Tag: pancreatic cancer

Categories : CancerTags :

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

Categories : CancerTags :

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

Categories : CancerTags :

Combining Diagnosis and Treatment into One to Treat Pancreatic Cancer

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Pancreatic cancer cells. Credit: NIH

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

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

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

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

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

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

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

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

Source: Osaka University

Categories : Cancer GastrointestinalTags :

Study Finds No Evidence of Fungus Link to Pancreatic Cancer

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Source: CC0

Four years ago, a report that a common species of fungus might fuel pancreatic cancer offered a promising new view of the deadly disease. But in working to validate the finding, Duke Health researchers have found no such association. In a study published in the journal Nature, the researchers conducted a multi-pronged analysis of data from the earlier study and found no link between the pancreatic microbiome and the development of pancreatic cancer.

“We were intrigued by the original finding, as were many research teams,” said senior author Peter Allen, MD, professor in the Department of Surgery and chief of the Division of Surgical Oncology at Duke University School of Medicine.

“There is a growing body of literature connecting the human microbiome to disease, and this was particularly compelling for pancreatic cancer,” Allen said. “But our findings did not support an association between fungi and the development of pancreatic cancer in humans.”

Allen and colleagues worked to recreate the 2019 findings published in Nature by a different research team. The original study raised hopes that there might be a possible method of preventing pancreatic cancer with the use of antifungals or some other approach to protect from infection.

Focusing on the research team’s original raw sequencing data, the Duke researchers were unable to reproduce the findings. Additional studies, using pancreatic cancer tissue in Duke repositories, also failed to produce the original results.

“We believe our findings highlight the challenges of using low biomass samples for microbiome sequencing studies,” Allen said. “The inclusion of appropriate negative controls and efforts to identify and remove sequencing contaminants is critical to the interpretation of microbiome data.”

Source: Duke University Medical Center

Categories : Cancer GenderTags :

In Women, Certain Immune Cell Hinders Pancreatic Cancer Immunotherapy

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Photo by Tima Miroshnichenko on Pexels

Immunotherapy has limited effect for pancreatic cancer, and differs between men and women. A new study published in Cancer Research reveals certain immune cells in women with pancreatic cancer that, instead of fighting the tumour, interferes with the body’s immune response. These findings may pave the way for a more sex-specific treatment.

“More and more evidence is coming in that male and female hormones affect our immune system, but much remains to be done before sex can be included as a self-evident biological factor in medical research and therapy,” says the paper’s first author Fei He, former visiting researcher at Karolinska Institutet. “Our results provide new perspectives that can have high impact on the treatment of cancer.”

In recent years, immunotherapy, which stimulates the immune system to attack cancer cells, has contributed significantly to the treatment of different kinds of cancer, such as melanoma and lung, kidney and liver cancer. However, it is much less effective against pancreatic cancer, which remains one of the deadliest kinds of cancer that leaves patients, on average, with four to six months left to live after diagnosis.

Sex-biased differences in the immune response

Previous studies have shown that there are sex-bound biological differences in the male and female immune system that, amongst other effects, determine how tumours grow and the body’s ability to defend itself against them. The present study addressed what might cause such sex-related disparities in the immune response to pancreatic cancer.

The study revealed the presence of a subpopulation of myeloid cells in women that protect the tumour and prevents the immune system’s T cells from infiltrating the tumour and attacking the cancer cells.

“This sub-group of immune cells correlates with poor survival exclusively in female cancer patients,” says the study’s corresponding author and principal investigator Dhifaf Sarhan, assistant professor at the Department of Laboratory Medicine, Karolinska Institutet. “Our results show that the immune cells express a specific protein called FPR2 and can serve both as a sex-specific prognostic factor and a therapeutic target.”

New target for immunotherapy in women

The results can be useful to the development of diagnostic tools and immunotherapy for pancreatic cancer that take into account biological differences between men and women. The study used a combination of methods including single-cell RNA sequencing, proteomics, test tube and patient validation, and treatments of 3D pancreatic cancer models and mice.

“The next step is to follow up our new immunotherapy target for women,” says Dr Sarhan. “We’re also performing extensive analyses to understand how immunological sex differences drive tumour development in different ways in male and female cancer patients with the goal to find and develop immunotherapy targets for each group.”

Source: Karolinska Institutet

Categories : CancerTags :

Stress-tolerant Cells may Drive Pancreatic Cancer’s Extreme Tenacity

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This image shows pancreatic cancer cells (nuclei in blue) growing as a sphere encased in membranes (red). Credit: NIH

Researchers at have discovered a molecular pathway critical to the initiation of pancreatic tumours, which could partly explain the disease’s high resistance to chemotherapy and its propensity for metastasis.

The study, published in Nature Cell Biology, found that pancreatic tumour-initiating cells must first overcome local ‘isolation stress’ by creating their own tumour-promoting microenvironment, and then recruit surrounding cells into this network. By targeting this tumour-initiating pathway, new therapeutics could limit the progression, relapse and spread of pancreatic cancer.

Pancreatic cancer is one of the most lethal cancers, notoriously resistant to treatment. Almost all patients experience cancer recurrence or metastasis.

In the early stages of tumour formation, cancer cells (those with cancerous mutations, called oncogenes) experience a loss of adhesion to other cells and the extracellular matrix. This isolation leads to a local lack of oxygen and nutrients. Most cells do not survive such isolation stress, but a certain group of cells can.

Tumour-initiating cells (TIC) play a major role in the formation, recurrence and metastatic spread of tumours. What sets them apart from other cancer cells is their resilience to these early substandard conditions. Like cacti in a desert, they can adapt to the harsh environment and set the scene for further tumour progression.

“Our goal was to understand what special properties these tumour-initiating cells have and whether we can control the growth and spread of cancer by disrupting them,” said senior study author David Cheresh, PhD.

To answer these questions, first author Chengsheng Wu, PhD, a postdoctoral fellow in Cheresh’s lab, subjected pancreatic cell lines to various forms of stress, including low oxygen and sugar levels. He then identified which cells could adapt to the harsh conditions and observed which genes and molecules were modified in these cells.

The stress-tolerant tumour-initiating cells showed reduced levels of a tumour-suppressive microRNA, miR-139-5p. This in turn led to the upregulation of lysophosphatidic acid receptor 4 (LPAR4), a G-protein-coupled receptor on the cell surface.

“LPAR4 is not normally found on happy cells, but it gets turned on in stressful environments to help the cells survive, which is particularly advantageous for tumor-initiating cells,” said Cheresh.

The researchers found that LPAR4 expression promoted the production of new extracellular matrix proteins, allowing the solitary cancer cells to start building their own tumour-supporting microenvironment.

The new extracellular matrix was particularly rich in fibronectin, a protein that binds to transmembrane receptors called integrins on surrounding cells. Once the integrins on these cells sensed the fibronectin, they began signalling the cells to express their own tumour-initiating genes. Eventually, these other cells were recruited into the fibronectin matrix laid by the tumour-initiating cells and a tumour started to form.

“Our findings establish a critical role for LPAR4 in pancreatic tumour initiation, and a likely role in other epithelial cancers, such as lung cancer,” said Cheresh. “It is central to tumour-initiating cells’ ability to overcome isolation stress and build their own niche in which tumours can form.”

Chemotherapy drugs are also designed to put cancer cells under stress, and may use this pathway. Indeed, Cheresh’s team found that treating cultured tumour cells and pancreatic tumours in mice with standard-of-care chemotherapeutics also led to the upregulation of LPAR4. The researchers said this might explain how such tumour cells could develop a stress tolerance and resistance to the drugs.

Further experiments also showed that using integrin antagonists to block cells’ ability to utilise the fibronectin matrix reversed the stress tolerance benefit of LPAR4 expression. Thus, the authors suggest targeting the LPAR4 pathway or disrupting the fibronectin/integrin interaction could be effective in preventing the growth, spread and drug resistance of pancreatic tumours.

“We can think of tumour-initiating cells as being in a transient state that can be induced by different stressors, so our clinical goal would be to prevent oncogenic cells from ever entering this state,” said Cheresh. “Now that we’ve identified the pathway, we can assess all the different ways we can intervene.”

The researchers suggested a new drug targeting this pathway could be used as a prophylactic in patients at high risk of developing the disease, or to prevent new tumours from forming in cancer cases with a high likelihood of metastasis.

Pairing the new drug with existing chemotherapeutics that put stress on mature tumour cells could also mitigate the effects of drug resistance and make cancer treatments more effective, authors said.

“Treating cancer can feel a little like whack-a-mole,” said Cheresh, “but if we have two or three hammers and we know where the moles are going to pop up next, we can beat the game.”

Source: University of California – San Diego

Categories : Cancer GeneticsTags :

Novel Approach Targets Pancreatic Cancers Which Depend on Mutant KRAS Gene

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KRAS Protein Structure. RAS is a family of related proteins that is expressed in all animals. KRAS is one of three RAS genes found in humans. RAS genes are mutated in approximately one-third of all human cancers. Photo by National Cancer Institute on Unsplash

Researchers have identified a novel drug that effectively thwarts pancreatic tumours that are addicted to the cancer-causing mutant KRAS gene.

Because early detection of pancreatic cancer is difficult, it has a low survival rate, accounting for just over 3% of all new cancer cases in the US, but leading to nearly 8% of all cancer deaths, according to the National Cancer Institute.

The KRAS gene was recognised more that 25 years ago as the component of Kirsten sarcoma virus responsible for oncogenesis. Since then, mutations of KRAS have been described in a large proportion of solid tumors ranging from more than 90% of pancreatic carcinomas to 20% to 30% of pulmonary adenocarcinomas.

Through a pre-clinical study, Said Sebti, PhD, associate director for basic research at VCU Massey Cancer Center, identified a novel drug that effectively thwarts pancreatic tumors that are addicted to the cancer-causing mutant KRAS gene. 

“We discovered a link between hyperactivation of the CDK protein and mutant KRAS addiction, and we exploited this link preclinically to counter mutant KRAS-driven pancreatic cancer, warranting clinical investigation in patients afflicted with this deadly disease,“ said Dr Sebti, who is also the Lacy Family Chair in Cancer Research at Massey and a professor of pharmacology and toxicology at the VCU School of Medicine. “Our findings are highly significant as they revealed a new avenue to combat an aggressive form of pancreatic cancer with very poor prognosis due mainly to its resistance to conventional therapies.”

In 90 percent of pancreatic cancers, KRAS is mutated. Prior studies have shown that some tumours harbouring mutant KRAS are in fact addicted to the mutant gene, meaning they cannot survive or grow without it. Sebti set out to discover if there is a drug that can specifically kill those tumours with a mutant KRAS addiction.

Searching for a suitable drug

Dr Sebti and colleagues used a three-pronged approach to tackle this question.

First of all, they mapped the blueprint of pancreatic cancer cells through global phosphoproteomics, showing them how the addicted and non-addicted tumours differ at the phosphoprotein level. They found two proteins, CDK1 and CDK2, which signalled which cells were addicted to mutant KRAS.

Additionally, they analysed a comprehensive database from the Broad Institute of MIT and Harvard which contains genome-wide CRISPR gRNA screening datasets. They discovered that CDK1 and CDK2 as well as CDK7 and CDK9 proteins were associated with mutant KRAS-addicted tumors.

Finally, they evaluated 294 FDA drugs to selectively kill mutant KRAS-addicted cancer cells over non-KRAS-addicted cancer cells in the lab. They determined the most effective drug in preclinical experiments was AT7519, an inhibitor of CDK1, CDK2, CDK7 and CDK9.

“Using three entirely different approaches, the same conclusion presented itself clearly to us: pancreatic cancer patients whose tumors are addicted to mutant KRAS could benefit greatly from treatment with the CDK inhibitor AT7519,” Dr Sebti said.

To further validate these findings in fresh tumours taken from pancreatic cancer patients the researchers found that AT7519 suppressed the growth of xenograft cells from five mutant KRAS pancreatic cancer patients who relapsed on chemotherapy and/or radiation therapies.

Though AT7519 had previously been tested unsuccessfully in a number of clinical trials, none of the trials were for pancreatic cancer.

“If our findings are correct and translate in humans, then we should be able to see a positive response in pancreatic cancer patients whose tumors are addicted to mutant KRAS,” Dr Sebti said.

As well as pancreatic cancer, the study authors believe these findings may also have clinical implications for colorectal and non-small cell lung cancer patients with prevalent KRAS mutations.

Source: Virginia Commonwealth University

Journal information: Kazi, A., et al. (2021) Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer. Clinical Cancer Research. doi.org/10.1158/1078-0432.CCR-20-4781.

Categories : CancerTags :

CD40 Agonists Before Therapy Kick Off T Cell Response

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Giving a CD40 immune-stimulating drug to early-stage pancreatic cancer patients helped kick off a T cell attack on the tumour’s stubborn microenvironment before surgery and other treatments, according to a new study.

Altering the tumour microenvironment to host more T cells using a CD40 agonist earlier could help slow cancer progression and prevent metastasis.

The data was presented by Katelyn T Byrne, PhD, an instructor of Medicine in the division of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania, during a plenary session at the American Association for Cancer Research annual meeting.

“Many patients with early-stage disease undergo surgery and adjuvant chemotherapy. But it’s often not enough to slow or stop the cancer,” Dr Byrne said. “Our data supports the idea that you can do interventions up front to activate a targeted immune response at the tumor site–which was unheard of five years ago for pancreatic cancer–even before you take it out.”

CD40 is a tumour necrosis factor receptor superfamily member expressed broadly on antigen-presenting cells (APC) such as dendritic cells, B cells, and monocytes as well as many non-immune cells and a range of tumours.

CD40 agonists serve to accelerate the immune system by activating antigen-presenting cells, such as dendritic cells, to “prime” T cells and also through enhancement of destruction of the tumour site through non-immune system means. This has been investigated mostly in combination with other therapies for pancreatic cancer patients. This is the first study showing the drug drove immune response in early-stage patients both at the tumour site and systemically, mirroring mouse study findings.

Prior to surgery, 16 patients were treated with selicrelumab. Of those, 15 underwent surgery and received adjuvant chemotherapy and a CD40 agonist. Data collected from those patients’ tumours and responses were compared to data from controls (CD40 not received before surgery) treated at Oregon Health and Science University and Dana Farber Cancer Institute.

Multiplex imaging of immune responses revealed that in patients who received the CD40 agonist before surgery, 82% of tumours were T cell enriched, compared to 37% of untreated tumors and 23% chemotherapy or chemoradiation-treated tumours.

Selicrelumab tumours also had less tumour-associated fibrosis, which are tissue bundles inhibiting T cell and drug entry, and antigen-presenting cells known as dendritic cells were more mature.

Disease-free survival was 13.8 months in the treatment group, and median overall survival was 23.4 months, with eight patients alive at a median of 20 months after surgery.

“This is a first step in building a backbone for immunotherapy interventions in pancreatic cancer,” Dr Byrne said.

On the strength of these findings, researchers are pursuing combining CD40 with other therapies to help further boost immune response in pre-surgery pancreatic cancer patients.

“We’re starting to turn the tide. This latest study adds to growing evidence that therapies such as CD40 before surgery can trigger an immune response in patients, which is the biggest hurdle we’ve faced,” said senior author Robert H Vonderheide, MD, DPhil, and Director, Abramson Cancer Center (ACC), University of Pennsylvania. “We’re excited to see how the next-generation of CD40 trials will take us even closer to better treatments.”

Source: News-Medical.Net