Breaking News
March 24, 2018 - Men have greater hospital readmission risk following firearm injury, study shows
March 24, 2018 - Pediatric psychologist shares 11 warning signs of childhood depression
March 24, 2018 - OncoBreak: ‘I Was Normal Once’; Ending Cervical Cancer; Mammo Controversy
March 24, 2018 - Gum Disease by the Numbers
March 24, 2018 - Studies show tool can identify individual needs, supports to help youths with autism, intellectual disabilities
March 24, 2018 - Study reveals cause of extreme nausea in pregnancy
March 24, 2018 - New findings highlight need to reconsider cervical cancer screening guidelines
March 24, 2018 - Smartwatch App Might Help Detect A-Fib
March 24, 2018 - TAVR Reasonable for Low-Flow, Low-Gradient Aortic Stenosis
March 24, 2018 - Kids with severe brain injuries may develop ADHD: study
March 24, 2018 - Researchers explore ways to help older adults taper off and stop using sedatives
March 24, 2018 - Back pain being mismanaged globally
March 24, 2018 - Fingerprint test accurately and noninvasively detects heroin, cocaine users
March 24, 2018 - Leading experts to promote cardiovascular health at EuroPrevent 2018
March 24, 2018 - A Role for Rituximab in Lupus?
March 24, 2018 - New osteoarthritis genes discovered
March 24, 2018 - Maternal intake of DHA supplement linked to higher fat-free body mass in children
March 24, 2018 - Royal College of Pathologists‘ bulletin provides summary of Tissue Handling Workshop
March 24, 2018 - Maternal alcohol use early in pregnancy may be risk factor for infant abdominal malformation
March 24, 2018 - Savara Initiates Phase 2a Clinical Study of Molgradex for the Treatment of NTM Lung Infection
March 24, 2018 - Accelerated WBI Should be the Norm for Most Breast Cancers
March 24, 2018 - Experts seek to standardize treatments for childhood rheumatic diseases
March 24, 2018 - Foil-based measuring chip rapidly detects Legionella
March 24, 2018 - Bariatric surgery linked to positive outcomes in very obese adolescents with type 2 diabetes
March 24, 2018 - Are there risks from secondhand marijuana smoke? Early science says yes.
March 24, 2018 - NUST MISIS researchers produce elastic metal rods for scoliosis treatment
March 24, 2018 - New University of Bath project seeks to make injections safer
March 24, 2018 - Higher-dose RT does not improve survival but reduces recurrence risk for prostate cancer patients
March 24, 2018 - Researchers examine link between knee pain and depression in older adults
March 24, 2018 - FDA Alert: BD Vacutainer Blood Collection Tubes by Becton, Dickinson and Company (BD): Class I Recall
March 24, 2018 - Daytime Sleepiness Linked to Amyloid Accumulation Without Dementia
March 24, 2018 - Energy storehouses in the brain may be source of Alzheimer’s, targets of new therapy
March 24, 2018 - Praising people with autism shows promise for producing more exercise
March 24, 2018 - Using harmless red or infrared light to diagnose breast cancer
March 24, 2018 - Clash over abortion hobbles a health bill. Again. Here’s how.
March 23, 2018 - Virtual nature environment could be new way to recover from stress
March 23, 2018 - New study identifies key cellular mechanisms behind vascular aging in mice
March 23, 2018 - Nightmares Common Among U.S. Troops, But Seldom Reported
March 23, 2018 - Another Record Low for Tuberculosis in U.S.
March 23, 2018 - Changes in the eye connected to a decline in memory
March 23, 2018 - Radiologist creates dramatic teaching tool using power of VR
March 23, 2018 - Grilled meat could be raising the risk of hypertension finds study
March 23, 2018 - Mutations found in bassoon gene may help explain cause of rare brain disorder
March 23, 2018 - Childhood Brain Injuries May be Linked to ADHD Years Later
March 23, 2018 - Why treating addiction with medication should be carefully considered
March 23, 2018 - Researchers make key discovery about cellular pathway linked to myriad of diseases
March 23, 2018 - Researchers uncover cause of rare childhood neurodegenerative disease
March 23, 2018 - Measles infection in early childhood could contribute to later COPD
March 23, 2018 - Opioid painkiller is top prescription in 11 states
March 23, 2018 - Sienna Biopharmaceuticals Announces First Patient Dosed In Proof-of-Concept Trial of Topical By Design™ JAK Inhibitor SNA-125 for Atopic Dermatitis
March 23, 2018 - In Teen Girls, Neural Patterns May Drive Emotional Resilience
March 23, 2018 - Gene-based test for urine detects, monitors bladder cancer
March 23, 2018 - BD to introduce new digital solution for IV chemotherapy administration process at EAHP 2018
March 23, 2018 - New computational method helps to identify tumor cell mutations with greater accuracy
March 23, 2018 - Researchers identify potential obesity treatment in freezing hunger-signaling nerve
March 23, 2018 - Wales participates in the 100,000 Genomes Project
March 23, 2018 - 24-Hr Paging Cuts ED Visits for Kids with Endocrine Issues
March 23, 2018 - The brain learns completely differently than we’ve assumed since the 20th century
March 23, 2018 - Less nutritious diet mainly contributes to Type 2 diabetes among U.S.-based South Asians
March 23, 2018 - Stony Brook Medicine expert provides tips for healthy diet to decrease cancer risk
March 23, 2018 - New findings could have revolutionary impact on quality of life of older people
March 23, 2018 - Restoring enzyme may help reverse effects of vascular aging, study shows
March 23, 2018 - Protein profiling reveals new prostate cancer mechanisms
March 23, 2018 - Depression may be linked to increased risk of atrial fibrillation
March 23, 2018 - FDA Takes Aim at Flavored Tobacco
March 23, 2018 - SMART Strategy Lowers Asthma Exacerbation Risk
March 23, 2018 - Cold open water plunge provides instant pain relief
March 23, 2018 - Portable and wearable technology supports future of military medical devices
March 23, 2018 - Patients with vascular malformations have poor health-related quality of life
March 23, 2018 - Researchers develop unique technology to overcome global antibiotic resistance crisis
March 23, 2018 - New DOD grant to support testing of promising therapy for triple-negative breast cancer
March 23, 2018 - Novel vaccine technologies can help better prepare for future infectious disease threats
March 23, 2018 - OncoBreak: Colonoscopy TV; Coverage for Genomic Testing; Care for Caregivers
March 23, 2018 - For some surgeries, nerve blocks mean better outcomes, fewer opioids
March 23, 2018 - Maternal obesity and androgen excess induce sex-specific anxiety in offspring, study suggests
March 23, 2018 - The tale of Theranos and the mysterious fire alarm
March 23, 2018 - USC researchers create algorithm to optimize substance abuse intervention groups
March 23, 2018 - Impulsivity may be associated with greater weight loss during treatment in obese children
March 23, 2018 - CTI BioPharma Announces Publication of Pacritinib Phase 3 PERSIST-2 Clinical Trial in JAMA Oncology
March 23, 2018 - Senate Panel Addresses Native Americans’ Opioid Troubles
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.


Tagged with:

About author

Related Articles