Cancer Deaths in UK Plummet in Middle-aged People March 13, 2024
Introduction:
(Eurekalert)
• A first of its kind study by Cancer Research UK reveals premature cancer death rates in 35–69-year-olds fell by more than a third over 25 years
• Improvements in the UK are a result of smokefree policies, prevention measures, early detection programmes like cancer screening, and more effective treatment options
• But the study paints a mixed picture with cancer cases on the rise and cancer mortality rates still too high
• The charity’s manifesto, ‘Longer, better lives’ outlines action the UK Government can take to save 20,000 lives from cancer every year by 2040
Making a personalized T cell therapy for cancer patients currently takes at least six months; scientists at the German Cancer Research Center (DKFZ) and the University Medical Center Mannheim have shown that the laborious first step of identifying tumor-reactive T cell receptors for patients can be replaced with a machine learning classifier that halves this time.
Personalized cellular immunotherapies are considered promising new treatment options for various types of cancer. One of the therapeutic approaches currently being tested is so-called "T-cell receptor transgenic T-cells." The idea behind this is that immune T cells from a patient are equipped in the laboratory to recognize the patient's own unique tumor and then reinfused in large numbers to effectively kill the tumor cells.
The MYCN oncoprotein (proteins related to the growth of cancer cells) plays a key role in starting, advancing and making it difficult to treat various human cancers. When MYCN is overactive, especially in high-risk neuroblastoma (childhood cancer often found in the adrenal glands), the tumors become less responsive to immunotherapy—a treatment that uses the body's immune system to fight cancer. Still, recognition of this problem has not led to any effective strategies to tackle this problem.
In a new study from Boston University Chobanian & Avedisian School of Medicine, researchers found that MYCN selectively increases the levels of a signaling molecule, CKLF, in neuroblastoma cells to suppress anti-tumor immune responses and promote tumor aggressiveness. The findings appear online in Science Advances.
Researchers Gain Insight into Why T Cells Lose Energy in Solid Tumors by Jessica Thaxton
March 15, 2024
Introduction:
(UNC Health) New research by the lab of Jessica Thaxton, PhD, MsCR, in the Department of Cell Biology and Physiology at the UNC School of Medicine and colleagues in the Immunotherapy Group at Lineberger Comprehensive Cancer Center, has unveiled new clues behind T-cell metabolism, that could enhance immunotherapies that rely on T cells to fight cancer.
T cells are often called “assassins” or “killers” because they can orchestrate and carry out missions to hunt down bacteria, viruses, and cancer cells throughout the body. Mighty as they may be, recent research has shown that once T cells infiltrate the environment of a solid tumor, they lose the energy needed to combat the cancer.
A research team led by Jessica Thaxton, PhD, MsCR, associate professor of cell biology and physiology and co-leader of the Cancer Cell Biology Program at the UNC Lineberger Comprehensive Cancer Center, aimed to understand why T cells do not sustain energy in tumors.
Using their expertise in tumor immunity and metabolism, the Thaxton Lab, led by the Katie Hurst, MPH, and 4th year graduate student Ellie Hunt, found that a metabolic enzyme called Acetyl-CoA Carboxylase (ACC) causes T cells to store fat rather than burning fat for energy.
“Our discovery fills a long-standing gap in knowledge regarding why T cells in solid tumors don’t appropriately generate energy,” said Thaxton. “We inhibited the expression of ACC in mouse cancer models, and we observed that T cells were able to persist much better in solid tumors.”
Researchers at the University of Toronto's Donnelly Centre for Cellular and Biomolecular Research have found two enzymes that work against the chemotherapy drug gemcitabine, preventing it from effectively treating pancreatic cancer.
The enzymes—APOBEC3C and APOBEC3D—increase during gemcitabine treatment and promote resistance to DNA replication stress in pancreatic cancer cells.
This, in turn, counteracts the effects of gemcitabine and allows for the growth of cancer cells.
"Pancreatic cancer has proven to be very challenging to treat, as it is usually diagnosed at stage 3 or 4," said Tajinder Ubhi, first author on the study and a former Ph.D. student in biochemistry in U of T's Temerty Faculty of Medicine.
Monitoring levels of DNA shed by tumors and circulating in the bloodstream could help doctors accurately assess how gastroesophageal cancers are responding to treatment, and potentially predict future prognosis, suggests a new study led by researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg–Kimmel Institute for Cancer Immunotherapy.
The study tracked minimal residual disease (the amount of cancer left following treatment) by analyzing circulating tumor DNA (ctDNA), showing how these "liquid biopsies" can provide valuable insights into treatment outcomes over time. Absence of ctDNA was seen occurring together with specific activation of T cells that are part of the immune system's defense to recognize and fight cancer.
A collaboration between scientists from St. Jude Children's Research Hospital and Dana-Farber Cancer Institute uncovered four proteins that govern the identity of anaplastic large cell lymphoma (ALCL), an aggressive form of cancer. These proteins comprise a core regulatory circuit (CRC) that surprisingly incorporates a dysregulated signaling protein.
Establishing the CRC for this lymphoma gives researchers insight into potential vulnerabilities that may be future therapeutic targets. The findings were published in Cell Reports Medicine.
"Mutations in signaling pathways have long been known to drive oncogenic transformation and tumor progression," said senior co-corresponding author Mark Zimmerman, Ph.D., currently of Foghorn Therapeutics, previously of Dana-Farber Cancer Institute and Boston Children's Hospital.
Thanks to an unusual application of game theory and machine learning technology, a large team of scientists led by experts at Cincinnati Children's has published the world's most detailed "atlas" of the many types of stem cells and early progenitors involved in producing human blood from diverse donors.
The team has identified more than 80 distinct subsets of hematopoietic stem and progenitor cells (HSPCs)—early-stage cells that kick off production of mature red cells, white cells and other elements of our complex blood system. Details were published in Nature Immunology.
"We believe our highly focused capture strategy of the earliest HSPCs, intermediate cell states plus stromal populations, and the most abundant end states provides the deepest view of bone marrow stem and progenitor compartments described to date," the co-authors state.
The study was led by co-first authors Xuan Zhang, Ph.D., and Baobao Song, Ph.D., and co-corresponding authors Nathan Salomonis, Ph.D., and H. Leighton Grimes, Ph.D., all researchers with Cincinnati Children's. Overall, the study includes 26 co-authors from four academic medical centers and two biotech companies.
A pair of medications that make malignant cells act as if they have a virus could hold new promise for treating colorectal cancers and other solid tumors, reports a study published in Science Advances.
The preclinical research, led by Van Andel Institute scientists, determined how low doses of a DNMT inhibitor sensitize cancer cells to an EZH2 inhibitor, resulting in a one-two punch that combats cancer cells better than either drug alone.
The findings are the foundation for an upcoming Phase I clinical trial to evaluate this combination in people with colorectal cancer or other solid tumors.
"DNMT inhibitors are approved to treat blood cancer while EZH2 inhibitors are approved to treat blood cancer and a rare type of sarcoma. To date, they've had limited individual success in solid tumors like colorectal cancer," said Van Andel Institute Professor Scott Rothbart, Ph.D., the study's corresponding author.
"Our findings highlight the promise of combination cancer therapies by revealing how these two medications interact, with the DNMT inhibitor priming cancer cells in a way that makes the EZH2 inhibitor more effective."
Neuroblastoma, one of the most common childhood cancers, is classified as a developmental cancer because it arises prenatally during the formation of organs and tissues. It originates from cancer cells that develop in neuroblasts, a type of immature nerve tissue, and primarily affects the adrenal glands.
One of the research focal points of Dr. Josep Samitier's group (Nanobioengineering Group of IBEC), led by Dr. Aránzazu Villasante, is the creation of in vitro neuroblastoma models that replicate its characteristic vasculature in order to search for new biomarkers and develop effective therapies against this type of cancer.
A second-generation melanoma vaccine being developed at UVA Cancer Center improves long-term survival for melanoma patients compared with the first-generation vaccine, new research shows. Interestingly, the benefit of the second-generation vaccine was greater for male patients than for female patients. That finding could have important implications for other cancer vaccines, the researchers say.
The vaccine developers, led by Craig L. Slingluff Jr., MD, found that they could enhance the effectiveness of their melanoma vaccine by simultaneously stimulating important immune cells known as "helper T cells" to recognize melanoma proteins, in addition to stimulating killer T cells against melanoma. This boosted patient survival and helped prevent reoccurrences of the cancer.
Researchers Turn Back the Clock on Cancer Cells to Offer New Treatment Paradigm March 27, 2024
Introduction:
(Eurekalert) St. Jude Children’s Research Hospital scientists reversed an aggressive cancer, reverting malignant cells towards a more normal state. Rhabdoid tumors are an aggressive cancer which is missing a key tumor suppressor protein. Findings showed that with the missing tumor suppressor, deleting or degrading the quality control protein DCAF5 reversed the cancer cell state. These results suggest a new approach to curing cancer — returning cancerous cells to an earlier, more normal state rather than killing cancer cells with toxic therapies — may be possible. The results were published today in Nature.
“Rather than making a toxic event that kills rhabdoid cancer, we were able to reverse the cancer state by returning the cells toward normal,” said senior author Charles W.M. Roberts, MD, PhD, Executive Vice President and St. Jude Comprehensive Cancer Center director. “This approach would be ideal, especially if this paradigm could also be applied to other cancers.”
“We found a dependency which actually reverses the cancer state,” said first author Sandi Radko-Juettner, PhD, a former St. Jude Graduate School of Biomedical Sciences student, now a Research Program Manager for the Hematological Malignancies Program at St. Jude. “Standard cancer therapies work by causing toxicities that also damage healthy cells in the body. Here, it appears that we’re instead fixing the problem caused by the loss of a tumor suppressor in this rhabdoid cancer.”
Drugging the un-targetable
In many cancers, there is no easily druggable target. Often, these cancers are caused by a missing tumor suppressor protein, so there is nothing to target directly as the protein is missing. Loss of tumor suppressors is much more common than a protein gaining the ability to drive cancer. Consequently, finding a way to intervene therapeutically in these tumors is a high priority. The researchers were looking for a way to treat an aggressive set of cancers caused by the loss of the tumor suppressor protein SMARCB1 when they found a new approach to treatment.
Purdue Researchers Create Biocompatible Nanoparticles to Enhance Systemic Delivery of Cancer Immunotherapy March 27, 2024
Introduction:
(Eurkelert) WEST LAFAYETTE, Ind. — Purdue University researchers are developing and validating patent-pending poly (lactic-co-glycolic acid), or PLGA, nanoparticles modified with adenosine triphosphate, or ATP, to enhance immunotherapy effects against malignant tumors.
The nanoparticles slowly release drugs that induce immunogenic cell death, or ICD, in tumors. ICD generates tumor antigens and other molecules to bring immune cells to a tumor’s microenvironment. The researchers have attached ATP to the nanoparticles, which also recruits immune cells to the tumor to initiate anti-tumor immune responses.
Yoon Yeo leads a team of researchers from the College of Pharmacy, the Metabolite Profiling Facility in the Bindley Bioscience Center, and the Purdue Institute for Cancer Research to develop the nanoparticles. Yeo is the associate department head and Lillian Barboul Thomas Professor of Industrial and Molecular Pharmaceutics and Biomedical Engineering; she is also a member of the Purdue Institute for Drug Discovery and the Purdue Institute for Cancer Research.
The researchers validated their work using paclitaxel, a chemotherapy drug used to treat several types of cancers. They found that tumors grew slower in mice treated with paclitaxel enclosed within ATP-modified nanoparticles than in mice treated with paclitaxel in non-modified nanoparticles.
“When combined with an existing immunotherapy drug, the ATP-modified, paclitaxel-loaded nanoparticles eliminated tumors in mice and protected them from rechallenge with tumor cells,” Yeo said.
Beating by Overheating: New Strategy to Combat Cancer March 27, 2024
Introduction:
(Eurekalert) Many new drugs inhibit the processes that cancer cells need to divide rapidly. So as to inhibit the cancer as a whole. But cancer cells have all sorts of workarounds to get around that effect. As a result, the tumor becomes unresponsive to treatment.
That's why researcher Matheus dos Santos Dias is taking a completely different approach. He had to convince some colleagues before he could start working on this quite surprising idea. After all, you're not going to give cancer cells a boost, are you? "We're going against the prevailing view that you can only fight cancer cells by inhibiting them," he knows. "But we had strong evidence that it also works if you overstimulate and exhaust them."
Everyone makes inhibitors
And so he set out to find a drug that stimulates cancer cells, as well as a perfectly suited partner drug that can then finish the job. By doing so, he wants to upset the balance in cancer cells to the point where they can no longer save themselves. "Compare it to the engine of a racing car: if you crank up the RPM and then turn off the cooling, it's bound to crash. This is exactly what we are trying to do with the drugs."
Tricky though: "Activating drugs are not that common, almost everyone makes inhibitors. But we did find one we could work with," he says. That drug acts on the protein PP2A. In a large-scale experiment with all kinds of drug combinations, he and his colleagues then found a WEE1 inhibitor to be the best partner in crime. That inhibitor targets overactive, stressed cells and keeps them from functioning properly.
Higher gear
Cancer cells and mice with patient tumors respond well to the drug combo. And, not insignificantly, the side effects seem manageable. Dos Santos Dias: "This obviously does not mean it will not have side effects in humans. But we suspect that normal cells can defend themselves against this activation much better than cancer cells, which of themselves are already in a higher gear."
Imperial College London researchers have developed a new platform for the synthesis, analysis and testing of new compounds which may one day treat cancer. The findings are published in the journal Angewandte Chemie International Edition.
The discovery of new compounds with pharmacological properties can be expensive and time-consuming. Therefore, there is an increasing interest in developing workflows that allow for the rapid synthesis and testing of multiple compounds in parallel.
Imperial scientists, Professor Ramon Vilar and Dr. Tim Kench from the Department of Chemistry, have developed a workflow that focuses on metal-based compounds that become highly toxic to cancer cells upon exposure to light.
Using this light-activated toxicity to kill cancerous cells is known as photodynamic therapy (PDT).
A team of medical researchers at Zhejiang University, in China, has developed a way to use cryo-shocked tumor cells to fight lung cancer. In their study, published in the journal Science Advances, the group used fast liquid nitrogen treatment to modify tumor cells to carry gene-editing tools to fight tumors in mouse models.
As noted by the researchers, CRISPR-mediated genome editing tools and techniques hold great promise for treating cancer. However, problems with tumor targeting and off-target side effects hamper their effectiveness. For this new research, the team found a way to improve targeting by converting tumor cells into carriers for the gene editing tools.
The work involved cryo-shocking tumor cells extracted from a patient, which involved rapid freezing using liquid nitrogen. Such freezing removed their pathogenicity while preserving their structure, and more importantly, their surface receptor functions. After freezing, the CRISPR-Cas9 system was loaded into the cryo-shocked tumor cell, which made its way to the tumor, where it was ablated.
