(Press-News.org) An innovative approach to treating bone tumors - starving cancer cells of the energy they need to grow - could one day provide an alternative to a commonly used chemotherapy drug without the risk of severe side effects, suggests a new study from Washington University School of Medicine in St. Louis. Studying human cancer cells and mice, the researchers said that a two-drug combination targeting a tumor's energy sources could be as effective and less toxic than methotrexate, a long-used chemotherapy drug often given in high doses to treat osteosarcoma, a bone cancer.
The study appears Jan. 26 in the journal Cell Reports.
Osteosarcoma is the most common tumor of the bone in adults and children. It accounts for about 4% of all pediatric cancers and more than half of all pediatric bone cancers. Standard treatment for osteosarcoma includes surgery, radiation and a cocktail of chemotherapy drugs including high-dose methotrexate, which can cause liver and kidney damage.
"We are interested in developing therapies that kill cancer cells without harming healthy cells, potentially avoiding the sometimes severe side effects of traditional chemotherapy," said senior author Brian Van Tine, MD, PhD, an associate professor of medicine. "In high doses, methotrexate can lead to liver failure and the need for kidney dialysis. We would like to get rid of the methotrexate in this regimen and replace it with a targeted metabolic therapy that would shorten the treatment, reduce the side effects and potentially eliminate the need for multiple hospitalizations."
The researchers studied an investigational drug called NCT-503, a member of a relatively new class of drugs called PHGDH inhibitors that have gained interest as potential metabolic therapies for cancer. Metabolic therapies target the chemical reactions that cancer cells perform to sustain life. This investigational drug prevents cancer cells from manufacturing the amino acid serine, a source of energy that fuels cancer growth. Losing serine production stops cell division but doesn't kill cancer cells. Unfortunately, osteosarcoma cells can then quickly adapt and turn to another energy source, said Van Tine, an oncologist who treats patients at the Adolescent and Young Adult Sarcoma program at Siteman Cancer Center at Barnes-Jewish Hospital and Siteman Kids at St. Louis Children's Hospital, both at Washington University School of Medicine.
Studying the cells that adapt to being treated with this drug, the researchers revealed a way that the cells' metabolism shifts to try to burn another type of fuel. Without serine, the osteosarcoma cell can't move through its typical metabolic cycle, so parts of that cycle build up. The buildup of these cellular components - which includes fats, other amino acids, and waste products - then activates a central metabolic signaling molecule called mTORC1. Triggering mTORC1 tells the cell to start burning all the built-up products.
So, the researchers added a second drug that blocks mTORC1. Now deprived of both serine and the secondary fuel source, the cancer cells were starved of energy and died.
"When we added an mTORC1 inhibitor, suddenly we could control tumor growth in mice for a prolonged period of time, well past when the cells would adapt to treatment with either drug alone," said first author Richa Rathore, PhD, who just completed her doctoral studies in Van Tine's lab.
The mTORC1 inhibitor is called perhexiline and has been used since the 1970s to treat angina, or chest pain. More recently, it has been investigated as a treatment for certain types of heart failure.
The researchers studied mice implanted with human osteosarcoma tumors. In mice receiving either drug alone or a control treatment, the tumors increased in volume by almost 800% over less than 30 days. In contrast, in the mice receiving the two-drug combination, the tumors increased in volume by only 75% over 30 days.
"We are still working to optimize these drug treatments, but we hope to be able to take these findings into a clinical trial," Van Tine said. "In the future, we would like to add more metabolic therapies so that one day we might be able to eliminate the remaining chemotherapy drugs that these patients will still receive. The ultimate goal is to transform therapy by going after the metabolic properties that are inherent to osteosarcoma and move away from the classic drugs that damage the whole body."
INFORMATION:
This work was supported by an anonymous donor; Dawn Merkel's Bad to the Bone Chili Cook Off; Kellsie's Hope Foundation; the Sarcoma Foundation of America; the National Institutes of Health (NIH) grant number R01CA227115; and the Washington University Surgical Oncology Training Grant, number T32CA009621. The authors thank Laura Shelton for guidance with analysis of metabolomics data from Human Metabolome Technologies; NanoString for guidance with analysis; the Washington University Diabetes Research Center, NIH grant number 5P30DK020579 for use of the Seahorse Bioanalyzer; and the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis for the use of the Immunomonitoring Laboratory, which provided the Luminex FlexMap service. Siteman Cancer Center is supported in part by a National Cancer Institute (NCI) Cancer Center Support Grant, number P30 CA091842.
Rathore R, et al. Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma. Cell Reports. Jan. 26, 2021.
Washington University School of Medicine's 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
PITTSBURGH, Jan. 26, 2021 - The mechanism by which acute viral respiratory infections promote secondary bacterial growth and infection in the airways depends on iron-carrying extracellular sacs secreted by the cells lining the host's airways, report researchers from the University of Pittsburgh School of Medicine in a paper published today in Cell Reports.
The sacs, or "vesicles," which carry iron bound to a protein called transferrin, associate with bacterial cells and supply them with essential nutrients, promoting the growth of expansive bacterial communities. The finding gives us a glimpse into how bacteria ...
Although the protein ITIH4 is found in large amounts in the blood, its function has so far been unknown. By combining many different techniques, researchers from Aarhus University have discovered that ITIH4 inhibits proteases in the innate immune system via an unknown mechanism. The research results have just been published in the prestigious scientific journal Science Advances.
Proteases are enzymes that cleave other proteins. Most often, proteases occur in cascade networks, where a particular event triggers a chain reaction in which several proteases cleave and thereby activate each other. Most well known is probably the coagulation cascade, which causes clotting of our blood when a vessel is punctured.
But a similar network of proteases called the complement ...
There are an estimated 40,000 to 50,000 species of micro-organism per gram of soil. Addition of certain microbes can tailor soil characteristics: removing contaminants, improving fertility and even making barren land available for farming.
The Microbiology Society's report calls for increased access to research into soil health, promoting outreach activities in agricultural colleges and schools and showcasing work in non-academic outlets. This, say microbiologists, is the best way to collaborate with farmers to improve soil health and agricultural productivity.
Tilling and excessive use of fertilisers have major effects on soil health. Microbiology can be used to help understand the impact of intensive farming and design feasible mitigation practices.
The report ...
Authors from the German Center for Diabetes Research (DZD) presented data showing that the longevity gene mammalian Indy (mINDY) is involved in blood pressure regulation in the Journal of Clinical Investigation (JCI) insight. Reduced expression of mINDY, which is known to extend life span in lower organisms and to prevent from diet induced obesity, fatty liver and insulin resistance in mice, has now been shown to lower blood pressure and heart rate in rodents. The authors provided mechanistic insights for the underlying physiological mechanism based on in vivo data in a genetic knock out model as well as microarray and in vitro studies. Furthermore, ...
Children determine emotion by what they hear, rather than what they see, according to new research.
The first-of-its-kind study, by Durham University's Department of Psychology, looked at how children pick up on the emotions of a situation.
They found that whilst adults prioritised what they see, young children showed an auditory dominance and overwhelmingly prioritised what they could hear.
The researchers say their findings could benefit parents currently managing home learning and professional educators by increasing their understanding of how young children pick up on what is going on around them.
The research may also provide new avenues to understanding ...
Theories were introduced as far back as the 1960s about the possible existence of superheavy elements. Their most long-lived atomic nuclei could give rise to a so-called "island of stability" far beyond the element uranium. However, a new study, led by nuclear physicists at Lund University, shows that a 50-year-old nuclear physics manifesto must now be revised.
The heaviest element found in nature is uranium, with a nucleus containing 92 protons and 146 neutrons. The nuclei of heavier elements become more and more unstable due to the increased number of positively charged protons. They therefore decay faster and faster, usu-ally within a fraction of a second. ...
As the world prepares to commemorate International Holocaust Remembrance Day on January 27th, communities and memorials around the world are addressing how to meaningfully commemorate the day while protecting public health and safety. The day marking the anniversary of the liberation of Auschwitz is ordinarily commemorated with hundreds of individual memorial events across the globe. This year, most of those events will be impossible for any sizable gathering of people due to COVID-19.
With the goal of proposing relevant solutions to this challenge, Dr. Tobias Ebbrecht-Hartmann and research student Tom Divon of the Hebrew ...
ATLANTA - JANUARY 26, 2021 - A new study shows 4 in 10 cancer deaths are attributable to cigarette smoking in parts of the South region and Appalachia. For this study, appearing in Cancer Causes & Control, Farhad Islami, MD, PhD, and colleagues at the American Cancer Society examined the proportion of cancer deaths from 2013 to 2017 attributed to cigarette smoking in 152 metropolitan and micropolitan statistical areas (MMSAs).
Data show the proportion of cancer deaths attributable to cigarette smoking was greater in men than in women in all evaluated MMSAs. In both sexes combined, the proportion of smoking-related cancer deaths ranged from 8.8% in Logan ...
The battle to stop false news and online misinformation is not going to end any time soon, but a new finding from MIT scholars may help ease the problem.
In an experiment, the researchers discovered that fact-checking labels, when attached to online news headlines, actually work better after people read false headlines, compared to when they precede the headline or accompany it.
"We found that whether a false claim was corrected before people read it, while they read it, or after they read it influenced the effectiveness of the correction," says David Rand, an MIT professor and co-author of a new paper detailing the study's results.
Specifically, the researchers found, when "true" and "false" labels were shown immediately after participants in the experiment read headlines, ...
A new neural network developed by researchers at the University of Eastern Finland and Kuopio University Hospital enables an easy and accurate assessment of sleep apnoea severity in patients with cerebrovascular disease. The assessment is automated and based on a simple nocturnal pulse oximetry, making it possible to easily screen for sleep apnoea in stroke units.
Up to 90% of patients experiencing a stroke have sleep apnoea, according to earlier studies conducted at Kuopio University Hospital. If left untreated, sleep apnoea can reduce the quality of life and rehabilitation of patients with stroke and increase ...
