu Therapeutics. This current study was supported by the National Institutes of Health (NIH) grants R35 GM127040, R01 CA194864, R21 CA201717, and R01 CA212608, as well by NIH fellowship F32 CA225131, American Cancer Society fellowship PF-18-180-01-TBE, and Perlmutter Cancer Center support grant P30CA016087.

Featured image: Shohei Koide © IMAGE: NYU LANGONE STAFF


Reference: Teng, K.W., Tsai, S.T., Hattori, T. et al. Selective and noncovalent targeting of RAS mutants for inhibition and degradation. Nat Commun 12, 2656 (2021). https://doi.org/10.1038/s41467-021-22969-5


Provided by NYU Langone

Study Shows Pancreatic Cancer Cells Hit Reverse To Advance in Malignancy (Medicine)

 A Ludwig Cancer Research study has identified a previously unrecognized mechanism by which cancer cells of a relatively benign subtype of pancreatic tumors methodically revert—or “de-differentiate”—to a progenitor, or immature, state of cellular development to spawn highly aggressive tumors that are capable of metastasis to the liver and lymph nodes.

The study, led by Ludwig Lausanne’s Douglas Hanahan and published in Cancer Discovery, a journal of the American Association for Cancer Research, also shows that engagement of the mechanism is associated with poorer outcomes in patients diagnosed with pancreatic neuroendocrine tumors (PanNETs). Further, its findings provide concrete evidence that such cellular de-differentiation, widely observed across cancer types, is a not merely a random consequence of cancer cells’ other aberrations.

“Our study provides a clear example in a single tumor type that de-differentiation is an independently regulated and separable step in multi-step tumorigenesis,” said Hanahan, distinguished scholar at the Ludwig Lausanne Branch. “Moreover, this is not nonspecific de-differentiation, but rather, the result of a precise reversion of a developmental pathway that generated the mature cell type from which the cancer arose.”

PanNET tumors originate from the islet beta-cells of the pancreas, which produce the hormone insulin. Hanahan and his colleagues had previously reported that these tumors can be divided into two subtypes: a relatively benign, ‘well-differentiated’ subtype that maintains many features of insulin producing beta-cells, and a more aggressive and poorly-differentiated subtype that lacks those features.

Using a PanNET mouse model, they showed in the current study that the ‘poorly differentiated’ cancer cells have many characteristics of normal islet progenitor cells, and that the progression from benign to aggressive PanNET tumors requires cancer cells to retrace the pathway of beta cell differentiation and maturation to assume the progenitor state.

The researchers also uncovered a molecular circuit in cancer cells that governs this de-differentiation. They report that tumor cells poised to de-differentiate step up their production of a type of RNA molecule that regulates gene expression known as microRNA18. This ultimately causes the activation of Hmgb3, a protein that controls the expression of a suite of genes that pushes the cells into a progenitor state.

The results of this study provide new insights on de-differentiation as part of the puzzle of cancer and furnish preliminary evidence supporting its inclusion as a distinct and separable step, or perhaps sub-step, in the deadly progression toward malignancy.

This study was supported by Ludwig Cancer Research, the Swiss National Science Foundation and the Human Frontier Science Program Organization.

In addition to his Ludwig post, Douglas Hanahan is a professor emeritus at École Polytechnique Fédérale de Lausanne (EPFL).


Reference: Sadegh Saghafinia, Krisztian Homicsko, Annunziata Di Domenico, Stephan Wullschleger, Aurel Perren, Ilaria Marinoni, Giovanni Ciriello, Iacovos P Michael and Douglas Hanahan, “Cancer cells retrace a stepwise differentiation program during malignant progression”, Cancer Discovery, 2021. DOI: 10.1158/2159-8290.CD-20-1637


Provided by Ludwig Cancer Research

Ludwig Cancer Research Study Shows Pancreatic Cancer Cells Reverse to Advance Malignancy (Medicine)

A Ludwig Cancer Research study has identified a previously unrecognized mechanism by which cancer cells of a relatively benign subtype of pancreatic tumors methodically revert–or “de-differentiate”–to a progenitor, or immature, state of cellular development to spawn highly aggressive tumors that are capable of metastasis to the liver and lymph nodes.

The study, led by Ludwig Lausanne’s Douglas Hanahan and published in Cancer Discovery, a journal of the American Association for Cancer Research, also shows that engagement of the mechanism is associated with poorer outcomes in patients diagnosed with pancreatic neuroendocrine tumors (PanNETs). Further, its findings provide concrete evidence that such cellular de-differentiation, widely observed across cancer types, is a not merely a random consequence of cancer cells’ other aberrations.

“Our study provides a clear example in a single tumor type that de-differentiation is an independently regulated and separable step in multi-step tumorigenesis,” said Hanahan, distinguished scholar at the Ludwig Lausanne Branch. “Moreover, this is not nonspecific de-differentiation, but rather, the result of a precise reversion of a developmental pathway that generated the mature cell type from which the cancer arose.”

PanNET tumors originate from the islet beta-cells of the pancreas, which produce the hormone insulin. Hanahan and his colleagues had previously reported that these tumors can be divided into two subtypes: a relatively benign, ‘well-differentiated’ subtype that maintains many features of insulin producing beta-cells, and a more aggressive and poorly-differentiated subtype that lacks those features.

Using a PanNET mouse model, they showed in the current study that the ‘poorly differentiated’ cancer cells have many characteristics of normal islet progenitor cells, and that the progression from benign to aggressive PanNET tumors requires cancer cells to retrace the pathway of beta cell differentiation and maturation to assume the progenitor state.

The researchers also uncovered a molecular circuit in cancer cells that governs this de-differentiation. They report that tumor cells poised to de-differentiate step up their production of a type of RNA molecule that regulates gene expression known as microRNA18. This ultimately causes the activation of Hmgb3, a protein that controls the expression of a suite of genes that pushes the cells into a progenitor state.

The results of this study provide new insights on de-differentiation as part of the puzzle of cancer and furnish preliminary evidence supporting its inclusion as a distinct and separable step, or perhaps sub-step, in the deadly progression toward malignancy.

This study was supported by Ludwig Cancer Research, the Swiss National Science Foundation and the Human Frontier Science Program Organization.

In addition to his Ludwig post, Douglas Hanahan is a professor emeritus at École Polytechnique Fédérale de Lausanne (EPFL).

Featured image: Ludwig Lausanne’s Douglas Hanahan © Ludwig Cancer Research


Provided by Ludwig Institute for Cancer Research


About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for 50 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested nearly $3 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit www.ludwigcancerresearch.org.

Improving Survival in Pancreatic Cancer (Medicine)

Suppressing a gene regulator could reduce pancreatic cancer resistance to vital chemotherapeutic treatment.

Nagoya University researchers and colleagues in Japan have uncovered a molecular pathway that enhances chemotherapy resistance in some pancreatic cancer patients. Targeting an RNA to interrupt its activity could improve patient response to therapy and increase their overall survival.

“Pancreatic cancer is one of the most aggressive human malignancies, with an overall median survival that is less than five months,” says cancer biologist Yutaka Kondo of Nagoya University Graduate School of Medicine. “This poor prognosis is partially due to a lack of potent therapeutic strategies against pancreatic cancer, so more effective treatments are urgently needed.”

Kondo and his colleagues focused their attention on a long noncoding RNA (lncRNA) called taurine upregulating gene 1 (TUG1). lncRNAs are gene regulators, several of which have recently been identified for helping some cancers resist chemotherapy. TUG1 is already known for being overexpressed in gastrointestinal cancers that have poor prognosis and are resistant to chemotherapy.

The researchers found TUG1 was overexpressed in a group of patients with pancreatic ductal adenocarcinoma. These patients were resistant to the standard chemotherapy treatment 5-fluorouracil (5-FU), and died much sooner compared to cancer patients with low TUG1 expression levels.

Further laboratory tests showed TUG1 counteracts a specific microRNA, leading to increased activity of an enzyme, called dihydropyrimidine dehydrogenase, which breaks down 5-FU into a compound that can’t kill cancer cells.

Kondo and his team found they could suppress TUG1 during 5-FU treatment of mice with pancreatic cancer by using antisense oligonucleotides attached to a specially designed cancer-targeting drug delivery system. Antisense oligonucleotides interfere with gene expression.

“Our data provides evidence that our therapeutic approach against pancreatic cancer could be promising,” says Kondo.

The team now plans to conduct further laboratory investigations to test the effectiveness of their therapeutic strategy.

Their study, “Cancer-specific targeting of taurine upregulated gene 1 enhances the effects of chemotherapy in pancreatic cancer,” was published online in the journal Cancer Research on March 1, 2021 at DOI: 10.1158/0008-5472.CAN-20-3021.

Authors:

Yoshihiko Tasaki, Miho Suzuki, Keisuke Katsushima, Keiko Shinjo, Kenta Iijima, Yoshiteru Murofushi, Aya Naiki Ito, Kazuki Hayashi, Chenjie Qiu, Akiko Takahashi, Yoko Tanaka, Tokuichi Kawaguchi, Minoru Sugawara, Tomoya Kataoka, Mitsuru Naito, Kanjiro Miyata, Kazunori Kataoka, Tetsuo Noda, Wentao Gao, Hiromi Kataoka, Satoru Takahashi, Kazunori Kimura, and Yutaka Kondo

Featured image: Kondo and his team found TUG1 overexpression in some pancreatic cancer patients leads to increased release of an enzyme (DPD), which breaks down the chemotherapeutic, 5-FU, into a compound that can’t kill cancer cells. Targeting this pathway reduced chemotherapy resistance in mice.     (Credit: Yutaka Kondo)


Provided by Nagoya University