A new UCSF study sheds light on the diversity within the most common type of pediatric liver tumor and suggests a way forward for more precise chemotherapy treatment.
The study, published in Nature Communications, used single-cell transcriptomic techniques to analyze hepatoblastoma specimens from infants and children under age four. From nine samples, the researchers identified five hepatoblastoma tumor signatures that may account for the heterogeneity in this cancer, and that may predict responses to chemotherapy treatments.
"Many pediatric tumors originate from an embryonic cell and some are bland in terms of their mutational burden," said study co-author Amar Nijagal, assistant professor in the Division of Pediatric Surgery at UCSF Benioff Children's Hospital, San Francisco. "The fact that this tumor has significant heterogeneity made us question what was driving this heterogeneity, and we wanted to learn more."
Researchers from three different labs at UCSF worked on the study, combining expertise in pediatric surgery, hepatology, and genomics, which facilitated the rare opportunity to analyze tumors directly from the operating room, Nijagal said.
Researchers are exploring a potential new therapeutic approach for triple negative breast cancer treatment. Amir Abdo Alsharabasy, a CÚRAM doctoral candidate working in the laboratory of Professor Abhay Pandit, is working on the design of nitric oxide scavengers to form a new treatment approach for this aggressive form of breast cancer.
Triple-negative breast cancer is invasive breast cancer that does not respond to hormonal therapy medicines or the current medicines that target the HER2 protein. Triple-negative breast cancer is usually more aggressive, harder to treat, and more likely to recur than cancers that are hormone receptor-positive or HER2-positive.
"Nitric oxide is one of the prominent free radicals produced by the tumor tissue", explains Amir, "It, at certain concentrations, plays a significant role in breast cancer progression by inducing the cancer cells to spread to other parts of the body Our goal is to develop injectable hydrogel formulations, which can reduce the levels of, or 'scavenge' the nitric oxide, while enhancing the generation of carbon monoxide, so that we can potentially design a new treatment approach for triple negative breast cancer."
Nitric oxide interacts with different components of the large network of proteins and other molecules that surround, support, and give structure to tumor cells and tissues in the body. Hyaluronic acid is one of the main components of this network and is the material of choice for fabricating these hydrogels.
The immune system has evolved to safeguard the body from a wildly diverse range of potential threats. Among these are bacterial diseases, including plague, cholera, diphtheria and Lyme disease, and viral contagions such as influenza, Ebola virus and SARS CoV-2.
Despite the impressive power of the immune system's complex defense network, one type of threat is especially challenging to combat. This arises when the body's own native cells turn rogue, leading to the phenomenon of cancer. Although the immune system often engages to try to rid the body of malignant cells, its efforts are frequently thwarted as the disease progresses unchecked.The illustration shows a cancer cell (center) surrounded by immune T-cells augmented with an oncolytic (cancer-fighting) virus. A new study describes how a combination of immunotherapy and virotherapy, using myxoma virus, provides new hope for patients with treatment resistant cancers.
In new research appearing in the journal Cancer Cell, corresponding authors Grant McFadden, Masmudur Rahman and their colleagues propose a new line of attack that shows promise for treatment-resistant cancers.
A joint research team led by Prof. Wang Hui, Prof. Zhang Xin and Prof. Qian Junchao from the Hefei Institutes of Physical Science (HFIPS) of the Chinese Academy of Sciences (CAS) has proposed a new kind of near-infrared-triggered nanozyme based on iron oxide nanocrystals embedded in N-doped carbon nanosheets (IONCNs), which is promising for synergistic cascade tumor therapy.
The study was published in ACS Applied Materials & Interfaces.
Chemodynamic therapy is an efficient cancer treatment method determined by the striking difference between the tumor microenvironments and normal tissues. By triggering the Fenton or Fenton-like reaction, it can generate highly toxic hydroxyl radical (·OH) to kill tumor cells.
Unfortunately, the overexpression of glutathione in tumor microenvironments limits the therapeutic efficacy by counteracting ·OH generation. Moreover, the normal cells or inflammatory cells are easily affected simultaneously owing to their similar characteristics to the tumor microenvironments. Therefore, it is necessary to develop an exogenous triggered nanozyme to realize tumor-specific catalytic therapy.
EPFL scientists have discovered a rare gene in the tumors of some colorectal cancer patients. This finding could lead to more accurate diagnoses and, eventually, personalized treatments that target the protein expressed by the gene.
Colorectal cancer is one of the most common forms of cancer in the Western world, especially in people over 50. Some 4,500 patients are diagnosed with it every year in Switzerland alone. Major therapeutic advancements in recent decades have drastically reduced the mortality rate, but scientists are still struggling to understand the molecular abnormalities that lead to tumor formation. And diagnosing colorectal cancer can be difficult, since symptoms generally don't appear until the disease has progressed to an advanced stage—at which point effective treatment options are lacking.
Colorectal cancer occurs when alterations in the DNA of cells in the colon or rectum lining cause the cells to proliferate and become tumorous. To better understand the underlying mechanisms, a team of scientists at EPFL's Laboratory of Virology and Genetics (Trono Lab) combed through data from a study in Denmark that analyzed the tumors of over 300 colorectal cancer patients. They found that some tumors contain a gene that promotes the growth and metastatic potential of cancer cells. Their findings were published in Nature Communications on 20 August 2022.
In animal studies led by researchers at Duke Cancer Institute, a drug approved to treat leukemia successfully disrupted the ability of HER2-positive breast cancer tumors from colonizing the brain.
The finding, appearing online Aug. 30 in the journal Cell Reports, provides evidence for human trials and suggests a potential new approach to derail one of the main ways that breast cancer turns deadly.
"We have made huge strides in treating HER2-positive breast cancers, but when tumors escape the therapies, they often metastasize to the brain," said senior author Ann Marie Pendergast, Ph.D., professor and vice chair of the Department of Pharmacology and Cancer Biology at Duke University School of Medicine.
"When brain metastasis occurs, treatments are unsuccessful either because the tumors have developed resistance, or the therapies cannot penetrate the blood-brain barrier," Pendergast said. "This remains a devastating diagnosis for patients."
Pendergast and colleagues looked at how HER2 promotes breast cancer growth, particularly after becoming resistant to targeted treatments that have been highly successful in prolonging lives. The HER2 protein is a driving force in 30% of breast cancers, with approximately 45% of these leading to brain metastases.
A groundbreaking study at Tel Aviv University effectively eradicated glioblastoma, a highly lethal type of brain cancer. The researchers achieved the outcome using a method they developed based on their discovery of two critical mechanisms in the brain that support tumor growth and survival: one protects cancer cells from the immune system, while the other supplies the energy required for rapid tumor growth. The work found that both mechanisms are controlled by brain cells called astrocytes, and in their absence, the tumor cells die and are eliminated.
The study was led by Ph.D. student Rita Perelroizen, under the supervision of Dr. Lior Mayo of the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience, in collaboration with Prof. Eytan Ruppin of the National Institutes of Health (NIH) in the U.S.. The paper was published in the journal Brain and was highlighted with special commentary.
Researchers at Sanford Burnham Prebys, led by Ze'ev Ronai, Ph.D., have shown for the first time that inhibiting a key metabolic enzyme selectively kills melanoma cells and stops tumor growth. Published in Nature Cell Biology, these findings could lead to a new class of drugs to selectively treat melanoma, the most severe form of skin cancer.
"We found that melanoma is addicted to an enzyme called GCDH," says Ronai, professor and director of the NCI-designated Cancer Center at Sanford Burnham Prebys. "If we inhibit the enzyme, it leads to changes in a key protein, called NRF2, which acquires its ability to suppress cancer. Now, our goal is to find a drug, or drugs, that limit GCDH activity, potentially new therapeutics for melanoma."
Because tumors grow rapidly and require lots of nutrition, researchers have been investigating ways to starve cancer cells. As promising as this approach may be, the results have been less than stellar. Denied one food source, cancers invariably find others.
GCDH, which stands for Glutaryl-CoA Dehydrogenase, plays a significant role in metabolizing lysine and tryptophan, amino acids that are essential for human health. When the Ronai lab began interrogating how melanoma cells generate energy from lysine, they found GCDH was mission-critical.
In the summer and fall of 2019, some cancer patients experienced interruptions in their treatment. The reason was a shortage of the drugs vinblastine and vincristine, essential chemotherapeutic medicines for several types of cancer.
There are no alternatives to these drugs that are isolated from the leaves of the Madagascar periwinkle plant, Catharanthus roseus. Two active ingredients from the plant-vindoline and catharanthine—together form vinblastine, which inhibits the division of cancer cells.
Although the plant is common, upwards of 2000 kg of dried leaves are needed to produce 1 g of vinblastine. The 2019 shortage that lasted until 2021 was mainly caused by delays in the supply of these ingredients.
A cross-disciplinary international team of scientists led by DTU researchers has genetically engineered yeast to produce vindoline and catharanthine. They have also managed to purify and couple the two precursors to form vinblastine. Thus, a new, synthetic approach to making these drugs has been discovered. Their results are published today in the journal Nature.
A study led by researchers at the University of Arizona Health Sciences discovered new information about the inner workings of the immune system that could have a profound impact on T cell therapies for cancer and other diseases.
T cells are a type of white blood cell essential to the immune system and defending the body against infection. The CD4 molecule is found on the surface of many T cells and has historically been thought to only play a supporting role in the cell's functions. The paper, "Enhancing and inhibitory motifs regulate CD4 activity," published in eLife, shows CD4 plays a more active role in regulating T cell receptor signaling.
The study took a unique evolutionary approach to the immune system by examining the ways T cells have changed or remained the same over time. Michael Kuhns, Ph.D., associate professor in the UArizona College of Medicine—Tucson's Department of Immunobiology, and Koenraad Van Doorslaer, Ph.D., assistant professor in the UArizona College of Agriculture and Life Sciences' School of Animal and Comparative Biomedical Sciences, assembled a team that focused on the evolution and function of CD4.
"This study is giving us a better appreciation for how CD4 works in concert with the T cell receptor to naturally direct T cells," said Dr. Kuhns, who serves on the Center for Advanced Molecular and Immunological Therapies advisory committee. "CD4 is very much a co-equal player in antigen recognition and T cell activation."
A new method of separating cancer cells from non-cancer cells has been developed by researchers at the Wellcome Sanger Institute, in a boost for those working to better understand cancer biology using single-cell mRNA sequencing.
The study, published today in Communications Biology, improves on existing methods to identify which cells in a sample are cancerous and provides crucial data on the microenvironment of tumors. The software is openly available for researchers around the world to apply to their own data, advancing the effectiveness of single-cell sequencing to understand cancer.
Single cell mRNA analysis of cancer cells is one of the leading edge techniques being used to better understand cancer biology. The data generated can be used to try to disrupt cancers with drugs or work out how cancers arise in the first place.
A fundamental step in this process is separating cancer and non-cancer cells, but this isn't always an easy task. As well as the many types of cancer, there will also be molecular differences between cancer cells of the same type within a single tumor.
Currently, the best method of doing this is to measure the average gene expression of cells in the sample, with higher or lower expression used to distinguish cancer cells from healthy cells. But this method can lead to false conclusions.
In this new study, researchers at the Wellcome Sanger Institute performed whole genome sequencing and single-cell mRNA sequencing on samples collected by Great Ormond Street Hospital (GOSH).
Blood tests—simple, noninvasive and economically feasible—promise to become the next major milestone in cancer diagnosis. However, most of these tests, dubbed liquid biopsies, are currently not reliable enough for widespread use. A new, multiparameter approach developed at the Weizmann Institute of Science may lead to a blood test that will diagnose cancer with unprecedented accuracy. This research is being published today in Nature Biotechnology.
"Many of the conventional methods clinically available today to detect and diagnose cancer are invasive and unpleasant," explains Dr. Efrat Shema of Weizmann's Immunology and Regenerative Biology Department, who headed the research team. Obtaining biopsy samples via needle, endoscopy or surgery can be painful and sometimes risky, and imaging methods, such as MRI or PET scans, require costly, bulky equipment that is not universally available. Effective blood tests for cancer screening or diagnosis could provide an attractive alternative.
"Eliminating the discomfort means that people would be less likely to avoid getting tested—and more likely to have their cancers detected earlier," says Vadim Fedyuk, who led the study together with fellow graduate student Nir Erez.
The idea for diagnosing cancer using liquid biopsies arose from the fact that blood contains free-floating DNA and proteins shed by dead blood cells in healthy people—and in cancer patients, by dead tumor cells as well. "Some of the byproducts of cell destruction, including cancer DNA and proteins, are dumped into the bloodstream, and we know how to collect and analyze them," Shema says.
The billions of immune cells that help protect us from diseases do amazing things, but sometimes they need a little boost. For decades, scientists have been trying to figure out ways to engineer living immune cells to better combat aggressive diseases, like cancer.
One big, relatively recent advancement in the fight against cancer is CAR T-cell therapy, a treatment that involves modifying immune cells called T cells, microscopic powerhouses that take on infections. Scientists have figured out a way to remove T cells from a person's blood, insert a special kind of gene called a receptor, which binds to cancer cells, and transfer the engineered T cells back to the patient. This type of receptor—a chimeric antigen receptor, or CAR—is tailored to match the specific cancer being targeted and has been found to be effective for treating certain types of cancer, especially leukemia. Once CAR-T cells reenter the bloodstream, they start to replicate and begin their fight.
"It is very exciting technology," says Wilson Wong, a Boston University College of Engineering associate professor of biomedical engineering, who has been studying CAR-T cells for over 10 years. But there are problems with safety, he says, that can make the therapy extremely risky.
At times, CAR-T cells overstimulate the immune system, which triggers the release of a substance called cytokine. This can cause a potentially fatal inflammatory condition known as cytokine release syndrome. Other serious complications can include neurological difficulties, or other organs in the body being mistakenly targeted by the immune cells.
To make this groundbreaking therapy less risky for patients, Wong and a team of researchers are working to create a safety switch built into the CAR-T cell design. In a new paper in Cancer Cell, the researchers reveal a new type of CAR-T cell that can be turned on or off, making it possible to stop cells from activating before severe side effects occur.
A team of researchers from Japan has discovered that the distribution of platinum within a tumor following platinum-based chemotherapy treatment of ovarian cancer may predict whether the tumor will be resistant to further treatment. The research could offer ways to manage treatment for women whose tumors may be resistant to further platinum-based chemotherapy.
One of the biggest problems with treating ovarian cancer is completely removing the cancer surgically. To facilitate easier surgical removal, patients are given platinum-based chemotherapy drugs early in treatment to shrink the tumor. These drugs introduce platinum into the DNA of the cancer cells making up the tumor, which makes the DNA difficult to read and causes the cells to die.
However, if the tumor is not completely removed, it takes advantage of the body's weakened immunity and comes back, often growing faster than before.
Because the tumor has experienced the treatment before, it develops increased resistance to it, in the same manner that bacteria can become resistant to antibiotics. Repeated exposure leads to 80% of women developing ovarian cancer tumors that are resistant to further treatment. Therefore, a technique that would allow doctors to tell if the patient will develop resistance to these commonly used drugs would make this process a lot more effective.
Vaping may ‘wake up’ cancer cells and trigger wave of disease in a decade
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Vaping could cause a new wave of cancer in ten years’ time, according to scientists.
Researchers at the Francis Crick Institute (FCI) say while vaping is safer than smoking cigarettes, the long-term health risks are unclear.
Around 3.6 million people in Britain smoke e-cigarettes and are commonly used by ex-smokers to help them quit.
Professor Charles Swanton, clinical scientist at the FCI and chief clinician at Cancer Research UK, says vaping poses a potential threat to people’s health.
“I don’t think we can say vaping is necessarily a safe option to quit smoking. It may be safer but that doesn’t mean it’s safe,” he said.
The HSD3B1 gene could hold clues for predicting and treating endometrial cancer, according to a novel finding from the Cleveland Clinic's Lerner Research Institute.
Researchers found a certain HSD3B1 genotype was more common in women with type 2 endometrial cancer, according to the results published in JNCI Cancer Spectrum. Those patients show lower survival rates than those diagnosed with type 1 endometrial cancer, likely driven by the fact that type 2 patient cells are less hormone-dependent.
The results are the latest step in untangling the role HSD3B1's genotype plays in hormone-driven cancers, with previous research revealing associations with breast and prostate cancer. This body of work was in part led by Cleveland Clinic researchers and physician-scientists, and continues today with translational research and clinical trials.
Mount Sinai researchers have made two important discoveries about the mechanism by which bladder cancer cells foil attacks from the immune system. The research, published in Cancer Cell in September, could lead to a new therapeutic option for patients with these types of tumors.
Advanced bladder cancer is aggressive and patients generally have poor prognoses. Several immune checkpoint inhibitors have been approved by the Food and Drug Administration for bladder cancer, but they only sustain good responses in about 20 percent of patients.
When people get cancer, a type of immune cell called a "natural killer cell" swings into action to try to kill off the tumor cells. However, the tumor cells are often able to foil the attacks from the natural killer cells. The Mount Sinai researchers reported that they had found a subset of CD8 T cells that adapts to tumor evasion strategies by appropriating innate-like properties traditionally ascribed to natural killer cells, offering a strategy to reduce the tumor cells' ability to fight them off.
To create additional killer cells, the researchers showed that they could induce CD8+ T cells to express a molecule known as NKG2A on their surface, allowing them to behave more like natural killer cells. This study showed that NKG2A is associated with improved survival and with responsiveness to a cancer-fighting immunotherapy known as PD-L1 checkpoint blockade.
Tumor cells are notoriously good at evading the human immune system; they put up physical walls, wear disguises and handcuff the immune system with molecular tricks. Now, UC San Francisco researchers have developed a drug that overcomes some of these barriers, marking cancer cells for destruction by the immune system.
The new therapy, described in Cancer Cell, pulls a mutated version of the protein KRAS to the surface of cancer cells, where the drug-KRAS complex acts as an "eat me" flag. Then, an immunotherapy can coax the immune system to effectively eliminate all cells bearing this flag.
"The immune system already has the potential to recognize mutated KRAS, but it usually can't find it very well. When we put this marker on the protein, it becomes much easier for the immune system," said UCSF chemist and Howard Hughes Medical Institute Investigator Kevan Shokat, Ph.D., who also helped lead the new work.
KRAS mutations are found in about one quarter of all tumors, making them one of the most common gene mutations in cancer. Mutated KRAS is also the target of sotorasib, which the Food and Drug Administration (FDA) has given preliminary approval for use in lung cancer, and the two approaches may eventually work well in combination.
University of Minnesota researchers and their collaborators at the National Cancer Institute (NCI) investigated the role of a new intracellular checkpoint gene in regulating T-cell function against solid tumors. Known as CISH, the team published results in Med that show the checkpoint gene plays a key role in suppressing the ability of human T-cells to recognize and attack cancer cells.
When CISH is disabled, T-cells more effectively recognize mutated proteins produced by tumors. CISH inhibition also preserved T-cell fitness and made T-cells more responsive to existing checkpoint therapies, suggesting a new avenue to make breakthroughs in cancer immunotherapy.
"It is a true bench-to-bedside story that is currently being deployed in patients with metastatic gastrointestinal cancer who have exhausted virtually all other treatment options," said Beau Webber, Ph.D., an assistant professor at the University of Minnesota Medical School and member of the Masonic Cancer Center. "We are applying what we found in the lab to patients seeking care for gastrointestinal cancer."
The treatment of blood cancers has dramatically improved in the last five years, thanks to a new class of cancer immunotherapies called CAR-T cell therapy. This therapy—which involves engineering a patient's own T cells in the lab to kill cancer cells and then infusing them back into the patient—cures about 40% of people with otherwise incurable lymphoma. But others relapse or don't respond to the treatment at all.
To learn about the molecular mechanisms underlying such different responses, researchers at the Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute, and Massachusetts General Hospital, studied blood samples of patients who received CAR-T therapy. They found molecular markers that indicate how a patient responded to the treatment, and also identified specific types of immune cells that likely contribute to relapse.
The authors say their study, which appears today in Nature Medicine and is part of a Broad and IBM collaboration investigating resistance to cancer treatment, could one day help doctors select the best treatment for their patients and help scientists optimize these therapies to improve response rates.
"Gaining understanding of the T cell phenotypes of CAR-T cells before and after infusion provides us with insight into the basis for why patients do or do not respond to this potentially life-saving therapy," said Catherine Wu, co-senior author on the study and an institute member at Broad, professor of medicine at Harvard Medical School and Dana-Farber, and staff physician at Dana-Farber and Brigham and Women's Hospital.
