Navigation Links
Novel target for existing drug may improve success of radiation therapy

Scientists at Washington University School of Medicine in St. Louis have discovered a new drug target that could improve the effectiveness of radiation for hard-to-treat cancers.

The finding, published in the Journal of the National Cancer Institute, focuses on the role of the enzyme cytosolic phospholipase A2 (cPLA2). This enzyme promotes development and functioning of blood vessel networks that feed malignant tumors, enabling them to overcome the effects of radiation.

They have also identified a drug that stops production of the enzyme. Inhibiting the enzyme can stop the flow of blood tumors need to survive.

Cancers thrive and spread thanks to a unique ability to recruit networks of new blood vessels that penetrate into tumors, bringing oxygen and nutrients and potentially transporting cancer cells to other parts of the body.

Cancer cells start the process of new blood vessel construction, called angiogenesis, by releasing specific molecules into surrounding normal tissue, kicking off a cascade of molecular signals that cause cells lining existing blood vessels to divide and create new vessels. These new vessel networks link the tumor to the circulatory system and its life-sustaining cargo.

Lung cancer and glioblastoma, the most common type of primary brain tumor, are particularly adept at inducing new blood vessel creation via angiogenesis. They are also highly resistant to treatment by radiation.

"Our original objective was to measure the signaling molecules that enable lung and brain cancer to be resistant to radiation," says Dennis Hallahan, MD, the Elizabeth H. and James S. McDonnell III Distinguished Professor in Medicine and chair of the Department of Radiation Oncology at the School of Medicine and senior author of the study.

"There are hundreds of signaling molecules, but the enzyme cPLA2 stood out," Hallahan says. "Radiation of tumor cells triggers production of cPLA2 within two minutes and it contributes to tumor survival."

The cPLA2 enzyme is known to regulate the levels of at last three molecules that promote tumor angiogenesis (the creation of new blood vessel networks to feed cancer cells).

The researchers set out to learn if they could enhance the effect of radiation therapy for lung and brain cancers by inhibiting this enzyme.

The idea was to implant tumors into normal mice and into mice that had been genetically engineered to be unable to produce cPLA2 and then compare the effect of radiation therapy on tumor progression in each.

The immense power of cPLA2 became apparent to Hallahan when a graduate student complained that her experiment failed because she could not grow tumors in mice that lacked the gene that produces cPLA2.

"While implanted tumors progressed as expected in normal mice used in the experiment, they were virtually undetectable in cPLA2 deficient mice," Hallahan says. "The 'failed experiment' was actually a significant discovery of the enormous control cPLA2 has in regulating tumor angiogenesis."

The scientists then examined the blood vessels of the cPLA2 deficient mice. While the blood vessels of cPLA2 deficient mice appeared normal, close inspection revealed the absence of a certain type of contractile cell that regulates blood flow.

"Without these cells, blood vessels can still grow into the tumor but blood cannot flow to the tumor," Hallahan says. "Cancer cannot survive without blood flow to feed it."

The central role of cPLA2 in determining the presence or absence of these contractile cells makes it a prime target for interventional therapy.

"Drugs that target cPLA2 have enormous potential for improving the success of radiation against highly angiogenic tumors," Hallahan says.

Hallahan has already identified an existing drug that inhibits cPLA2. It is a compound originally developed by Wyeth, now part of Pfizer, as a treatment for arthritis. The drug had advanced to Phase 2 testing before being discontinued as a potential arthritis treatment.

Reaching Phase 2 testing, however, suggests that a compound has been proven safe, regardless of whether or not it meets performance standards for the specific medical condition for which it was made. These drugs are typically then tested for other uses.

Hallahan learned of the Pfizer compound from an innovative collaboration between Pfizer and Washington University that allows Washington University scientists to view extensive research data on a large array of Pfizer pharmaceutical candidates that are or were in clinical testing.

Don Frail, PhD, chief scientific officer of Pfizer's Indication's Discovery Unit, says the majority of drug candidates tested in development do not give the desired result.

"Yet those drugs that do succeed typically have multiple uses," Frail says. "Hallahan's research has led to an entirely new potential use for one of these compounds in an area of high patient need that otherwise might have been overlooked. This is exactly what our partnership with Washington University is about and is among the first to be funded through the new relationship."

Hallahan is currently partnering with Craig Wegner, PhD, in the Indications Discovery Unit of Pfizer to further understand the pathways impacted by cPLA2 and to evaluate the drug that inhibits its action.


Contact: Joni Westerhouse
Washington University in St. Louis

Related medicine news :

1. Novel nanotechnology collaboration leads to breakthrough in cancer research
2. Novel autoantibodies identified in patients with necrotizing myopathy
3. Novel role: EZH2 boosts creation of ovarian cancer blood vessels
4. FSU study takes novel approach to understanding pituitary function
5. OU researcher developing novel therapy for Alzheimers disease
6. Vitamin B3 as a novel approach to treat fungal infections
7. Announcing: Intrinsic Imaging : Radiology Experts Launch Novel Medical Imaging CRO for Clinical Trials
8. Novel approaches to R&D in Africa needed
9. Novel radiotracer shines new light on the brains of Alzheimers disease patients
10. Team led by LA BioMed scientist develops novel approach to study neurological disorders
11. Novel paclitaxel formulation encouraging for treating advanced lung cancer
Post Your Comments:
(Date:11/28/2015)... ... , ... Safe storage for contraceptive devices may not always be easy to ... and the other from Bradley Beach, New Jersey, there is an easy solution to ... to replace NuvaRings more often than necessary. As such, it affords peace of mind ...
(Date:11/27/2015)... (PRWEB) , ... November 28, 2015 , ... There is ... we outperform our billings from last year? , This question has not been an ... are coming to the retirement age and the younger workforce don’t share the same ...
(Date:11/27/2015)... ... November 27, 2015 , ... The rapid speed at ... people age, more care is needed, especially with Alzheimer’s, dementia and other cognitive ... being overworked. The forgotten part of this equation: 80 percent of medical care ...
(Date:11/27/2015)... (PRWEB) , ... November 27, 2015 , ... Lizzie’s Lice ... The company is offering customers 10% off of their purchase of lice treatment product. ... at full price. According to a company spokesperson. “Finding lice is a sure way ...
(Date:11/27/2015)... ... 27, 2015 , ... Consistent with the Radiology Business ... Better Radiology Marketing Programs meeting will showcase some of the best 2015 ... Caesars Palace in Las Vegas with a pre-conference session on a collaborative approach ...
Breaking Medicine News(10 mins):
(Date:11/26/2015)... , November 26, 2015 ... the addition of the  "2016 Future ... European Therapeutic Drug Monitoring (TDM) Market: ... Intelligence, Emerging Opportunities"  report to their ... has announced the addition of the  ...
(Date:11/26/2015)... 26, 2015 ) ... Administration of High Viscosity Drugs" report to ... announced the addition of the "Self Administration ... offering. --> Research and Markets ( ... "Self Administration of High Viscosity Drugs" ...
(Date:11/26/2015)... November 26, 2015 ... the "Radioimmunoassay Market by Type (Reagents ... Industry, Academics, Clinical Diagnostic Labs), Application (Research, ... to 2020" report to their offering. ... the addition of the "Radioimmunoassay Market ...
Breaking Medicine Technology: