Category: Cancer

Categories : Cancer ImmunologyTags :

New Biomarker Can Predict Response to Checkpoint Inhibitor Therapy

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A team of researchers at Roswell Park Comprehensive Cancer Center have identified a biomarker that could be used to predict how well immune checkpoint inhibitors will be tolerated.

Immune checkpoint inhibitors (ICI) activate anti-tumour defences either through the disruption of inhibitory interactions between antigen-presenting cells and T cells at so-called checkpoints or else through the stimulation of activating checkpoints. Not all patients can tolerate ICI well; side effects can be severe, including colitis, which is one of the most common.

Pre-treatment biomarkers are of limited value in predicting response to ICI. Tumour biopsy shortly after ICI therapy is started can provide helpful information, but is invasive and difficult to do in some certain cancers.
Uncovering blood-based biomarkers that reflect the change of the tumour microenvironment and can predict a patient’s response to ICIs could improve current treatment regimens significantly, Dr. Ito notes. The team’s previous research indicates that T cells with varying levels of the chemokine receptor CX3CR1 responded differently to ICI therapy.

Based on those findings, the researchers sought to test CX3CR1 as a T cell biomarker in ICI therapy. They found that ICI therapy is linked to increased frequency and clonality of some CX3CR1-positive T cells; that the frequency of these CD8+ T cells stays high during ICI therapy; and that there are many genomic similarities between CD8+ tumour-infiltrating lymphocytes and this subset of CX3CR1-positive T cells.

Fumito Ito, MD, PhD, FACS, explained: “Although ICIs revolutionized the cancer treatment for significant numbers of people, many cancer patients do not respond to them, and some develop severe toxicity.”

“Currently, we are in need of a better biomarker to predict the response to immunotherapy, which is part of standard treatment in advanced and metastatic lung cancer,” said Hongbin Chen, MD, PhD. “This study sheds light on a promising blood-based biomarker that is potentially very useful in identifying which patients with lung cancer are most likely to benefit from immunotherapy. We look forward to investigating its utility in further clinical research.”

Source: News-Medical.Net

Journal information: Yamauchi, T., et al. (2021) T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors. Nature Communications.doi.org/10.1038/s41467-021-21619-0.

Categories : CancerTags :

Iron is a ‘Double-edged Sword’ For Cancer Cells

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A grant by the American Cancer society will be used to investigate the treatment of certain neuroblastoma by forcing them to overloading on iron.

Neuroblastoma is a cancer that forms in nerve tissue, and most commonly in the glands around the kidneys. It is the most frequently occurring childhood cancer that occurs outside the cranium. MYCN is overexpressed in 20-25% of neuroblastoma, and these cancers contribute to a considerable portion of paediatric cancer-related deaths. Recent research has shown that the MYCN gene introduces a weakness to ferroptosis-inducing drugs because MYCN draws on a lot of iron to help the cancer grow.  

“Iron is a double-edged sword in a cancer cell. It can help the cancer grow and survive, but it also creates these toxic molecules within the cell called reactive oxygen species,” explained Anthony Faber, PhD.

Reactive oxygen species (ROS) are unstable molecules that react with other molecules, causing DNA damage and cell death. This recently discovered form of cell death, largely influenced by iron accumulation, is called ferroptosis. Little is known about ferroptosis, and even less about cancers which may be vulnerable to ferroptosis-inducing drugs. By boosting cellular toxin removal systems, MYCN produces so much iron that it also creates a vulnerability to drugs which prevent cells from eliminating ROS. Blocking these toxin removal systems causes death among MYCN-amplified cells. 

“As MYCN continues to be one of the most important targets in cancer therapeutics, this study highlights a new and clinically important strategy for treating MYCN-associated cancers,” Dr Faber said.

“Fortunately, the Cancer Mouse Models Core run by Jennifer Koblinski, PhD, and Bin Hu, PhD, at Massey is spectacular and will allow us to robustly test these FDA-approved drugs in both patient-derived models and orthotopic models, where the tumors grow atop the adrenal glands similar to the way they grow in patients,” Dr Faber said.

If these models show positive results for the testing of these drugs, they can move on to clinical trials. He added that this study may have far reaching implications, as in certain small cell lung cancers and triple negative breast cancer, whose growth is driven c-MYC, a similar protein .

Source: Medical Xpress

Journal information: Konstantinos V. Floros et al, MYCN-amplified neuroblastoma is addicted to iron and vulnerable to inhibition of the system Xc-/glutathione axis, Cancer Research (2021). DOI: 10.1158/0008-5472.CAN-20-1641

Categories : Cancer Medical Research & TechnologyTags :

Neural Network Matches Dermatologists’ Assessment of Skin Lesions

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Researchers have developed an AI-based tool that can use smartphone camera pictures to spot suspicious pigmented lesions (SPLs) with an accuracy close to that of professional dermatologists.

Such technology would hardly put dermatologists out of work; on the contrary, there is a great need for readily available skin cancer screening. In the US, there are only 12 000 practising dermatologists, who would need to see over 27 000 patients each per year in order to screen the entire population for SPLs which could lead to cancer. Computer-aided diagnosis (CAD) has thus been developed over previous years to help assist in diagnosis, but thus far had failed to spot melanomas in a meaningful way. Such CAD programs only analyse individual SPLs, while dermatologists compare other lesions on the same patient to reach a diagnosis, called ‘ugly duckling’ criteria.

This shortcoming has been addressed in a new CAD system that uses convolutional deep neural networks (CDNNs) developed by researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Massachusetts Institute of Technology (MIT).

The new system was able to distinguish SPLs from non-suspicious lesions in photos of patients’ skin at ~90% accuracy, and established an ‘ugly duckling’ criteria which could match three dermatologists’ consensus 88% of the time.

“We essentially provide a well-defined mathematical proxy for the deep intuition a dermatologist relies on when determining whether a skin lesion is suspicious enough to warrant closer examination,” said first author Luis Soenksen, PhD, a Postdoctoral Fellow at the Wyss Institute who is also a Venture Builder at MIT. “This innovation allows photos of patients’ skin to be quickly analyzed to identify lesions that should be evaluated by a dermatologist, allowing effective screening for melanoma at the population level.”

The researchers used a database of 33 000 images to train the system, which also included background elements and non-skin elements. These extraneous elements were left in so that the CDNN would be able to use normal images taken by consumer-grade cameras. The images contained SPLs and non-suspicious skin lesions identified by three certified dermatologists.
The software then developed a ‘map’ of how far away a lesion was from the others in terms of similarity, giving an ‘ugly duckling’ criteria. To test the software, they used 135 photos from 68 patients, which assigned an ‘oddness’ score to each lesion. This was then compared to dermatologists’ assessments of those lesions, matching individual dermatologists 88% of the time and their consensus 86% of the time
“This high level of consensus between artificial intelligence and human clinicians is an important advance in this field, because dermatologists’ agreement with each other is typically very high, around 90%,” said co-author Jim Collins, PhD, of the Wyss Institute, who is also the Termeer Professor of Medical Engineering and Science at MIT. “Essentially, we’ve been able to achieve dermatologist-level accuracy in diagnosing potential skin cancer lesions from images that can be taken by anybody with a smartphone, which opens up huge potential for finding and treating melanoma earlier.”

Source: Medical Xpress

Journal information: “Using deep learning for dermatologist-level detection of suspicious pigmented skin lesions from wide-field images” Science Translational Medicine, 2021.

Categories : CancerTags :

Osmium in Cancer Cells May Be a Useful Weapon

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Using powerful X-ray beams to probe inside a cancer cell, researchers have determined that osmium could be a viable element for new cancer drugs.

About half of all chemotherapy drugs use platinum, but this has platinum which reacts in the nucleus, possibly leading to undesirable side effects. Osmium is a rare metal which could replace platinum in chemotherapy drugs, but first researchers needed to know where the osmium would wind up. To determine this, the researchers used the Diamond synchrotron to precisely track osmium in human lung cancer cells with a precision of 100 nanometres.

The researchers revealed the functioning of osmium in the cells using synchrotron X-ray Fluorescence (XRF) imaging. This enabled the researchers to observe the osmium in a single lung cancer cell. However, since osmium’s reactivity is determined by its ligand coating, these were labelled with bromine.

Once in the cell, the researchers observed that the osmium stayed in the cytoplasm, while the ligands penetrated into the nucleus, suggesting a twin attack on the cell.

Professor Peter Sadler, from the Department of Chemistry at the University of Warwick explained the use of osmium and their research process: “Osmium is a rare precious metal, however, since it can act as a catalyst, a very little amount is needed for reactions in the cancer cell, therefore it could be a sustainable treatment going forward. We wanted to see how exactly it worked in a single cancer cell, which involved a variety of novel techniques, including taking water molecules out of the cell and rapidly flash-freezing it. Whereas usually cells are chemically altered to see the reactions, in our method they are close to their natural state, making our results more authentic.”

It was hard work, as Dr Elizabeth Bolitho, from the Department of Chemistry and Diamond explained: “We worked 24 hours a day, 5 days a week to collect these exciting data, allowing us to see inside cancer cells to a nanoscale resolution. This has provided crucial insights into potential cellular targets of such Osmium catalysts.

“Not only were we able to track the osmium in a lung cancer cell, but more widely in breast cancer, ovarian and prostate cancer cells, for example, which provides hope that in the future osmium could be used to treat a range of different cancer.”

Source: News-Medical.Net

Journal information: Bolitho, E. M., et al. (2021) Tracking Reactions of Asymmetric Organo‐Osmium Transfer Hydrogenation Catalysts in Cancer Cells. Angewandte Chemie. doi.org/10.1002/anie.202016456.

Categories : Cancer Diet and NutritionTags :

Decreasing Cancer Deaths with Population-wide Vitamin D

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Supplementation Scientists have estimated that supplementing the over-50 population in Germany with sufficient vitamin D would save 30 000 lives which would otherwise be lost to cancer, gaining some 300 000 extra years of life, all while reducing healthcare costs.

Vitamin D is created in the body through the interaction of UV-B radiation with dehydrocholesterol, which is produced in the skin, into vitamin D3 (cholecalciferol). In many countries, populations have chronically low vitamin D levels due to more time being spent indoors. Vitamin D supplementation is associated with the prevention and treatment of nutritional rickets and osteomalacia, but it is important for other aspects of health such as prevention of respiratory tract infections and asthma. In countries such as Germany, low sunlight levels for much of the year combined with more time spent indoors results in much of the population having inadequate vitamin D levels. 

Three large meta-analyses had indicated that mortality due to cancer is reduced by 13% with vitamin D supplementation.

“In many countries around the world, the age-adjusted rate of cancer mortality has fortunately declined over the past decade,” said Hermann Brenner, epidemiologist at the German Cancer Research Centre (DKFZ).  However, given the often considerable costs of many new cancer drugs, this success has often come at a high price. Vitamin D, on the other hand, is comparatively inexpensive in the usual daily doses.”

To get their figures, the scientists used a daily administration of 1000 international units of vitamin D, costing 25 Euros per person per year. Since about 36 million people over the age of 50 live in Germany, this results in an annual cost of 900 million Euros.

The researchers calculated the number of years lost to cancer death, and also did not account for testing of vitamin D levels, as the proposed 1000 international units were far short of an overdose danger. The study estimated that if the entire German population over the age 50 were given sufficient supplements to achieve the recommended levels of vitamin D, 30 000 cancers deaths annually would be prevented.

“In view of the potentially significant positive effects on cancer mortality – additionally combined with a possible cost-saving – we should look for new ways to reduce the widespread vitamin D deficiency in the elderly population in Germany. In some countries, foods have even been enriched with vitamin D for many years – for example, in Finland, where cancer mortality rates are about 20 percent lower than in Germany. Not to mention that there is mounting evidence of other positive health effects of adequate vitamin D supply, such as in lung disease mortality rates,” said Brenner, adding, “Finally, we consider vitamin D supplementation so safe that we even recommend it for newborn babies to develop healthy bones.”

Spending about 12 minutes two to three times a week in the sun, with face, hands and parts of the arms and legs all uncovered and without sunscreen is sufficient to provide enough vitamin D.

Source: News-Medical.Net

Journal information: Niedermaier, T., et al. (2021) Vitamin D supplementation to the older adult population in Germany has the cost‐saving potential of preventing almost 30,000 cancer deaths per year. Molecular Oncology. doi.org/10.1002/1878-0261.12924.

Categories : CancerTags :

Tumour Weakened against Radiation by Tweaking a Certain Protein

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The vulnerability of specific tissues to ionising radiation has been linked to the time-varying levels of a tumour-suppressing protein, opening new avenues for cancer combination therapy.

The ability for cells to survive radiation damage has been known to be connected to p53, but tissues with vastly different levels of p53 have been shown to have great differences in sensitivity. In the face of this apparent paradox, researchers from Blavatnik Institute at Harvard Medical School, Massachusetts General Hospital, and the Novartis Institutes for BioMedical Research investigated the behaviour of p53 in irradiated tissues.

“Dynamics matter. How things change over time matters,” said co-corresponding author Galit Lahav, the Novartis Professor of Systems Biology at HMS. “Our ability to understand biology is limited when we only look at snapshots. By seeing how things evolve temporally, we gain much richer information that can be critical for dissecting diseases and creating new therapies.”

Ionising radiation randomly damages a cell’s molecular machinery, causing it to initiate cell death if it is too serious. The arbitrator of cellular suicide is p53, which is also involved in tumour suppression. 

The findings opened new avenues for combination cancer therapies, as they discovered that administering a drug that blocks p53 levels from oscillating resulted in tumours in mice being more susceptible to radiation. 
Administering to the mice an experimental anti-cancer drug that inhibits MDM2, a protein which degrades p53, they forced p53 to stay elevated. The large intestine, which is normally radiation resistant, showed increased vulnerability.

Testing out this enhanced vulnerability on human tumours transplanted into mice, a significant tumour shrinkage was seen following radiation and then MDM2 inhibitor administration.

Co-corresponding author Galit Lahav, Novartis Professor of Systems Biology, Harvard Medical School explained: “By irradiating first, we force the cancer cells to activate p53, and by adding MDM2 inhibitor on top of that, we can keep p53 active longer. This combination has a much stronger effect than either alone.”

The findings showed the importance of understanding the role of p53 in cancer, the dynamic nature of which is not being looked at in studies testing MDM2. More research into the biological pathways of p53 is called for. 
“For a lab studying p53, cancer is always a major motivation. Our goal is to acquire knowledge to help develop better and more efficient therapies,” Lahav said. “Understanding how p53 behaves over time in different conditions is a critical piece of the puzzle.”

Source: News-Medical.Net

Journal information: Stewart-Ornstein, J., et al. (2021) p53 dynamics vary between tissues and are linked with radiation sensitivity. Nature Communications.doi.org/10.1038/s41467-021-21145-z

Categories : Cancer ImmunologyTags :

Immune Cells in Prostate Tumours Boost Survival with Immunotherapy

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A new Northwestern Medicine study discovered the reason why black men are more likely to survive prostate cancer when given immunotherapy. 

Black men die more often from prostate cancer, yet are more likely to respond to immunotherapy. The increased presence of a type of immune cell in the tumours of black men appears to be related to their increased odds of survival with immunotherapy. The findings will be published on February 10 in Nature Communications.

A research team by Dr Edward Schaeffer, chair of urology at Northwestern University Feinberg School of Medicine and Northwestern Medicine, found that men who survive prostate cancer with immunotherapy have been found to have more plasma cells. Plasma cells are a type of specially differentiated B cell, which secrete antibodies and play a key role in the adaptive immune response.

“If a man’s prostate cancer has numerous plasma cells, we found he had improved cancer survival,” Schaeffer said. “Our study suggests plasma cells are important in the body’s response to cancer.”

Recent studies have shown that black men with advanced prostate cancer have on average better response to immunotherapy than white men. However, there has been no way to determine which individuals would have a better response, regardless of race.

Schaeffer’s team went through the genomics of 1300 tumour samples classified to genetic ancestry or self-identified race, and found more plasma cells in the tumours of black men than those of white men. However, the finding was not unique to black men alone, as elevated plasma cells in all men raised the odds of cancer-free survival after surgery.

“The finding comes at a time as researchers are discovering plasma cells may play a greater role in cancer immunotherapy than previously thought,” said first author Dr. Adam Weiner, a Northwestern Medicine urology resident. “Testing for plasma cells in prostate cancer may help identify men who will benefit from immune-based treatments.”

Source: Medical Xpress

Categories : Cancer GeneticsTags :

RNA Knockout Halts the Spread of Triple-negative Breast Cancer

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The University of Westminster has released a new study showing that taking out small chunks of human DNA called microRNA can reverse the spread of triple negative breast cancer cells.

The study also suggested that microRNAs could be targeted to spot and treat triple negative breast cancer. Breast cancer is the most common cancer in women, and triple negative breast cancer makes up 10-20% of cases.

MicroRNAs (miRs) have important roles in cellular functioning and signalling, and are heavily involved in the growth and metastasis of cancers. The researchers found that miR-21, a major breast cancer-related RNA, is increased in triple negative breast cancer and is also associated with metastasis.

Using CRISPR/Cas9, the researchers knocked out miR-21 from the cancer cells, and discovered that the cancer cells’ metastatic properties were reversed. They also observed that they released smaller vesicles, which release lipid blobs that play an important part in cancer spread. There was also less miR-21 carried in the vesicles, which also carry disease-related molecules to other cells.

Lead researcher Dr Pinar Uysal-Onganer of the University of Westminster, said: “This is an important study which contributes to better understanding of roles of miRs in aggressive cancer types such as triple negative breast cancer. We are now aiming to clarify the relationships between miR-21 and cancer drug resistance, which is another important factor that limits cancer cure.”

Source: Medical Xpress

Journal information: Elif Damla Arisan et al. MiR-21 is Required for the Epithelial–Mesenchymal Transition in MDA-MB-231 Breast Cancer Cells, International Journal of Molecular Sciences (2021). DOI: 10.3390/ijms22041557

Categories : CancerTags :

New Ultrasonic Tumour Therapy

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A new technique has been developed that uses ultrasound to vapourise encased nano-droplets, at the tumour site. This technology could be used to image the tumour, damage it or even deliver chemotherapy drugs with precision.

Existing applications of ultrasound therapy include thermal excitation of tissues, for example to dilate blood vessels, and creating cavitation to break up kidney stones. Ultrasonic toothbrushes have also been shown to remove dental plaque with better efficiency than conventional toothbrushes, and about the same as that of mechanical electrical toothbrushes. Micrometre-sized droplets, encased in a stabilising shell, can already be visualised with ultrasound, but these are too large to enter tumours. Nanometre-sized droplets can do so, however.

Vapourisation is tricky to control in reality, since the process requires a point of nucleation. The researchers demonstrated an efficient way to achieve vapourisation: by applying a frequency at the exact resonant frequency of the droplet, the pressure inside suddenly drops and the liquid vapourises. This is much the same principle as shattering a crystal glass by bombarding it with sound at its resonant frequency.

The researchers used hydrofluorocarbons,  which have a very low boiling point,   for the droplets. The resonance of the droplet being six times higher makes vapourisation much easier. The speed of sound of the droplet fluid being lower than the speed of sound in the bodily fluids surrounding it.
This resonant droplet vapourisation technology has a number of possible medical applications. The bubbles from the bursting droplets could be used to physically damage the tumour. Or, the droplets could contain chemotherapy drugs and made to break open precisely inside the tumour and reducing exposure of the rest of the body.

Source: News-Medical.Net

Journal information: Lajoinie, G. et al. (2021) High-Frequency Acoustic Droplet Vaporization is Initiated by Resonance’ by Guillaume Lajoinie, Tim Segers, and Michel Versluis. Physical Review Letters. doi.org/10.1103/PhysRevLett.126.034501.

Categories : Cancer Cardiovascular DiseaseTags :

Simvastatin Treatment Hope for Subtype of Ovarian Cancer

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Researchers have found that simvastatin has anti-proliferative potential against ovarian clear cell carcinoma, a highly lethal gynaecological cancer.

Dr Ingrid Hedenfalk from The Lund University explained: “Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) accounting for 5–10% of cases diagnosed in Europe and America, while the incidence in Asia is reported to be higher (10–20%).”

GTPases are a range of enzymes that hydrolyse guanosine triphosphate (GTP) to guanosine diphosphate (GDP). They are also involved in cells as switches and timers. Rho GTPases have been studied for their role in cancers. However, it is difficult to target Rho GTPases directly, so research has involved indirect strategies.

The researchers tested three cell lines of OCCC and one line of high-grade serous ovarian carcinoma (HGSOC) with simvastatin, which is a Rho GTPase interfering drug, and another GTPase interfering drug, CID-1067700, as a control. CID-1067700 is a pan-GTPase, which makes it useful as a comparator.

The research was motivated by a study which found deregulated expression of both Rho GTPases and cytoskeletal pathways in primary human OCCC tumours. The OCCC cell lines treated with simvastatin showed reduced c-Myc protein expression and signs of cell death, as well as curbing proliferation and migration.

Simvastatin could act through Rho GTPase interference as simvastatin affects the cytoskeletal integrity of OCCC cells at clinically relevant levels. However, the mechanism involved is different from Rho GTPase inhibition by CID-1067700.

However, caution is warranted with simvastatin as combination with chemotherapy may yield an antagonistic response. Further research is warranted to develop simvastatin as a potential drug candidate for the treatment of OCCC. 

Source: Oncotarget

Journal information: Arildsen N, Hedenfalk I. Simvastatin is a potential candidate drug in ovarian clear cell carcinomas. Oncotarget. 2020;11(40):3660-3674. doi:10.18632/oncotarget.27747