Category: Cancer

Categories : Cancer GeneticsTags :

Comprehensive Genome Sequencing Can Improve Cancer Outcomes

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Image source: National Cancer Institute

Researchers from St Jude Children’s Research Hospital have demonstrated the feasibility of comprehensive genomic sequencing for all paediatric cancer patients, which maximises the lifesaving potential of precision medicine.

All 309 patients who enrolled in the study were offered whole genome and whole exome sequencing of germline DNA. For the 253 patients for whom adequate tumour samples were available, whole genome, whole exome and RNA sequencing of tumour DNA was carried out.

Overall, 86% of patients had at least one clinically significant variation in tumour or germline DNA. Those included variants related to diagnosis, prognosis, therapy or cancer predisposition. An estimated 1 in 5 patients had clinically relevant mutations that would not have been picked up with standard sequencing methods.

“Some of the most clinically relevant findings were only possible because the study combined whole genome sequencing with whole exome and RNA sequencing,” said Jinghui Zhang, PhD, St Jude Department of Computational Biology chair and co-corresponding author of the study.

While such comprehensive clinical sequencing is not widely available, as the technology becomes less expensive and accessible to more patients, comprehensive sequencing will become an important addition to paediatric cancer care.

“We want to change the thinking in the field,” said David Wheeler, PhD, St Jude Precision Genomics team director and a co-author of the study. “We showed the potential to use genomic data at the patient level. Even in common pediatric cancers, every tumor is unique, every patient is unique.

“This study showed the feasibility of identifying tumour vulnerabilities and learning to exploit them to improve patient care,” he said.

Tumour sequencing resulted in a change in treatment for 12 of the 78 study patients for whom standard of care was unsuccessful. In four of the 12 patients, the treatment changes stabilised disease and extended patient lives. Another patient, one with acute myeloid leukaemia, went into remission and was cured by blood stem cell transplantation.

“Through the comprehensive genomic testing in this study, we were able to clearly identify tumor variations that could be treated with targeted agents, opening doors for how oncologists manage their patients,” said co-corresponding author Kim Nichols, MD, St Jude Cancer Predisposition Division director.

The results of the study were published online in the journal Cancer Discovery.

Source: St. Jude Children’s Research Hospital

Journal information: Newman, S., et al (2021) Genomes for Kids: The scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Discovery. doi.org/10.1158/2159-8290.CD-20-1631.

Categories : CancerTags :

Organ-on-a-chip Enables Rapid Cancer Treatment Evaluation

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Researchers at Texas A&M University are advancing organ-on-a-chip devices to new levels, which may change the way clinicians approach cancer treatment, particularly for ovarian cancer.

The research team, led by Abhishek Jain, an assistant professor in the Department of Biomedical Engineering with a joint appointment in the College of Medicine, has developed a device focusing on platelets. The ovarian tumour microenivornment-chip (OTME-Chip) is about the size of a USB and models the properties of a tumour in a laboratory setting. The microdevice is able to recreate events within platelets circulating in the blood as they approach the tumour, making it more potent and metastatic.

“We claim several novelties in technological design as well as biological capabilities that didn’t exist in prior organs-on-chips,” Prof Jain said.

Advances in organ-on-a-chip microdevices allow researchers to discover more about cancer outside the human body. These organs-on-chips serve as a model of the state a cancer patient is in, giving clinicians a chance to find the correct treatment before administering it to the patient.

“We are creating a platform technology using the organ-on-a-chip approach where tumour biology can be advanced, and new drugs can be identified by recreating the platelet-tumor and platelet-tumour-drug interactions under the influence of flow, supporting blood vessels and the extracellular matrix,” Jain said.

Ovarian cancer is one of the leading causes of cancer deaths for women in developed countries. Tumours typically form deep inside a patient’s tissue, and it can be difficult to obtain real-time information of the tumour’s properties and its interaction with blood cells. Ovarian tumours can also rapidly metastasise, meaning that analysis and intervention must be prompt.

The OTME-Chip builds on current understanding of how blood platelets move inside tumour tissue and what triggers them to spread outside the tumour. The actual mechanism behind this process, however, had remained mostly unknown, until now.

“For the first time, we identified a crucial interaction between platelets and the tumor via their surface proteins,” Prof Jain said. “By applying high-resolution imaging, advanced cell and molecular readouts and RNA sequencing methods leveraging the OTME-Chip, we discovered the actual genetic signaling pathways behind the blood cell triggered metastasis of ovarian cancer and a new drug strategy to stop this process.”

Their study was recently published in the journal Science Advances.

Prof Jain said the OTME-Chip has several applications, both in observing cancer cells interactions with vascular and blood cells and testing novel complementary ways to treat cancer.

“This multimodal OTME-Chip is going to provide an ideal platform to the health care researchers to evaluate their anti-cancer, vascular and haematological drugs individually or in combination in an artificially created human-level tumor microenvironment,” Prof Jain said.

Source: Texas A&M University

Journal information: Saha, B., et al. (2021) Human tumor microenvironment chip evaluates the consequences of platelet extravasation and combinatorial antitumor-antiplatelet therapy in ovarian cancer. Science Advances. doi.org/10.1126/sciadv.abg5283.

Categories : CancerTags :

Protein Markers Distinguish Between Stable and Progressive Leukaemia

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Photo by Louis Reed on Unsplash

Scientists have identified protein markers which are related to the most common form of leukaemia.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the Western world. A new study published in the Journal of Leukocyte Biology shows that certain protein markers may indicate which patients have stable forms of CLL and which have more aggressive types.

Identifying these proteins may not only help determine patients’ prognoses but also point to potential therapeutic targets for investigators who are searching for new CLL treatments.

The study examined CLL B-cells’ proteomic profile from untreated CLL patients to see which biologic processes  that are affected early on and during disease evolution as stable or progressive. Of the 11 patients included in the study, six evolved to either progressive and five to stable disease. Purified B cells from the  patients were tested at two time points by liquid chromatography–tandem mass spectrometry. 

First, at an early stage of the disease (Binet stage A), based on the relative abundance levels of 389 differentially expressed protein, samples were separated into stable and progressive clusters with the main differentiating factor being the RNA splicing pathway.

An RNA-Seq study was conducted which showed 4217 differentially spliced genes between the two clusters. Distinct longitudinal evolutions were observed with predominantly proteomic modifications in the stable CLL group and spliced genes in the progressive CLL group. Splicing events were shown to be six times more frequent in the progressive CLL group. 

The main aberrant biologic processes controlled by DEPs and spliced genes in the progressive group were cytoskeletal organisation, Wnt/β-catenin signaling, and mitochondrial and inositol phosphate metabolism with a downstream impact on CLL B-cell survival and migration. 

The study suggests that proteomic profiles of early stage CLL can discriminate progressive from stable disease. Furthermore, it appears RNA splicing dysregulation underlies CLL evolution, opening new avenues for biomarkers and therapy.

“The results offer a meaningful biological approach into the protein composition of CLL cells at an early stage of the disease, when the clinical characteristics of patients are similar and the course of the disease is difficult to predict. Our results showed that the protein profile can however predict how the disease will further evolve,” said lead author Cristina Bagacean, PhD, of CHU de Brest, in France. “This approach could identify putative therapeutic targets in order to prevent CLL progression.”

Source: Wiley

Journal information: Bagacean, C., et al. (2021) Identification of altered cell signaling pathways using proteomic profiling in stable and progressive chronic lymphocytic leukemia. Journal of Leukocyte Biology. doi.org/10.1002/JLB.4HI0620-392R.

Categories : CancerTags :

MRI Clear Cell Likelihood Score Matches Renal Carcinoma Growth

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Photo by MART PRODUCTION from Pexels

According to a new study, the MRI-derived standardised non-invasive clear cell likelihood score (ccLS) is correlated with the growth rate of small renal masses (cT1a, <4 cm) and could help guide personalised management.

The study was published in the American Roentgen Ray Society’s American Journal of Roentgenology. Extracted from clinical reports, “the ccLS scores the likelihood that the small renal mass represents clear cell renal cell carcinoma, from 1 (very unlikely) to 5 (very likely),” explained corresponding author Ivan Pedrosa from the University of Texas Southwestern Medical Center at Dallas. “Small renal masses with lower ccLS may be considered for active surveillance, whereas small renal masses with higher ccLS may warrant earlier intervention.”

The team’s retrospective study included consecutive small renal masses assigned a ccLS on clinical MRI exams performed from June 2016 to November 2019. Tumour size measurements were obtained from available prior and follow-up cross-sectional imaging examinations, up to June 2020.

Among 389 small renal masses in 339 patients (198 men, 141 women; median age, 65 years) on active surveillance that were assigned a ccLS on clinical MRI examinations, those with ccLS4-5 grew significantly faster (9% diameter, 29% volume yearly) than those with ccLS1-2 (5% diameter, p<.001; 16% volume, p<.001) or ccLS3 (4% diameter, p<.001; 15% volume, p<.001).

With a lack of validated imaging markers to characterise biologic aggressiveness of small renal masses hindering medical decision making, “growth is associated with ccLS in small renal masses,” the authors reiterated, “with higher ccLS correlating with faster growth.”

Source: EurekAlert!

Categories : Antibiotics CancerTags :

Old Antibiotics as New Weapons against Melanoma

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Researchers may have hit upon a new weapon in the fight against melanoma: antibiotics that target a vulnerability in the ‘power plants’ of cancer cells when they try to survive cancer therapy.

“As the cancer evolves, some melanoma cells may escape the treatment and stop proliferating to ‘hide’ from the immune system. These are the cells that have the potential to form a new tumor mass at a later stage,” explains cancer researcher and RNA biologist Eleonora Leucci at KU Leuven, Belgium. “In order to survive the cancer treatment however, those inactive cells need to keep their ‘power plants’—the mitochondria—switched on at all times.” As mitochondria derive from bacteria that, over time, started living inside cells, they are very vulnerable to a specific class of antibiotics. This is what gave us the idea to use these antibiotics as anti-melanoma agents.”

The researchers implanted patient-derived tumors into mice, which were then treated with antibiotics, either as alone or in combined with existing anti-melanoma therapies. Leucci observed: “The antibiotics quickly killed many cancer cells and could thus be used to buy the precious time needed for immunotherapy to kick in. In tumors that were no longer responding to targeted therapies, the antibiotics extended the lifespan of—and in some cases even cured—the mice.”

The researchers made use of nearly antibiotics rendered nearly obsolete because of antibiotic resistance. However, this does not affect the efficacy of the treatment in this study, Leucci explained. “The cancer cells show high sensitivity to these antibiotics, so we can now look to repurpose them to treat cancer instead of bacterial infections.”

However, patients with melanoma should not try to experiment, warned Leucci. “Our findings are based on research in mice, so we don’t know how effective this treatment is in human beings. Our study mentions only one human case where a melanoma patient received antibiotics to treat a bacterial infection, and this re-sensitized a resistant melanoma lesion to standard therapy. This result is cause for optimism, but we need more research and clinical studies to examine the use of antibiotics to treat cancer patients. Together with oncologist Oliver Bechter (KU Leuven/UZ Leuven), who is a co-author of this study, we are currently exploring our options.”

Source: KU Leuven

Journal information: Roberto Vendramin et al, Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma, Journal of Experimental Medicine (2021). DOI: 10.1084/jem.20210571

Categories : CancerTags :

Aspirin Could Cut Cancer Deaths by 20%

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Photo by HalGatewood.com on Unsplash

Patients with a wide range of cancers who take aspirin as part of their treatment could have their risk of death decrease by 20%, according to a major review of existing research.

Researchers at Cardiff University carried out a huge  systematic review of 118 published observational studies in patients with 18 different cancers. Pooling the results, 250 000 patients with cancer who reported taking aspirin, which was associated with a reduction of about 20% in cancer deaths.

The review said the available body of evidence regarding its efficacy and safety “justifies its use” as a supplementary treatment in a wide range of cancers—and that patients should be made aware of this.

Lead author Professor Peter Elwood, Honorary Professor at Cardiff University who has studied the effects of aspirin for over five decades, said: “In recent years, my research team and I have been struck by the actions of aspirin on the biological mechanisms relevant to cancer—and these seem to be the same in many different cancers.

“We therefore wanted to review the scientific evidence available on the use of aspirin as an additional treatment for a wide range of cancers.

“Overall, we found that at any time after a diagnosis of cancer, about 20% more of the patients who took aspirin were alive, compared with patients not taking aspirin.”

The team took into consideration aspirin taking risks and wrote to an author on each of the papers asking about any stomach or other bleeding episodes.

A minority of patients had experienced a bleed, but no evidence of any excess deaths attributable to bleeding in the patients on aspirin was found, the review noted.

“Our research suggests that not only does aspirin help to cut risk of death, but it has also been shown to reduce the spread of cancer within the body—so-called metastatic spread,” said Prof Elwood.

“There is now a considerable body of evidence to suggest a significant reduction in mortality in patients with cancer who take aspirin—and that benefit appears to not be restricted to one or a few cancers.

“Aspirin therefore appears to deserve serious consideration as an adjuvant treatment of cancer and patients with cancer and their carers should be informed of the available evidence.

“However, we must also stress that aspirin is not a possible alternative to any other treatment.”

It started in 1974 when a research team led by Professor Elwood and Professor Archie Cochrane at the Medical Research Council’s Unit in Wales showed for the first time that taking an aspirin tablet a day reduced deaths from heart disease and stroke by about 24%.

In 1990, the finding gained global traction and was judged by the BMJ to have been one of the top 50 most important research studies published since 1945. A meta-analysis of 13 randomised controlled studies found a major adverse cardiovascular event risk reduction for statin users (12%), non-smokers (10%) and males (11%).

Prof Elwood said his original study stimulated a new phase of research work on aspirin. At the time of the report about 100 clinical research studies on aspirin were published each year—but now, in excess of 1 000 are reported each year. He said a number of new clinical trials had been set up to test aspirin treatment in several cancers and the results of these should offer further clear evidence.

“Further research into aspirin and cancer would clearly be of great value, and new studies should be encouraged, especially if focused on some of the less common cancers,” said Prof Elwood.

Source: Medical Xpress

Journal information: Peter C Elwood et al, Aspirin and cancer survival: a systematic review and meta-analyses of 118 observational studies of aspirin and 18 cancers, ecancermedicalscience (2021). DOI: 10.3332/ecancer.2021.1258

Categories : CancerTags :

New Way to Assess Immune Checkpoint Effectiveness

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Chromosomes prepared from a malignant glioblastoma visualized by spectral karyotyping (SKY) reveal an enormous degree of chromosomal instability — a hallmark of cancer.
Credit: Thomas Ried, NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health

Researchers have used a new machine learning and protein profiling system to identify vulnerabilities in glioblastomas and to assess immune checkpoint blockade treatment effectiveness.

Neoadjuvant immune checkpoint blockade (ICB) is a promising treatment for melanoma and other cancer types, and has recently been shown to provide a modest survival benefit for patients with recurrent glioblastoma. To improve the treatment efficacy, researchers are looking for vulnerabilities in surgically removed glioblastoma tissues, but this has been difficult due to the vast differences within the tumours and between patients.

To tackle this problem, researchers at Institute for Systems Biology (ISB) and their collaborators developed a new way to study tumours. The method builds mathematical models using machine learning-based image analysis and multiplex spatial protein profiling of microscopic compartments in the tumour.

The team used this approach to analyse and compare tumour tissues gathered from 13 patients with recurrent glioblastoma and 23 patients with high-risk melanoma. Both groups had been treated with neoadjuvant ICB. Using melanoma to guide the interpretation of glioblastoma analyses, they were able to identify the proteins that correlate with tumour-killing T cells, tumour growth, and immune cell-cell interactions.

Co-lead author Dr Yue Lu described the research : “This work reveals similarities shared between glioblastoma and melanoma, immunosuppressive factors that are unique to the glioblastoma microenvironment, and potential co-targets for enhancing the efficacy of neoadjuvant immune checkpoint blockade.”

“This framework can be used to uncover pathophysiological and molecular features that determine the effectiveness of immunotherapies,” added Dr Alphonsus Ng, co-lead author of the paper.

ISB, UCLA and MD Anderson collaborated on the study, the findings of which were published in Nature Communications. Brain cancer represents one of the toughest settings for immunotherapy success. Collaboration between scientists and clinicians provides a great opportunity for improving patient care and achieving a deep understanding of cancer immunotherapy.


“We believe that the integrated biological, clinical and methodological insights derived from comparing two classes of tumors widely seen as at the opposite ends of the spectrum with respect to immunotherapy treatments should be of interest to broad scientific and clinical audiences,” said corresponding author and ISB President, Dr Jim Heath.

Source: PRWeb

Journal information: Yue Lu et al, Resolution of tissue signatures of therapy response in patients with recurrent GBM treated with neoadjuvant anti-PD1, Nature Communications (2021). DOI: 10.1038/s41467-021-24293-4

Categories : CancerTags :

FLASH Radiation Treatment for Tumours a Step Closer

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Heavy ion bombardment in FLASH radiation treatment could be the future of radiotherapy, with encouraging findings from a German lab.

The GSI Helmholtzzentrum für Schwerionenforschung and the future accelerator centre FAIR succeeded in performing a carbon ion FLASH experiment for the first time in their Phase 0 experiment. 

The scientists involved were able to achieve the very high dose rates required to irradiate tumours. The success was a collective effort of the GSI Biophysics Department and the accelerator crew on the GSI/FAIR campus in close collaboration with the German Cancer Research Center DKFZ and the Heidelberg Ion Therapy (HIT) center.

FLASH irradiation involves utra-short and ultra-high radiation, delivering the treatment dose in fractions of a second. Traditional radiation therapy, as well as proton or ion therapy, deliver smaller doses of radiation to a patient over an extended time period, whereas FLASH radiotherapy is thought to require only a few short irradiations, all lasting less than 100 milliseconds.

In the field of electron radiation, recent in vivo investigations have shown that the FLASH method’s ultra-high dose rate is less harmful to healthy tissue, but just as efficient as conventional dose-rate radiation to inhibit tumour growth. Such an effect has not yet been demonstrated for proton and for ion beam irradiation, which is the basis of the tumour therapy with carbon ions developed at GSI. There is still a lot of research to be done here. The results of the current experiment at GSI are now being evaluated and will contribute to new knowledge.

There have also been technical barriers to FLASH radiation. Until now, FLASH technique has only been applicable using electron and proton accelerators. While the required dose rates for electrons and protons can be achieved with a cyclotron (circular accelerator), this is more difficult with the synchrotrons required in heavy ion therapy, such as the SIS18 at GSI.

That is why the current FAIR Phase 0 experiment is a very crucial step: Thanks to the improvements at the existing GSI accelerator facility as part of the preparations for FAIR, the necessary dose rate in millisecond range can now also be achieved for carbon ions. However,  much development work remains to be done before this procedure is mature enough to be routinely used on patients in the field of electron radiation.

Professor Marco Durante, Head of the GSI Biophysics Research Department, was very pleased with this important milestone in  the development of FLASH irradiation:

“It is a forward-looking method that could significantly increase the therapeutic window in radiotherapy. I am very happy that the researchers and the accelerator team were able to demonstrate the possibility to create conditions with carbon beams that are necessary for FLASH therapy of tumors. If we can combine the great effect and precision of heavy ion therapy with FLASH irradiation while maintaining efficacy and causing little damage to healthy tissue, this could pave the way of a future radiation therapy several years from now.”

Professor Paolo Giubellino, The Scientific Managing Director of GSI and FAIR, expressed his delight at the results: “The combination of expertise in biophysics and medicine as well as engineering excellence allows the first world-class experiments FLASH irradiation with ion beams to be performed. This could result in important complements to existing radiation therapies. Applications in tumour therapy are one of the research areas that can benefit from the recent increased intensities of GSI accelerators. However, modern radiobiology will substantially benefit from beams with even higher intensities, such as we will have at the FAIR facility currently under construction. FLASH is a first example of these future directions of work”.

Source: GSI Helmholtzzentrum für Schwerionenforschung GmbH

Categories : CancerTags :

In Vitro Cancer Cells Differ to Those in Body

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Photo by Drew Hays on Unsplash

A new study has shown that most cancer cells grown in vitro have little in common genetically with cancer cells in humans.

Human cancer cells grown in culture dishes have the least genetic similarity to their human sources, according to a new computer-based technique developed by researchers at John Hopkins.

According to the researchers, the finding should help shift more resources to cancer research models such as genetically engineered mice and balls of human tissue known as ‘tumouroids’ to better evaluate human cancer biology and treatments, and the genetic errors responsible for cancer growth and progress.

“It may not be a surprise to scientists that cancer cell lines are genetically inferior to other models, but we were surprised that genetically engineered mice and tumouroids performed so very well by comparison,” says Patrick Cahan, PhD, associate professor of biomedical engineering at The Johns Hopkins University and the Johns Hopkins University School of Medicine and lead investigator of the new study.

The new computer modelling technique, CancerCellNet, compares the RNA sequences of a research model with data from a cancer genome atlas to see how closely the two sets match up.

On average, genetically engineered mice and tumouroids have RNA sequences most closely aligned with the genome atlas baseline data in 4 out of every 5 tumour types they tested, including breast, lung and ovarian cancers.

This adds to evidence that cancer cell lines grown in the laboratory have less parity with their human source due to the many differences between a human cell’s natural environment and a laboratory growth environment, the researchers said. “Once you take tumours out of their natural environment, cell lines start to change,” said Prof Cahan.

Around the world, scientists depend on a range of research models to enhance their understanding of cancer and other disease biology, and to develop treatments for conditions. Of these, one of the most widely used is cell lines created by extracting cells from human tumours and growing them with various nutrients in laboratory flasks.

Other methods involve mice that have been genetically engineered to develop cancer, or implanting human tumours into mice, known as xenografting, or use tumouroids.

To investigate the accuracy of these models, scientists often transplant lab-cultured cells or cells from tumouroids or xenografts into mice and see if the cells behave as they should — that is, grow and spread, retaining the genetic hallmarks of cancer. However, the researchers contend that this process is expensive, time-consuming and scientifically challenging and so they developed a more streamlined method. The new technique is based on genetic information about cellular RNA.

“RNA is a pretty good surrogate for cell type and cell identity, which are key to determining whether lab-developed cells resemble their human counterparts,” said Prof Cahan. “RNA expression data is very standardised and available to researchers, and less subject to technical variation that can confound a study’s results.”

To start, Prof Cahan and his team had to choose a standard set of data that acted as a baseline to compare the research models. They used data from The Cancer Genome Atlas as ‘training’ data, which includes RNA expression information of hundreds of patient tumour samples, and other information on the tumour.

They also tested their CancerCellNet tool by applying it to data where the tumour type was already known, such as from the International Human Genome Sequencing Consortium.

The John Hopkins researchers combed through The Cancer Genome Atlas data to select 22 types of tumours for study, and used that data as the baseline for comparing RNA expression data from cancer cell lines, xenografts, genetically engineered mouse models and tumouroids.

Some differences observed included prostate cancer cells from a line called PC3 that started to look genetically more like bladder cancer, Prof Cahan noted. It’s also possible, he said, that originally  the cell line was simply labelled incorrectly, or else it could have in fact been derived from bladder cancer. But, from a genetic standpoint, the prostate cancer cell line was not a representative surrogate for what happens in a typical human with prostate cancer.

According to a 0-1 scoring method, cell lines had, on average, lower scoring alignment to atlas data than tumouroids and xenografts.

Prof Cahan said he and his team will be improving the reliability of CancerCellNet by adding additional RNA sequencing data.

Source: John Hopkins Medicine

Journal information: Da Peng et al, Evaluating the transcriptional fidelity of cancer models, Genome Medicine (2021). DOI: 10.1186/s13073-021-00888-w

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.