Breaking News
August 14, 2018 - Wearable devices and ‘mhealth’ technology emerge as promising tools for better health
August 14, 2018 - Phase 2 Clinical Data Published Showing Summit’s Ridinilazole Preserved Gut Microbiome of Patients with CDI
August 14, 2018 - Cardiac progenitor cells undergo a cell fate switch to build coronary arteries
August 14, 2018 - Revealed: The molecular mechanism underlying hypertrophic cardiomyopathy, or “workaholic heart”
August 14, 2018 - New technology shows potential to streamline the analysis of proteins
August 14, 2018 - Rethinking the stroke rule ‘time is brain’
August 14, 2018 - Incidence of coronary artery compression in children may be more common than previously thought
August 14, 2018 - Study helps to better understand disease caused by Alpha-1 antitrypsin deficiency
August 14, 2018 - AI platform identifies acute neurological illnesses faster than human diagnosis
August 14, 2018 - American College of Rheumatology receives grants to support development of lupus clinical trials
August 14, 2018 - New study explains why women get more migraines than men
August 14, 2018 - American Heart Association Urges Screen Time Limits for Youth
August 14, 2018 - Brief interventions during routine care reduce alcohol use among men with HIV
August 14, 2018 - New genome analysis could identify people at higher risk of common deadly diseases
August 14, 2018 - NIH grant for Mount Sinai to study use of inhaled corticosteroids for treatment of sickle cell disease
August 14, 2018 - Daicel supplies free nanodiamond samples to international researchers
August 14, 2018 - Switching anti-psychotic drugs in first-episode schizophrenia patients does not improve clinical outcomes
August 14, 2018 - Study to examine whether modulating gut bacteria can improve cardiac function in heart failure patients
August 14, 2018 - AI technology could hold key to improving health services
August 14, 2018 - One out of two children not getting enough nutrients needed for their health
August 14, 2018 - Mono-antiplatelet therapy after aortic heart valve replacements may work as well as two drugs
August 14, 2018 - Aid-in-dying patient chooses his last day
August 14, 2018 - Exercise Really Can Chase Away the Blues, to a Point
August 14, 2018 - Surgical mesh implants may cause autoimmune disorders
August 14, 2018 - Researchers develop revolutionary zebrafish model to gain more insight into bone diseases
August 14, 2018 - Researchers discover secret communication hotline between breast cancers and normal cells
August 14, 2018 - Study examines how a person adapts to visual field loss after stroke
August 14, 2018 - Researchers show how specialized nucleic acid-based nanostructures could help target cancer cells
August 14, 2018 - Reducing opioid prescriptions for one operation can also spill over to other procedures
August 14, 2018 - E-cigarettes not so safe but still better than cigarettes
August 14, 2018 - Researchers find link between common ‘harmless’ virus and cardiovascular damage
August 14, 2018 - Initiation of PIMs associated with higher risk of fracture-specific hospitalizations and mortality
August 14, 2018 - Genetically modified mosquitoes and special bed nets help tackle deadly diseases
August 14, 2018 - Advances in treating hep C lead to new option for transplant patients
August 14, 2018 - Study finds quality of doctor-patient discussions about lung cancer screening to be ‘poor’
August 14, 2018 - MSU researchers uncover the effects of aging on regenerative ability of kidneys
August 14, 2018 - Better conditioning, throwing mechanics can help reduce elbow injuries in young baseball pitchers
August 14, 2018 - Brain game doesn’t offer brain gain
August 14, 2018 - Reproductive choices facing women with disabilities require careful consideration
August 14, 2018 - Scientists pinpoint the cause of a rare childhood seizure disorder
August 14, 2018 - Lumpectomy plus radiation associated with reduced risk of breast cancer death, study finds
August 14, 2018 - UAB study shows how ion channel differentiates newborn and mature neurons in the brain
August 14, 2018 - Experts highlight key knowledge gaps that need to be addressed in Ebola vaccine research
August 14, 2018 - Discovery could lead to new drugs against infection and inflammation
August 14, 2018 - Infection Prevention Differs Between Small, Large Hospitals
August 14, 2018 - Mom still matters—In study, young adults tended to prioritize parents over friends
August 14, 2018 - Deep brain stimulation might benefit those with severe alcoholism, preliminary studies show
August 14, 2018 - Study finds increased rate of repeat pregnancies in women with intellectual and developmental disabilities
August 14, 2018 - Lighter sedation fails to reduce risk of postoperative delirium in older patients
August 13, 2018 - Asking better questions about person’s memory could improve doctors’ understanding of patients
August 13, 2018 - U.S. Trauma Doctors Push for Stricter Gun Controls
August 13, 2018 - Asthma and flu: a double whammy
August 13, 2018 - 5 Questions: Donna Zulman on engaging high-need patients in intensive outpatient programs | News Center
August 13, 2018 - Behavioral Nudges Lead to Drop in Prescriptions of Potent Antipsychotic
August 13, 2018 - Potential New Class of Drugs May Reduce Cardiovascular Risk by Targeting Gut Microbes
August 13, 2018 - How to get your kids to eat better
August 13, 2018 - The importance of hearing your patients
August 13, 2018 - Transmission of F. tularensis unlikely to happen through the food chain
August 13, 2018 - Researchers discover epigenetic mechanism underlying ischemic cardiomyopathy
August 13, 2018 - Adolescent health programs receive only a tiny share of international aid, finds research
August 13, 2018 - Fracture risk increases by 30% after gastric bypass, study shows
August 13, 2018 - Quality-improvement project to standardize feeding practices helps micro preemies gain weight
August 13, 2018 - Long-term cannabinoid exposure impairs memory, study shows
August 13, 2018 - New intervention to reduce risk of HIV in young transgender women
August 13, 2018 - Japan human trial tests iPS cell treatment for Parkinson’s
August 13, 2018 - Altered nitrogen metabolism may contribute to emergence of new cancer mutations
August 13, 2018 - Cycling provides greatest health benefits, study finds
August 13, 2018 - Scientists discover biomarker for kidney cancer
August 13, 2018 - New test predicts the risk of serious disease before symptoms appear
August 13, 2018 - Cianna Medical receives FDA 510(k) clearance to extend indication of SCOUT reflector for use in soft tissue localization
August 13, 2018 - Ground-breaking discovery offers new hope for treatment of Alzheimer’s, other neurological diseases
August 13, 2018 - Medical nutrition therapy provided by RDNs benefits patients with chronic kidney disease
August 13, 2018 - Prenatal Tdap vaccination not linked with increased risk of autism in children, study shows
August 13, 2018 - One-Third of Canadian Patients Get Hip Fx Repair Within 24 Hours
August 13, 2018 - ANA (Antinuclear Antibody) Test: MedlinePlus Lab Test Information
August 13, 2018 - Traffic jams in the brain
August 13, 2018 - NIH awards $6.5 million to establish multi-institution biomedical technology resource center
August 13, 2018 - New marker in the blood could help predict person’s risk of developing kidney cancer
August 13, 2018 - New biomarker may provide clues to create diagnostic tool for hypoglycemia-associated autonomic failure
August 13, 2018 - Oxidative Stress Hampers Blood Vessel Dilation in Men
Researchers block common siren call of glioblastoma and metastatic breast cancer

Researchers block common siren call of glioblastoma and metastatic breast cancer

image_pdfDownload PDFimage_print

Aggressive cancers like glioblastoma and metastatic breast cancer have in common a siren call that beckons the bone marrow to send along whatever the tumors need to survive and thrive.

Scientists say a logical and effective new treatment target is to block production of the chemical that initiates that call.

They have successfully used an inhibitor of the chemical 20-HETE to control the growth and spread of human glioblastomas and breast cancer in laboratory models, says Dr. Ali S. Arbab, leader of the Tumor Angiogenesis Initiative at the Georgia Cancer Center and professor in the Department of Biochemistry and Molecular Biology at the Medical College of Georgia at Augusta University.

“Our idea is that the most aggressive tumors have the same basic mechanisms of growth and spread,” says Arbab, senior author on separate review articles on both the deadly cancers in the International Journal of Molecular Sciences. “We have good evidence that blocking 20-HETE production is a good way to inhibit that growth.”

20-HETE is an essential partner for our healthy body and apparently for cancer as well. 20-HETE, or 20-Hydroxyeicosatetraenoic acid, is a metabolite of arachidonic acid, a fatty acid we make and constantly use for a wide variety of functions like helping make lipids for our cell membranes.

20-HETE’s normal functions include helping regulate blood pressure and blood flow. It’s also a known mediator of inflammation, which under healthy conditions can help us fight infection and actually protect us from cancer and other invaders.

But tumors express too much 20-HETE and the chemical turns on us, first by activating immune cells that will send the cytokines that become the siren call to our bone marrow, says Dr. B.R. Achyut, cancer biologist in the MCG Department of Biochemistry and Molecular Biology and corresponding author of the paper on glioblastoma.

Once the bone marrow cells show up, 20-HETE also turns the cells’ usually lifesaving functions, like making blood vessels and populating our immune system, against us, Achyut says. This includes bolstering the primary tumor site and in the case of breast cancer, helping prepare remote sites in places like the brain, lung and liver, he says.

Arbab and his team have shown that 20-HETE aids activation of things like protein kinases that can change the function of proteins, their location and what cells they associate with, as well as growth factors that can make cells grow in size, proliferate and differentiate. It can even help recruit cells that make blood vessels that enable additional growth. 20-HETE also activates signaling kinases that enable cell division. It encourages inflammation-promoting factors like tumor necrosis factor alpha and several of the interleukins, another class of proteins that help regulate the immune response. In this scenario, these factors are turning up inflammation, a hallmark of cancer and other diseases, to support – not fight – cancer.

To reduce the many ill effects of too much 20-HETE, the scientists have used an inhibitor, called HET0016, in combination with chemotherapy, says Dr. Thaiz F. Borin, molecular biologist in the MCG Department of Biochemistry and Molecular Biology and corresponding author of the paper on breast cancer metastasis. They expect its clinical usage also will be as an adjuvant therapy.

They have given the drug alternately with the chemotherapy drug temozolomide for three to six weeks. They have found in rats with glioblastoma, for example, the rodents survived for at least six months – at which time they were euthanized as part of the study – instead of for only a few weeks as likely would have been the case.

Like many ironies of cancer, hypoxia, a lack of adequate blood and oxygen often associated with disease and death, seems to be a survival tactic for both these rapidly growing tumor types. When a glioblastoma reaches the diameter of just .1 inch, for example, the rapid growth and cell division makes the center of this very vascular tumor become hypoxic, the scientists say. That leads to the need to recruit from the bone marrow a myriad of factors like vascular endothelial growth factor, or VEGF, that enable blood vessel and tumor growth, which the misguided 20-HETE enables.

The bone marrow cells the tumor cytokines woo also include endothelial progenitor cells to make the lining for all the new blood vessels that VEGF and myeloid cells are making. Myeloid cells are immature, multitasking cells that can drive protective inflammation, but in this case, help tumors suppress the usual immune response in addition to making blood vessels.

Increased numbers of these myeloid-derived suppressor cells, or MDSCs, are recruited to both the main tumor and its metastatic sites. Higher rates of these cells are associated with higher rates of recurrence and metastasis.

One of the team’s many findings is that targeting the arachidonic acid pathway by inhibiting the production of 20-HETE resulted in a reduction of MDSCs in the usual sites of breast cancer spread like the lungs, liver, brain or bones. There was less communication between the tumor’s base camp and these deadly satellite locations. When they examined the lungs, they saw fewer cytokines to summon the bone marrow cells and fewer enzymes that also support invasiveness of the breast cancer cells. HET0016, the inhibitor of 20-HETE, also was able to decrease the amount of growth factors, cytokines and enzymes called metalloproteinases responsible for the aggressiveness and invasiveness of the tumor cells, Borin says.

The primary tumors also shrank because they are no longer recruiting the factors that enable growth, Arbab says. “They are becoming static,” he adds, noting that the 20-HETE blocker does not kill tumor cells, rather essentially puts them on hold.

The Georgia Cancer Center team notes that chemotherapy does kill tumor cells but when the tumors start dying they actually increase their release of cytokines as another cry for survival, which is another good reason to also directly target the call for assistance that tumors are sending, Arbab says.

“Cytokines are the point of action and cancer releases a lot of them,” Borin says of these molecules well known for their role in regulating the immune response.

The 20-HETE inhibitor they are using for the preclinical studies is made by Dr. Iryna Lebedeva, assistant professor in the Department of Chemistry and Physics at Augusta University. The scientists already have identified companies that could make a clinical grade inhibitor. To date they have studied only one dose of the research drug, and Arbab has submitted a grant to the National Cancer Institute to look at escalating doses in the rat model of glioblastoma.

They are also working now to learn more about how the inhibitor works, including its impact on the tumor microenvironment, and more about what happens to the bone marrow cells that tumors recruit.

While a 20-HETE inhibitor has not yet been used in humans, commonly used drugs like aspirin and Celebrex, which target other arachidonic acid pathways, are widely used. The scientists’ studies indicate that healthy bone marrow production is untouched by 20-HETE inhibition because it’s blocking the tumor’s signals not the bone marrow directly. And nobody wants bone marrow cells once tumors get their attention, they note. “They are working for the tumor,” Borin says.

Adjuvant therapies that directly target the tumor microenvironment – several of which are currently in clinical trials – are a promising approach for both new and recurrent glioblastoma’s, the researchers write, along with those that target 20-HETE. More labs with a focus on glioblastomas could also help move science to the bedside faster, they say.

The researchers even suggest pursuing drugs that could normalize blood vessel production, reducing the recurring hypoxia and the tumor’s cue to grow.

Unlike breast cancer, glioblastoma typically does not spread to other organs rather increasingly occupies more and more space that should be occupied by the healthy brain. Patients can die from the pressure the tumor puts on the brain.

Research support included funding from the American Cancer Society and the National Institutes of Health.

Source:

http://www.augusta.edu/mcg/

Tagged with:

About author

Related Articles