MIT chemical engineers have developed a way of swiftly screening compounds to determine their therapeutic potential for certain kinds of cancers. With a genetically engineered sensor and high-throughput technology, their method probes for changes in cellular concentrations of hydrogen peroxide (H2O2), a specialized molecule known as an oxidant.
"The regulatory pathways of some tumors depend on elevated levels of H2O2," says Hadley Sikes, associate professor and Esther and Harold E. Edgerton Career Development Professor in the Department of Chemical Engineering. "But further increases in concentrations of this oxidant can lead to programmed cell death." In the researchers' screens of 600 small-molecule compounds, they were able to identify those that selectively boosted H2O2.
Other research efforts have used probes that respond indiscriminately to different kinds of oxidants, making it difficult to determine precisely which compounds make the greatest impact on these specialized molecules. The MIT screen is the first to zero in on a single oxidant. This enabled the team to characterize the cellular responses to potential drugs and to demonstrate that some of these compounds activated H2O2-mediated toxicity in susceptible cancer cell lines.
Their research appears in Cell Chemical Biology. Yining Hao and Troy F. Langford are first co-authors. The other contributors are Sun Jin Moon, a graduate student in chemical engineering, Kristen A. Eller, who worked on the project while an undergraduate, and Sikes.
New findings by UT Southwestern researchers promote understanding of how one of the most commonly mutated genetic drivers of cancer passes signals that cause the disease.
The study, published in Nature Structural & Molecular Biology, focuses on a family of proteins called RAS, which is mutated in 20 to 25% of all cancers, especially in lethal cancers such as pancreatic, colorectal and lung cancers.
"A framework to develop RAS inhibitor strategies is badly needed because recently approved RAS inhibitors such as sotorasib only work against one specific mutation, and many other RAS mutations also cause cancer," said Kenneth Westover, M.D., Ph.D., Associate Professor of Radiation Oncology and Biochemistry, member of the Chemistry and Cancer Research Program in the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, and an author of the study. "This work sets the stage for development of new targeted RAS inhibitors to address major drivers of lethal cancers, such as pancreatic and colon cancer."
Starting in 2012, Dr. Westover's lab worked with the Dana-Farber Cancer Institute to develop drugs that bind to a specific RAS mutant where a glycine amino acid at position 12 in the RAS protein is changed to a cysteine, the so-called KRAS G12C.
"Cysteine is a distinctive amino acid that allows us to irreversibly attach drugs using special chemistries. Other major cancer-associated RAS mutations do not give us the same foothold," Dr. Westover said.
A team led by scientists at Baylor College of Medicine uncovered new evidence supporting a cancer-promoting role for enzyme MAPK6. The study, published in the journal Science Advances, shows that MAPK6 furthers cancer growth by activating the AKT pathway, a known cancer-promoting cellular mechanism. The findings suggest that therapies directed at interfering with MAPK6 activity in cancer may offer an effective treatment approach for this condition.
"Studies on the role of MAPK6 in human cancer have produced inconclusive results," said corresponding author Dr. Feng Yang, assistant professor of molecular and cellular biology at Baylor. "Some studies concluded that MAPK6 promoted cancer growth while others indicated the opposite effect. In the current study, we investigated the role of MAPK6 in several cancer cell lines and animal models of the condition and also studied the mechanism mediating MAPK6 effects."
Yang and his colleagues began by investigating the effect of overexpressing the MAPK6 gene in normal human prostate or breast epithelial cells grown in the lab.
Immune checkpoint inhibitors are a type of cancer treatment that help the immune system's T cells recognize and attack tumors. But these immunotherapy drugs aren't effective against all cancers. In a study published today in Science Advances, University of Pittsburgh and UPMC researchers reveal how certain cells drive immunotherapy resistance in a mouse model of ovarian cancer and show that targeting a signaling pathway in these cells improved tumor responses to immunotherapy.
Senior author Ronald Buckanovich, M.D., Ph.D., professor of medicine at Pitt and co-director of the Women's Cancer Research Center—a collaboration between UPMC Hillman Cancer Center and Magee-Womens Research Institute—discusses the significance of these findings and outlines how this research is informing a clinical trial for patients with ovarian cancer.
What is the background for this study?
RB: Immunotherapy can be very effective for patients with many different cancers, such as melanoma, head and neck cancer, and lung cancer. However, immunotherapy has worked relatively poorly in ovarian cancer: Only about 10 percent of patients gain a benefit, and that benefit tends to be less substantial than for patients with other tumor types. The goal of this study was to understand why ovarian cancer is resistant to immunotherapy and determine if we could develop new therapeutic approaches to increase the effectiveness of immunotherapy.
Activating the immune system at the site of a tumor can recruit and stimulate immune cells to destroy tumor cells. One strategy involves injecting immune-stimulating molecules directly into the tumor, but this method can be challenging for cancers that are not easily accessible.
Now, Stanford researchers have developed a new synthetic molecule that combines a tumor-targeting agent with another molecule that triggers immune activation. This tumor-targeted immunotherapy can be administered intravenously and makes its way to one or multiple tumor sites in the body, where it recruits immune cells to fight the cancer.
Three doses of this new immunotherapy prolonged the survival of six of nine laboratory mice with an aggressive triple negative breast cancer. Of the six, three appeared cured of their cancer over the duration of the monthslong study. A single dose of this molecule induced complete tumor regression in five of 10 mice. The synthetic molecule showed similar results in a mouse model of pancreatic cancer.
"We essentially cured some animals with just a few injections," said Jennifer Cochran, Ph.D., the Shriram Chair of the Department of Bioengineering. "It was pretty astonishing. When we looked within the tumors, we saw they went from a highly immunosuppressive microenvironment to one full of activated B and T cells—similar to what happens when the immune-stimulating molecule is injected directly into the tumor. So, we're achieving intra-tumoral injection results but with an IV delivery."
Early-stage research has found 10 metabolites associated with bile duct cancer which might one day help create a urine test to identify the cancer.
The work is the result of a collaboration between Imperial College London and the Khon Kaen University in Thailand, who are working together to understand and reduce the disproportionately high rates of bile duct cancer in the Isaan peoples from the North-Eastern region of Thailand and Laos. The research is published in the journal Scientific Reports.
In the UK, bile duct cancer is rare, with around two in every 100,000 people developing it, and the cause is unknown. However, in Thailand it affects more than 30 times that figure in the North-Eastern region alone (85 cases in every 100,000 people) with still higher figures across the river in Laos.
In Thailand, bile duct cancers are associated with the O. viverrini parasite which may be inadvertently eaten in raw, partially cooked, or fermented fish dishes. The parasite enters the bile ducts and causes damage which can then lead to cancer.
"Early detection of bile duct cancer is vital as it is often symptomless. This means it is often recognized late when it is hard to treat and surgery to remove the cancer is not possible. Other than surgery there are no currently effective treatments for bile duct cancer." says Professor Simon Taylor-Robinson, senior author of the study, and Imperial's Envoy for International Affairs.
Under the right circumstances, the body's T cells can detect and destroy cancer cells. However, in most cancer patients, T cells become disarmed once they enter the environment surrounding a tumor.
Scientists are now trying to find ways to help treat patients by jumpstarting those lackluster T cells. Much of the research in this field, known as cancer immunotherapy, has focused on finding ways to stimulate those T cells directly. MIT researchers have now uncovered a possible new way to indirectly activate those T cells, by recruiting a population of helper immune cells called dendritic cells.
In a new study, the researchers identified a specific subset of dendritic cells that have a unique way of activating T cells. These dendritic cells can cloak themselves in tumor proteins, allowing them to impersonate cancer cells and trigger a strong T cell response.
"We knew that dendritic cells are incredibly important for the antitumor immune response, but we didn't know what really constitutes the optimal dendritic cell response to a tumor," says Stefani Spranger, the Howard S. and Linda B. Stern Career Development Professor at MIT and a member of MIT's Koch Institute for Integrative Cancer Research.
The results suggest that finding ways to stimulate that specific population of dendritic cells could help to enhance the effectiveness of cancer immunotherapy, she says. In a study of mice, the researchers showed that stimulating these dendritic cells slowed the growth of melanoma and colon tumors.
Researchers at Lawrence Livermore National Laboratory (LLNL) have shown for the first time the potential for linear induction accelerators (LIAs) to deliver effective, targeted doses of "FLASH" radiation to cancer patients. The new technique selectively kills cancer cells with minimal damage to healthy cells. The approach is outlined in a Scientific Reports paper.
For decades, cancer treatment has often meant weeks of low-dose radiation in hopes of delivering enough to malignant cells without too much damage to the patient's healthy cells. Efforts to deliver a rapid, high, targeted dose of therapy radiation, or FLASH radiotherapy (FLASH-RT) at the required depth, have required large, complex machines the size of gymnasiums and have so far proven impractical for clinical use. In the Scientific Reports paper, the authors note that LIAs powerful enough to deliver the necessary dose rate to cancer cells can be built only 3 meters long.
Developed as part of the Laboratory's stockpile stewardship program, powerful LIAs have been in use at LLNL since the 1960s in nuclear and stockpile experiments. Standard RF and microwave accelerators were not sufficiently powerful. At Site 300, the Nevada Test Site and Los Alamos National Laboratory, large versions of these accelerators are used to deliver flashes of radiation, some in a sequence to produce a motion-picture "flipbook" of a simulated nuclear implosions. Both of these uses in LLNL's weapons program, said Laboratory scientist and lead author Stephen Sampayan, have underpinned its potential use in cancer therapy. Although LIAs have been in use for decades, he said they were not previously considered for use in clinical applications, as the industry is unfamiliar with LIAs and devices can sometimes be rather large.
In a recent study published in Nature Biomedical Engineering, a team led by researchers at Massachusetts General Hospital (MGH) has demonstrated that magnetic resonance imaging (MRI) and artificial intelligence (AI) can be used to detect early signs of tumor cell death in response to a novel virus-based cancer therapy.
Recently, a promising therapeutic virus that selectively kills cancer cells while sparing normal tissue has sparked hope for treating aggressive brain tumors. To further optimize the virus-based therapy, frequent non-invasive monitoring of the treatment response must be performed. This monitoring is crucial for understanding the interactions between the virus and cancer cells, such as the extent of virus spread within the tumor and therapeutic response.
The researchers used quantitative molecular MRI images to measure multiple tissue properties, including tissue pH and protein concentration, that are altered with cell-death. This method allows therapeutic response monitoring much earlier than with previous techniques. The treatment responses were visible just 48 hours after viral therapy, long before any changes in tumor volume were observed.
"We programmed an MRI scanner to create unique signal "fingerprints" for different molecular compounds and cellular pH. A deep learning neural network was then used to decode the fingerprints and generate quantitative pH and molecular maps," says Christian Farrar, Ph.D., an investigator and faculty at the Athinoula A. Martinos Center for Biomedical Imaging. "The MRI molecular fingerprinting method was validated in a mouse brain tumor study where the tumors were treated with a novel virus-based therapy that selectively killed cancer cells."
Researchers at Karolinska Institutet, University of Oslo and Oslo University Hospital have developed a new kind of immunotherapy for leukemia. The results of a study published in Nature Biotechnology show that the therapy kills cancer cells from patients with acute lymphoblastic leukemia. The researchers now want to conduct a clinical study and also test the method on other types of cancer.
Acute lymphoblastic leukemia is the most common form of childhood leukemia, affecting approximately 70 children a year in Sweden. The disease is characterized by the unregulated growth of immature white blood cells, an essential component of the immune system, in the bone marrow and suppression of other healthy blood cells.
The condition is normally treated with chemotherapy or, in severe cases, bone marrow transplantation or immunotherapy, involving the genetic modification of the patient's own T cells to make them attack another type of white blood cell called B cells. However, the therapy, known as CAR-T after the name of the genetically modified receptor, only works on patients with B-cell leukemia and not those with T-cell leukemia, which affects an estimated 15 to 20 percent of patients with acute lymphoblastic leukemia. Side effects can also occur, as healthy B cells can also be affected.
Maharashtra: MIMER develops nano robot for rapid cancer diagnosis
The new nano robot-based diagnostic tool is likely to help improve cancer treatments and enable early interventions, a scientist at MIMER said. https://indianexpress.com/article/citie ... s-7655710/
By: Express News Service | Pune |
Maharashtra Institute of Medical Education and Research (MIMER), Pune has developed a nano robot that is programmed to capture and isolate circulating tumor cells. The tool is expected to lead to a new rapid and accurate diagnostic method for cancer, said Dr Shashwat Banerjee, Scientist at MIMER Medical College at Talegaon Dabhade in Pune.
“In search of better cancer diagnostics, scientists from MIMER, Pune, synthesized multifunctional nanorobot using magnesium-iron oxide Janus nanoparticles. The reported nano robot tested on blood containing a low number of cancer cells exhibited ~100% capture efficiency in less than five minutes. The nano robot was further clinically validated by testing it on a cancer patient’s blood samples and it exhibited rapid and efficient circulating tumour cells (CTC) capture ability,” Dr Banerjee said in a statement.
The findings were published recently in the peer-reviewed journal Communications Chemistry under the title ‘Water-Powered Self-Propelled Magnetic Nanobot for Rapid and Highly Efficient Capture of Circulating Tumor Cells’.
This new nano robot-based diagnostic tool may help in improving cancer treatments, allow for better treatment control, enable early interventions and change decision-making from reactive actions towards more predictive early interventions, he added.
Scientists have tracked and analyzed cancer cell behavior with a novel cellular "barcoding technology."
For the first time, research has shown cancer cells with the same genetic blueprint won't necessarily behave in the same way, with serious implications for how we target them.
A Peter Mac-led study involving a UNSW scientist demonstrating these non-genetic changes in acute myeloid leukemia cells was published today in Nature.
Joint first author Dr. Katie Fennell says: "We developed a novel cellular barcoding technology that can track individual cancer cells over time and identify patterns that lead to different cell behavior—even when the underlying genome is the same."
This barcoding technology (dubbed SPLINTR, which stands for Single-cell Profiling and LINeage TRacing) helps the researchers to identify the unique genes expressed in each leukemia cell, and monitor how this influences the cancer's behavior over time. They can then observe which acute myeloid leukemia cells are most likely to form cancerous tumors.
UNSW scientist and co-author Dr. Emily Wong, who is based at the Victor Chang Cardiac Research Institute, says the fact that regulatory changes are key contributors to disease in the absence of genetic mutations is only starting to be widely recognized.
"The Dawson Lab has developed an exciting method to track the regulatory genome of individual cancer cells over time. We are pleased to be able to contribute our computational analyses to this major advance."
While this study is in acute myeloid leukemia, the technology can be applied to many different cancers, presenting an opportunity to understand why some tumor cells survive drug treatment or relapse in specific organs.
There's not much good that can be said about asthma, a breathing disease in which the airways become narrowed and inflamed. But there's this: People with asthma seem to be less likely to develop brain tumors than others. And now, researchers at Washington University School of Medicine in St. Louis believe they have discovered why.
It comes down to the behavior of T cells, a type of immune cell. When a person—or a mouse—develops asthma, their T cells become activated. In a new mouse study, researchers discovered that asthma causes the T cells to behave in a way that induces lung inflammation but prevents the growth of brain tumors. What's bad news for the airways may be good news for the brain.
The findings, available online in Nature Communications, suggest that reprogramming T cells in brain tumor patients to act more like T cells in asthma patients could be a new approach to treating brain tumors.
"Of course, we're not going to start inducing asthma in anyone; asthma can be a lethal disease," said senior author David H. Gutmann, MD, Ph.D., the Donald O. Schnuck Family Professor of Neurology. "But what if we could trick the T cells into thinking they're asthma T cells when they enter the brain, so they no longer support brain tumor formation and growth? These findings open the door to new kinds of therapies targeting T cells and their interactions with cells in the brain."
Mount Sinai scientists have become the first to report a potentially serious side effect related to a new form of immunotherapy known as CAR-T cell therapy, which was recently approved for the treatment of multiple myeloma. Their findings were published as a case study in Nature Medicine in December.
Multiple myeloma is a complex and incurable type of blood plasma cancer that often requires multiple treatments as the disease progresses and becomes resistant to previous therapies, often resulting in chronic disease with periods of acute illness.
CAR-T cell therapy uses genetically engineered immune system cells known as chimeric antigen receptor (CAR) T cells. In the specific version at issue, the CAR-T cells were used to target a protein known as B cell maturation antigen (BCMA). BCMA is commonly found in multiple myeloma, and this therapy has shown impressive response rates in people with particularly complex, treatment-resistant multiple myeloma.
More than three months after finishing a course of BCMA-targeted CAR-T cell therapy, the patient described in the Mount Sinai case study started showing progressive neurological features of symptoms resembling Parkinson's disease, including tremors as well as handwriting and gait changes. The patient later died due to complications from infection, and researchers found evidence of BCMA protein in the brain's basal ganglia and scarring in that area, suggesting that this serious side effect may have been due to the therapy targeting the BCMA in the brain.
Lung cancer, the leading cause of cancer death, is usually diagnosed at a late stage when the survival rate is extremely low. Early-stage lung cancer is mostly asymptomatic, and low-dose spiral CT imaging, the current method for detecting early lung cancer lesions, isn't feasible as a widespread screening test for the general population due to high cost and the radiation hazard of repeated screenings.
A new study published in Proceedings of the National Academy of Sciences provides proof-of-concept for the ability of a drop of blood to reveal lung cancer in asymptomatic patients. The study was co-led by researchers at Massachusetts General Hospital (MGH): Leo Cheng, Ph.D., associate biophysicist, in Pathology, Radiology, and the Athinsula A. Martinos Center for Biomedical Imaging; and David Christiani, MD, MPH, pulmonary and critical care physician.
"Our study demonstrates the potential for developing a sensitive screening tool for the early detection of lung cancer," says Cheng. "The predictive model we constructed can identify which people may be harboring lung cancer. Individuals with suspicious findings would then be referred for further evaluation by imaging tests, such as low-dose CT, for a definitive diagnosis."
Targeted radioembolization alongside chemotherapy improved progress-free survival for patients with colon cancer that had metastasized to the liver, according to a study published in the Journal of Clinical Oncology.
Most patients with colorectal liver metastases (CLM) are poor candidates for resection surgery, so this new treatment could be a better option compared to chemotherapy alone, according to Mary Mulcahy, MD, '00 GME, professor of Medicine in the Division of Hematology and Oncology and lead author of the study.
"We know systemic chemotherapy will ultimately fail, so we're looking for non-surgical therapy that can address these patients," said Mulcahy, who is also a professor of Radiology and of Surgery in the Division of Organ Transplantation and associate director of clinical operations at the of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Riad Salem, MD, chief of Vascular and Interventional Radiology and vice chair of image guided therapy in the Department of Radiology, and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, was senior author of the study.
About 60 percent of patients diagnosed with colorectal cancer will eventually have their cancer spread, with the liver being the main site of spread. While the cancer in the colon is often treatable by surgical resection, diffuse liver metastases are much less amenable to surgical treatment.
A unique collection of tissue samples donated by people with chronic myeloid leukemia was the driving force behind the discovery of a potentially major new treatment approach for drug-resistant leukemia. As published this week in the Proceedings of the National Academy of Sciences, researchers report how a laboratory study of a specially engineered formulation of gas, composed of charged and highly reactive molecules, called "cold atmospheric plasma," or CAP, was highly effective in targeting drug-resistant leukemia cells while protecting nearby healthy cells.
There are many types of leukemias that arise in bone marrow cells. While research has led to major improvements in the survival of adult and child leukemia patients, some leukemias that were at one time responsive to treatment become resistant to the drugs used to target them. Therefore, scientists are working to improve treatment options for leukemia patients by understanding the characteristics of aggressive leukemias that are more likely to develop drug resistance.
The study was powered by a unique resource at Huntsman Cancer Institute (HCI) at the University of Utah (U of U) called the HCI Hematology Biobank. This resource provided patient-donated leukemia samples with the precise characteristics needed to conduct the study to determine how CAP blocks strategies leukemia cells use to survive.
As 5-year relative survival rates differ greatly between cancer patients treated at early or late stages, early detection of tumors is of great importance to cancer therapy. Cathepsin B (CTSB) is considered as a potential biomarker for the early diagnosis of cancers due to its increased expression in the early stage of many cancer types. As a result, the effective and precise monitoring of CTSB activity offers a way out.
In a recent study published in Angewandte Chemie International Edition, a research team led by Prof. Liang Gaolin and Prof. Yuan Yue from the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences realized the specific photoacoustic (PA) imaging of CTSB-overexpressing tumors through CTSB-initiated intracellular self-assembly of small-molecule PA imaging probes into nanoparticles.
PA imaging is a new type of non-invasive and non-ionizing biomedical imaging method, which has a huge potential in biomedical research and disease diagnosis due to its excellent tissue-penetrating depth and high spatial resolution.
To meet the challenge of early tumor detection, the researchers, using the self-assembly signal enhancement of PA imaging probe, designed a CTSB-activatable near-infrared PA probe Val-Cit-Cys(SEt)-Lys(Cypate)-CBT (Cypate-CBT). When Cypate-CBT enters CTSB-overexpressing tumor cells, its disulfide bond is reduced by intracellular glutathione and its specific cleavage substrate Val-Cit is cleaved by CTSB to produce Cypate-CBT-Cleaved, which undergoes an intermolecular CBT-Cys click reaction to yield Cypate-CBT-Dimer. The Cypate-CBT-Dimer then self-assembles into near-infrared nanoparticles Cypate-CBT-NPs.
While researchers have identified several genes that drive prostate cancer, a new study published in Nature reveals the puppet master controlling the strings.
The strings: Cancer-causing genes, or oncogenes, such as androgen receptor, FOXA1, ERG and MYC.
The puppet master: A chromatin remodeling complex called SWI/SNF, which controls the way in which DNA is arranged and compacted to fit within a cell's nucleus. A key subunit of this complex provides energy to unwrap DNA to provide access to enhancer elements that crank up the expression of cancer-driving genes.
In the current study, researchers at the University of Michigan Health Rogel Cancer Center demonstrated that the SWI/SNF complex facilitates access to enhancers that oncogenes can bind to and drive downstream gene expression in cancer. Degrading a subunit of this complex blocks the oncogenes, like cutting the puppet master's strings.
