Category: Treatments
Some Immune Cells Thought to Help Fight Mesothelioma and Other Cancers May Actually Aid Metastasis
The National Cancer Society reports that 90 percent of all cancer deaths occur when the cancer cells migrate beyond the primary cancer site to distant organs. Stopping tumor growth and preventing metastasis is especially critical for increasing survival in mesothelioma and other cancer patients. Now, researchers believe they have found yet another way cancer cells spread throughout a patient’s body.
According to an April 6 press release from the Georgia Cancer Center at Augusta University (http://jagwire.augusta.edu/archives/43129), a team of researchers report that while cytokines are primarily useful in helping fight cancer, they found that they can also lead to cancer metastasis. These “immature” immune cells may be hijacked by cancer cells to help the cancer spread beyond its primary site.
“There is a very intricate balance in the immune system that is usually anti-tumorigenic, meaning it eliminates tumors, but in some cases, if this balance is altered, these cells may actually help tumors grow and develop into full-blown metastatic disease,” said Dr. Hasan Korkaya, molecular and cancer biologist at the Georgia Cancer Center and Medical College of Georgia at Augusta University.
Cancer spreads through the blood stream, but when cancer cells break free they have to get past the immune system where they are attacked and broken down. According to the researchers, the cancer cells use myeloid-derived suppressive cells (MDSCs) that come from the bone marrow, like a support system to dodge the immune system and metastasize.
The researchers note that MDSCs have been shown to suppress the immune system, however, their discovery that they also enable the spread of cancer is surprising. MDSCs seem to be directed by the cytokines secreted by the tumor. Cytokines, typically secreted by the immune system, can influence other cell types. The researchers found that tumors can also secrete cytokines that then signal the immature MDSCs to support the cancer growth.
“They are being schooled toward facilitating tumor cell growth and metastasis,” Korkaya said. The tumors continue to control the cytokines, according to the researchers, to keep the MDSCs from maturing, thus they can keep using them to grow the cancer.
In a recent study one researcher said, “Metastasis is currently incurable and remains one of the key targets of cancer research.” The physicians and patients in the mesothelioma community hope the researchers at Augusta University continue this line of research to help bring a solution to halting cancer’s uncontrolled growth.
Mesothelioma is diagnosed in close to 3,000 Americans each year. There is no cure for the asbestos-caused cancer.
To find out more, read the full study in the Feb. 20 issue of Nature Communications. http://www.nature.com/ncomms/2016/160524/ncomms11734/full/ncomms11734.html
Anti-Cancer Drug Found Effective in Rare Cancers Could Be Used as Mesothelioma Treatment
The ability to halt the growth of mesothelioma cancer cells, and to kill the cells, often relies on finding a drug that can inhibit the cells’ ability to communicate. Cells communicate via complex signalling pathways, and finding the right one to focus on can mean the difference in survival in patients. Now, researchers report that the Notch signalling pathway may be the key to stopping cancer growth in rare cancers, such as mesothelioma.
Patients with a wide range of cancers who had mutations of the Notch protein were selected for a study conducted by researchers from the Institut Gustave Roussy Cancer Campus in France. They focused on the Notch signalling pathway because of its role in driving cancer cells to grow, divide, and spread throughout the body. In addition, they report the Notch pathway plays a role in growth of new blood vessels that feed tumor growth and helps cancers become chemo-resistant. The pathway uses four Notch proteins that transfer messages across the cell membrane.
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Dr. Christophe Massard
“One of the interesting results with implications for some patients is that the drug was active against rare cancers such as adenoid cystic carcinoma.”
When the patients in the Phase I clinical trial were given LY3039478, a novel and potent Notch inhibitor, some of the patients experienced tumor shrinkage, disease stabilization and no further progression. These results were also seen in the rare cancer, adenoid cystic carcinoma.
“The results from this phase I trial prove that LY3039478 has the effect on tumours that was expected, by inhibiting the Notch signalling and thereby preventing cancer cell growth and proliferation,” said Dr. Christophe Massard, senior medical oncology consultant and chair of the Early Drug Development program at Gustave Roussy.
Pleural mesothelioma is a rare form of cancer caused by exposure to airborne asbestos fibers. The cancer, that affects just 3,000 Americans each year, is highly aggressive and is resistant to many current treatments. Care often follows the same protocol as lung cancer. Currently, there is no known cure for mesothelioma, but research such as this brings hope to the mesothelioma community that an effective treatment is on the horizon.
The trial results were presented at the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Munich, Germany.
Researchers Identify Proteins to Target to Increase Sensitivity of Mesothelioma and Lung Cancer Treatments
As MesotheliomaHelp has reported countless times before, researchers focus much of their time on biomarkers in mesothelioma and lung cancer patients to help increase the effectiveness of treatment. By targeting the unique characteristics of a patient’s cancer the researchers aim to increase survival. Now, researchers believe ALK, a key gene often targeted with anti-cancer drugs, can be more effective when other proteins are also targeted.
Everyone has the abnormal anaplastic lymphoma kinase (ALK) gene in their cells, but when a part of it breaks off and reattaches in the wrong way, it becomes an abnormal ALK gene leading to out of control cell growth and ALK-positive lung cancer. By blocking the action of the abnormal ALK gene, crizotinib (Xalkori), an ALK-inhibitor, may shrink or slow the growth of tumors, according to Pfizer, the makers or Xalkori. However, some tumors do not respond to the drug or develop resistance to it.
Researchers from Moffitt Cancer Center focused on increasing the sensitivity of lung cancer tumors to ALK inhibitors. The team turned to proteomics to allow a large scale review of proteins so they could “identify potential drug targets that could boost ALK inhibitors and improve patient outcomes”, according to an Oct. 19 article in Medical News Today.
http://www.medicalnewstoday.com/releases/313580.php
They found a host of proteins, 64 of them, could be used to increase sensitivity to crizotinib, and nine of them could do the same for alectinib, another ALK-inhibitor. They eventually narrowed the list down to two “adaptor proteins FRS2 and CC2D1A” that can increase the sensitivity of lung cancers to ALK inhibitors.
“Knocking down either of these two proteins, the scaffolding proteins FRS2 and CC2D1A, sensitized cell lines to the ALK inhibitors crizotinib and alectinib,” wrote the researchers. “Thus, a clinical strategy that inhibits FRS2 or CC2D1A might enhance the efficacy of ALK inhibitors in some patients.”
Crizotinib, or Xalkori from Pfizer, is intended for the treatment of metastatic non-small cell lung cancers (NSCLC) in patients who express the abnormal anaplastic lymphoma kinase (ALK) gene. Approximately 3%-5% of people with NSCLC may test positive for the ALK fusion gene. There is a potential that the marker is also present in certain pleural mesothelioma cases making it a target for treatment.
Pleural mesothelioma is a rare form of lung cancer that invades the outer lining of the lungs called the mesothelium. The only known cause of mesothelioma is through inhalation or ingestion of airborne asbestos fibers. Both NSCLC and mesothelioma are aggressive cancers following equally aggressive, and similar, treatment protocols.
“Collectively, our data set provides a resource that enhances our understanding of signaling and drug resistance networks consequent to ALK fusions and identifies potential targets to improve the efficacy of ALK inhibitors in patients,” concluded the researchers.
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For the full study see the Oct. 18 issue of Science Signaling.
http://stke.sciencemag.org/content/9/450/rs12
Blood Samples May be Reliable Monitoring Tool for Patients
In January, Mesothelioma Help reported about a business venture by a San Diego-based company focused on developing a blood test to detect cancers that can be conducted in doctors’ offices. Now, another company reports that liquid biopsies, another term for the blood tests, can be used to monitor lung cancer patients’ response to treatment in real-time.
Researchers from the German Cancer Research Center (DKFZ), report that oncologists have come to rely on tissue biopsies as a way to manage a lung cancer patient’s treatment and to assess their progress. However, “tissue biopsy is much more invasive, and in some cases a risky procedure,” they report.
So the researchers delved deeper into the pros of liquid biopsies to help ease pain for patients and to improve the success rates of treatments for oncologists. What they found is that blood tests can be “a promising tool to monitor lung cancer patient tumors early.”
They reviewed the blood samples of 16 EGFR-positive lung cancer patients undergoing tyrosine kinase inhibitor treatment (erlotinib, gefitinib, or afatinib). Over the course of the two-year study the researchers were able to attribute three major categories of treatment to the changes in the circulating tumor cells: evidence for therapy response, periods of stable disease, and impending tumor progression.
“These findings highlight liquid biopsy’s sensitivity in detecting and reflecting tumor changes in real time, while providing the advantages of being less invasive,” said the authors.
The use of biopsy when determining the efficacy of a treatment was previously discussed by a panel of oncologists on OncLive’s Peer Exchange Series. The oncologists agreed that biopsy results can be used to not only diagnose cancer but to drive a cancer patient’s treatment plan. Anne S. Tsao, MD, Director, Mesothelioma Program, The University of Texas MD Anderson Comprehensive Cancer Center, said oncologists should use biopsies to “shoot for genetic testing and personalized medicine for treatment decisions.”
The DKFZ researchers explained that when tumor cells die after treatment they release their DNA (or cell free DNA, cfDNA), with all its mutations still intact, into the bloodstream. The team found that blood samples, or cfDNA, are as effective as tissue biopsies when assessing prognosis in EGFR-positive lung cancer patients.
Professor Holger Sültmann, one of the lead authors, cautions that more work remains to be done, saying, ‘’This is a ‘proof of concept’, we should really collect and measure cfDNA more systematically in order to learn what the liquid biopsy can do under these circumstances, and to fully comprehend the principles of lung cancer progression.’’
EGFR is a protein found on the surface of some cells to which epidermal growth factor binds, which causes the cells to divide and spread. It is found at abnormally high levels on the surface of many types of cancer cells, including more than 50% of pleural mesothelioma patients. Tyrosine kinase inhibitors work by blocking the activity of the EGFR tyrosine kinase enzyme, preventing the growth of new blood vessels that tumors need to grow, and, potentially, killing cancer cells.
Pleural mesothelioma is a cancer of the lining of the lungs caused by past asbestos exposure. The cancer is diagnosed in close to 3,000 Americans each year.
See the Sept. 19 issue of Scientific Reports for the study.
Sources
- Scientific Reports
http://www.nature.com/articles/srep23489 - German Cancer Research Center
https://www.dkfz.de/en/presse/pressemitteilungen/2016/dkfz-pm-16-39-Liquid-Biopsy-Level-of-mutated-DNA-in-the-blood-corresponds-to-patient-outcome.php
Mesothelioma Biomarker Could Lead to “Promising” Treatment
Researchers continue to focus on biomarkers as a target to increase the effectiveness of existing treatments for malignant mesothelioma. These genetic characteristics can be used to indicate the progress of mesothelioma, help determine an appropriate treatment, and assess the effectiveness of that treatment. Now, researchers have identified a biomarker that they believe points to poor prognosis in mesothelioma patients, but that could also lead to a promising therapeutic approach for the asbestos-caused cancer.
Researchers from Japan report the urokinase-type plasminogen activator receptor (uPAR), also known as CD87, that is normally expressed throughout the body, including in the colon and kidneys, was found at elevated levels in a mouse model with mesothelioma. The team from Nagoya University Graduate School of Medicine, Nagoya, Japan, found that the higher the level of uPAR, the worse the prognosis was for the mice.
“For the first time, we showed that uPAR overexpression is observed in asbestos-induced rat MM [malignant mesothelioma], regardless of the asbestos fibers used for carcinogenesis and the histological subtype of MM,” wrote the authors. “These data indicate that uPAR overexpression is a common and important expressional alteration in MM.”
The researchers then went on to discover that overexpression of uPAR is also associated with sensitivity to the platinum-based chemotherapy drug cisplatin. When they blocked the level of uPAR in the mice, there was a rise in the sensitivity to cisplatin. On the contrary, higher levels of uPAR “significantly decreased cisplatin sensitivity.”
According to the National Institute of Environmental Health Sciences, marker levels may be measured before treatment to help doctors plan the appropriate therapy. In some types of cancer, the level of a tumor marker reflects the stage (extent) of the disease and/or the patient’s prognosis (likely outcome or course of disease).
http://www.niehs.nih.gov/health/topics/science/biomarkers/
Mesothelioma is an aggressive, terminal cancer found in the lining of the lungs, heart and abdomen in patients previously exposed to asbestos. Although the cancer has been shown to be chemo-resistant, chemotherapy continues to be one of the primary treatment protocols for the disease, with the preferred combination being gemcitabine and cisplatin.
Patients nearly always develop resistance to chemotherapy, leading to metastasis of the cancer. However, studies like this where research is done to identify ways to increase the sensitivity, and thus the effectiveness, of cisplatin, and potentially other existing treatments, can lead to an increase in patient survival.
“In addition to the potential use of uPAR as a prognostic marker, the combination of uPAR abrogation and cisplatin may reveal a promising therapeutic approach for MM,” the researchers concluded.”
See the Sept. 2 issue of Oncotarget for the full report.
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=10430
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