One-two punch: Cancer therapy more potent when it hits two targets
Simultaneous targeting of two different molecules in cancer is an effective way to shrink tumors, block invasion, and stop metastasis, scientists at the University of California, San Francisco (UCSF) have foundwork that may improve the effectiveness of combination treatments that include drugs like Avastin.
The two-target approach, tested in mice with a type of cancer known as neuroendocrine pancreatic tumors, may have broad application for treating a wide variety of cancers, the UCSF team said. The drugs used in the tests belong to classes of pharmaceuticals that are either on the market or under development in clinical trials.
Clinical trials also are already underway to gauge effectiveness of the approach in humans with prostate cancer, breast cancer, and other tumor types. The UCSF study, described in the journal Cancer Discovery this week, is the first to show how the drug combination works in the laboratory.
The results are promising, said Donald McDonald, MD, PhD, a member of the UCSF Helen Diller Comprehensive Cancer Center and the Cardiovascular Research Institute and professor of anatomy, who led the research.
In the study, treating mice with the dual-target approach turned aggressive tumors with invasive fingers penetrating surrounding tissues and many metastases into tiny balls with few or no metastases.
"It's the combination of approachesthere's a synergy between the two," McDonald said. "You add two and two, and you get 10."
HOW EACH TARGET WORKS
The two targets are both proteins that scientists have known for years are involved in cancer. Both play important roles in malignant tumors.
The first, called c-MET, is involved in two processes associated with the most deadly cancers. A clinical marker of cancer aggressiveness, c-MET drives tumor invasion into surrounding tissues. It is also involved in metastasisthe spread of cancer cells to other parts of the body where they can establish new tumors.
The second target is a protein known as vascular endothelial cell growth factor (VEGF). VEGF is a protein that promotes the growth of new blood vessels. Growing tumors hijack this process to expand their network of blood vessels to provide nutrients. Drugs blocking VEGF have been developed based on the simple assumption that tumors cannot grow if you choke off their blood supply.
Drugs that target these molecules are in development, and a few are already on the market. The U.S. Food and Drug Administration (FDA) approved the first of these in 2004 to treat metastatic colon cancer. That drug, called Avastin, is manufactured by the South San Francisco-based company Genentech. Avastin was approved for metastatic breast cancer in 2008 under the FDA's accelerated approval program.
The FDA revoked approval of Avastin for breast cancer last year after further assessing the relative risks and benefits to women taking it. Blocking VEGF seemed to slow tumor growth for awhile, but the FDA determined that it did not significantly improve or extend the lives of most women taking it.
"It was not clear why some tumors responded and others did not. It was also unclear why some tumors would respond initially and then would stop responding," said McDonald, who has studied blood vessels in tumors and the effect of cancer drugs for years in his UCSF laboratory.
Two years ago former UCSF professor Douglas Hanahan and colleagues found in laboratory experiments that Avastin-like drugs would shrink tumors but unexpectedly did something else as well. The drugs also morphed tumors from roundish blobs into highly irregular growths with tendrils that penetrated surrounding tissues and even spread to other organssuggesting that the VEGF blockade could also make tumors more aggressive, invasive and metastatic.
McDonald's group confirmed Hanahan's findings and discovered that c-MET was involved. In their latest research, Barbara Sennino, PhD, with other investigators in his group set out to determine whether c-MET drove tumor aggressiveness during anti-VEGF therapy. What their paper shows is that blocking c-MET and VEGF together in mice is more powerful than blocking either alone because it not only slows tumor growth but also reduces invasion and metastasis.
They tested two inhibitors of VEGFa neutralizing antibody and sunitiniband three inhibitors of c-METcrizotinib, PF-04217903, and cabozantinib (XL184). Unlike the other agents, cabozantinib simultaneously inhibits both c-MET and VEGF. Inhibition of c-MET and VEGF together with a drug combination or with cabozantinib had more profound effects on tumors than any of the agents that blocked only one of the targets.
These promising laboratory results still need more tests of safety and effectiveness in the clinic, McDonald said, and it may be a year or more before the drugs are routinely available to patients.
More information: The article, "Suppression of Tumor Invasion and Metastasis by Concurrent Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine Tumors" by Barbara Sennino, Toshina Ishiguro-Oonuma, Ying Wei, Ryan M. Naylor, Casey W. Williamson, Vikash Bhagwandin, Sebastien P. Tabruyn, Weon-Kyoo You, Harold A. Chapman, James G. Christensen, Dana T. Aftab, and Donald M. McDonald appears in the March 1 issue of Cancer Discovery. It's available at cancerdiscovery.aa… ournals.org/
Provided by University of California, San Francisco
- Avastin, Sutent increase breast cancer stem cells, study shows Jan 25, 2012 | not rated yet | 0
- A longer lasting tumor blocker Apr 28, 2009 | not rated yet | 0
- Study sheds light on angiogenesis inhibitors, points to limitations, solutions Mar 02, 2009 | not rated yet | 0
- Combinatorial therapy allows viruses to destroy tumors Apr 01, 2010 | not rated yet | 0
- Anti-cancer drug damages brain vessels Feb 11, 2008 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
How can there be a term called "intestinal metaplasia" of stomach
15 hours ago Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
- More from Physics Forums - Medical Sciences
More news stories
The gap between life expectancy in patients with a mental illness and the general population has widened since 1985 and efforts to reduce this gap should focus on improving physical health, suggest researchers in a paper ...
Cancer 4 hours ago | not rated yet | 0
By studying the roles two proteins, thrombospondin-1 and prosaposin, play in discouraging cancer metastasis, a trans-Atlantic research team has identified a five-amino acid fragment of prosaposin that significantly reduces ...
Cancer 5 hours ago | not rated yet | 0
A novel transcriptome-based classification of colon cancer that improves the current disease stratification based on clinicopathological variables and common DNA markers is presented in a study published in PLOS Medicine this w ...
Cancer 5 hours ago | not rated yet | 0
A study of veterans at high risk for developing lung cancer shows that low-dose computed tomography (LDCT) can be highly effective in helping clinicians spot tiny lung nodules which, in a small number of patients, may indicate ...
Cancer 7 hours ago | not rated yet | 0
An attack on glioblastoma brain tumor cells that uses a modified poliovirus is showing encouraging results in an early study to establish the proper dose level, researchers at Duke Cancer Institute report.
Cancer 9 hours ago | not rated yet | 0
(Medical Xpress)—Native peoples in regions where cameras are uncommon sometimes react with caution when their picture is taken. The fear that something must have been stolen from them to create the photo ...
11 hours ago | 4.2 / 5 (5) | 0 |
(Medical Xpress)—Despite spending billions of dollars on research and development, drug companies have been unable to come up with effective treatments for dementia and Alzheimer's Disease (AD). Now, A. ...
9 hours ago | 4.9 / 5 (8) | 0 |
An experimental sleeping pill from US drug company Merck is effective at helping people fall and stay asleep, according to reviewers at the US Food and Drug Administration, which could soon approve the new drug.
4 hours ago | 3 / 5 (2) | 0
Activating an enzyme known to play a role in the anti-aging benefits of calorie restriction delays the loss of brain cells and preserves cognitive function in mice, according to a study published in the May ...
5 hours ago | 5 / 5 (3) | 0 |
Australian scientists have charted the path of insulin action in cells in precise detail like never before. This provides a comprehensive blueprint for understanding what goes wrong in diabetes.
11 hours ago | 4.8 / 5 (4) | 0 |
A drug commonly used to treat depression and anxiety may improve a stress-related heart condition in people with stable coronary heart disease, according to researchers at Duke Medicine.
6 hours ago | not rated yet | 0 |