Author: Nancy Meredith
Using Epigenetics To Understand Metastasis May Lead to Novel Mesothelioma Treatment
Researchers know that the best way to increase survival in cancer patients is to keep the disease from spreading to other areas. For aggressive cancers like pleural mesothelioma, cancer cells can outfox even the strongest treatments and metastasize, leaving patients with poor survival. Now, researchers report that through epigenetics they discovered a novel way to inhibit the spread of cancer that could lead to a new treatment that ends cancer growth.
In a break from traditional research looking into gene mutations, a team of researchers from Case Western Reserve University School of Medicine of Cleveland, Ohio, used epigenetics, the study of how genes are turned on and off, as a way to distinguish the differences in primary tumors and metastatic tumors. The team knew that “enhancer activity,” or the genes’ ability to turn switches on or off, “lend cells their unique characteristics” and contribute to normal development.
However, faulty activity within the cells can lead to tumor development and the spread of cancer. Upon further inspection of the metastasized tumors, the researchers discovered the on-off switches were “in different positions than in the cells of the source tumor.”
“Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumors to form in the first place,” said the study’s lead author, James J. Morrow, PhD, a medical student in the Medical Scientist Training Program at Case Western Reserve University School of Medicine. “So based on the knowledge that enhancers drive both normal cell development and tumor-formation, we hypothesized that they may play a similar role in the transition of cancer cells from one developmentally distinct tissue to another during metastatic progression.”
Metastasis, according to researchers, is the cause of nearly 90 percent of cancer deaths. Researchers agree that understanding how to stop metastasis is critical for increasing survival in mesothelioma, an asbestos-caused cancer, and other cancers.
Using mouse models of bone cancer (osteosarcoma) cells, the team wanted to find a way to halt the spread of the cancer to the lungs. Through epigenomic profiling, the team found “bunched clusters of enhancers,” metastatic variant enhancer loci (Met-VELs), near the cancer cells that had metastasized to the lungs. Turning to BET inhibitors, a promising class of anti-cancer drugs now in clinical trials, to interrupt the Met-VELs, the researchers were able to inhibit the cancer growth in the lungs.
Based on the success, the researchesr concluded Met-VELs “may be suitable targets” for treatments targeting metastasis.
Using epigenetics as a new approach for finding an effective treatment could bring the breakthrough needed for halting cancer growth and for increasing survival in the nearly 3,000 Americans diagnosed with mesothelioma each year.
The study was published Jan. 15 online in Nature Medicine.
Mesothelioma Treatment Breakthrough May Come From Another Rare Disease
Mesothelioma patients may someday benefit from research into Huntington’s Disease, another rare disease. Researchers discovered that patients with Huntington’s Disease have a significantly less chance than the general population of getting cancer. Now, the researchers report that better understanding what it is about the disease that can kill off cancer cells could lead them to a breakthrough treatment for all types of cancer.
A team of researchers from Northwestern University found that the gene that drives the progression of Huntington’s Disease, a rare neurodegenerative disorder, is also highly toxic to cancer cells. The huntingtin gene, that plays an important role in neurons in the brain, can become mutated by an over abundance of repeating RNA sequences, leading to the rare disorder. The nerve cells of the brain are vulnerable to these deadly genes, and, according to the researchers, cancer cells are even more susceptible to the genes. In fact, the scientists have dubbed it the “super assassin gene” due to the fact that it is so toxic that it kills off cancer cells.
“This molecule is a super assassin against all tumor cells,” said senior author Marcus Peter, the Tom D. Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine. “We’ve never seen anything this powerful.”
https://news.northwestern.edu/stories/2018/february/huntingtons-disease-provides-new-cancer-weapon/
In the United States, a rare disease status is assigned to a disease or disorder if it affects fewer than 200,000 Americans at any given time. There are approximately 30,000 cases of Huntington’s Disease in the U.S. An estimated 3,000 Americans are diagnosed with mesothelioma each year.
Huntington’s Disease deteriorates a person’s physical and mental abilities, most often affecting adults between the ages of 30 and 50. There is no cure for the fatal genetic disorder. Mesothelioma, an asbestos-caused cancer, typically affects men in their 60’s or older who worked around asbestos decades earlier. Mesothelioma is also an incurable, fatal condition.
The researchers found a way to deliver the molecule as a treatment compound via a nanoparticle, a microscopic drug delivery system, to mice models with human ovarian cancer tumors. The team reported three key results:
- The tumor growth was “significantly reduced;”
- There was no toxicity to the mice; and
- The tumors did not build up resistance to the drug.
Pleased with the results, the team will begin to explore using the molecule as a novel form of anticancer reagents. There is much more research to be done, however, the team is hopeful that this breakthrough will be useful on all types of cancer, possibly even mesothelioma.
The study was published in the Feb. 12 issue of the journal EMBO Reports.
http://embor.embopress.org/content/early/2018/02/07/embr.201745336
Drug That “Shows Promise” Against Rare Ovarian Cancer May Lead to Mesothelioma Therapy
A genomics company announced last week that a drug approved for the treatment of leukemia “shows promise” against a rare type of ovarian cancer. Researchers identified a gene found in the cancer, also known to be associated with lung cancer and pancreatic cancer, as the target saying the drug “holds the potential for rapidly improving outcomes” in cancer patients. Continued research could uncover benefits in the treatment of mesothelioma, another rare cancer.
Inspired by a 22-year-old woman who died from ovarian cancer over 10 years ago, a team of researchers, led by the Translational Genomics Research Institute (TGen), set out to find a drug that could effectively fight a rare form of the cancer, small cell carcinoma of the ovary hypercalcemic type (SCCOHT), according to a March 1 press release from Translational Genomics Research Institute (TGen). The team identified a mutation of the SMARCA4 gene as a driver for the deadly cancer that primarily affects women in their 20s. They then turned their focus to the drug ponatinib, a type of kinase inhibitor drug, that would interfere with the tumors’ reliance on particular kinase pathways.
In the study, the researchers found that the drug they considered the “most effective clinically approved RTK inhibitor” did its job. In laboratory models of SCCOHT tumors, ponatinb delayed tumor-doubling time by four-fold, while reducing tumor volumes by as much as 58.6 percent.
“Current treatment for this devastating cancer has such poor response rates and extreme toxicity that we must find better therapeutics,” said Dr. Jeffrey Trent, TGen President and Research Director, and the senior author of the study. “Our work identifies a new treatment strategy that could provide these young women with improved patient benefit.”
Like SCCOHT, mesothelioma, the signature cancer of asbestos exposure, is highly aggressive with a grim prognosis. The survival for mesothelioma patients varies from just four to 18 months after diagnosis. According to TGen, SCCOHT has a two-year survival rate of less than 35 percent.
Many researchers have found that kinases are involved in the gradual transformation of normal tissue in the lining of the lung into malignant pleural mesothelioma after exposure to asbestos. Various studies have confirmed that finding an effective kinase inhibitor may be the key to fighting mesothelioma as well.
The team concluded that further investigation of the anti-cancer drug for SCCOHT is warranted.
Read the study in the Feb. 9 issue of Clinical Cancer Research.
Could Vaccine Under Development “Eliminate” Mesothelioma and Other Cancers?
It has been years since there has been a significant breakthrough in the fight against lung cancer or mesothelioma. The cancers are still a death sentence for many patients, with the 10-year survival rate just five percent. However, scientists continue to spend countless hours in a quest to find an effective treatment for the aggressive cancers. Now, researchers report that by turning to the latest trend in research by targeting immune cells they may be one step closer to finding a cure for many types of cancer.
Ronald Levy, MD, professor of oncology, and Instructor of Medicine Idit Sagiv-Barfi, PhD, both of Stanford University School of Medicine, partnered up in research designed to activate T cells, or immune cells, in tumors. They injected two immune-stimulating agents into mouse models, according to a Jan. 31 press release from Stanford. What they found was that the drugs worked “startlingly well” and successfully eliminated “all traces of cancer” in the mice, including distant, untreated metastases.
“When we use these two agents together, we see the elimination of tumors all over the body,” said Dr. Levy. “This approach bypasses the need to identify tumor-specific immune targets and doesn’t require wholesale activation of the immune system or customization of a patient’s immune cells.”
Mesothelioma is a rare form of cancer typically affecting the lining of the lungs. Primarily caused by exposure to airborne asbestos fibers, most cases of mesothelioma are diagnosed 30 years or more after exposure. Like many cancers, treating mesothelioma is challenging. However, recent successes with immunotherapyhave given mesothelioma patients significant improvements in their health.
Immunotherapy uses the body’s own immune system to target and destroy cancer cells. The aim of immunotherapy is to harness the strength of the immune system in a specifically focused attack on cancer cells.
See the success Mavis Nye of England had with immunotherapy.
The Stanford pair wanted to build on these successes, but eliminate the major downsides of immunotherapy, such as life-threatening complications, extended preparation, and costly treatment, that the current immunotherapy treatments cause.
The Stanford researchers found that by injecting their compound directly into the tumor they can reactivate the T-cells to then “lead the charge” to kill the cancer cells. T-cells are a type of white blood cell that continuously roam around within our bodies, seeking out and destroying cancer cells and infections. In the case of mesothelioma, and many other aggressive cancers, the cancer cells avoid detection from the T-cells and the cancer thrives.
“All of these immunotherapy advances are changing medical practice,” Levy said. “Our approach uses a one-time application of very small amounts of two agents to stimulate the immune cells only within the tumor itself. In the mice, we saw amazing, bodywide effects, including the elimination of tumors all over the animal.”
In the study, the “dual immunotherapy” not only shrunk tumors that had metastasized but also led to long-term survival.
The agents used in the trial are currently in separate clinical trials, but the Stanford team hopes to combine them for “great benefit for cancer patients.”
Mesothelioma is diagnosed in close to 3,000 Americans each year with the same number dying from the disease. Research such as this is critical for bringing hope to the cancer community.
Find the results of the study in the Jan. 31 issue of Science Translational Medicine.
Understanding Reason for Drug Resistance May Lead to Increased Effectiveness of Mesothelioma Drug
Researchers report they better understand why patients eventually develop resistance to the anti-cancer drug Tagrisso (osimertinib) that targets the epidermal growth factor receptor (EGFR) mutation in lung cancer patients. Using quantum and molecular mechanics, the researchers found “subtle changes” in the biomarker that left the drug ineffective. This finding could point researchers to a way to enhance the drug’s effectiveness for lung cancer and mesothelioma patients.
EGFR is a protein that is an anti-cancer drug target due to its role in cell proliferation. Osimertinib is an EGFR inhibitor for the way it binds to the EGFR protein and switches off a cancer cell‘s ability to spread and divide. The drug is generally effective in stopping the spread of cancer, however, according to researchers from the University of Bristol in the UK, most patients develop resistance within one year of treatment. Drug resistance arises, note the researchers, “because the EGFR protein mutates, so that the drug binds less tightly.”
The researchers took a closer diagnosis at why one particular mutation, the L718Q EGFR mutation in which just a single amino acid was changed, led the cancer to fight off, or resist, osimertinib. It took a unique collaboration “between medicinal and computational chemists and clinical oncologists” from the Universities of Bristol and Parma in Italy to resolve the reason for the resistance, according to a Feb. 12 press release from the University of Bristol.
Through a series of sophisticated molecular simulations the team revealed that the mutant protein L718Q “changes in a way that stops the drug reacting and binding to it.” The simulations ultimately allowed them to delve into the chemical reactions in EGFR, and reveal the “mechanisms” behind the drug resistance that, according to the researchers, “can be subtle and non-obvious.”
“Now the challenge is to exploit this discovery in the development of novel drugs targeting EGFR mutants for cancer treatment in the future,” said Adrian Mulholland, Professor of Chemistry at the University of Bristol.
According to a 2009 article in Current Drug Targets, EGFR overexpression has been shown in more than 50% of pleural mesothelioma patients. Approximately 15% of patients with lung cancer in the U.S. express EGFR mutations.
Lung cancer is the leading cause of cancer death in the United States, with an estimated 234,030 new diagnoses and 154,050 deaths in 2018, according to the American Cancer Society. Pleural mesothelioma is a form of lung cancer, affecting the lining of the lungs, with 3,000 new diagnoses each year, and nearly the same number of Americans dying from the terminal cancer. These grim statistics make continued research into increasing the efficacy of cancer drugs critical.
Read the study in the Feb. 3 issue of Chemical Science.
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