Researchers at Stanford University School of Medicine have developed a receptor that attracts a key cancer-causing molecule called Gas6 and took it out of play, slowing the progression of pancreatic and ovarian cancer in mice.
The study will be published online in The Journal of Clinical Investigation.
When used alone or in combination with chemotherapy in mice, their “decoy receptor” showed a higher ability to reduce or stop cancer growth than other treatments did.
They also elucidated a previously unknown mechanism in the body.
In mice, when the researchers inhibited Gas6 from binding to its native receptor, Axl, the cancer cells began to release DNA-damaging molecules, causing the cells to die.
This suggests a potential method to improve current therapeutic approaches.
“We were even able to get some animals cured, even those that started out with widespread and aggressive metastatic disease,” said Amato Giaccia, PhD, professor of radiation oncology and lead author of the study.
The researchers wanted to test their molecule in animal models of ovarian and pancreatic cancer, which are hard to detect in early stages.
Current treatment options for ovarian and pancreatic cancer patients are limited and usually require a combination of surgery, radiation and chemotherapy. The therapies can have toxic side effects and rarely lead to a complete cure.
So researchers have been increasingly turning to other medications, such as antibiotics or small compounds called tyrosine kinase inhibitors, to use with them.
Although they can sometimes stop tumour growth, they rarely result in complete eradication of cancer.
“A lot of treatments out there are very toxic because they are not specifically targeting the cancer cells, and they have a huge burden on the liver and kidney,” said Rebecca Miao, PhD, a Stanford research associate who shares lead authorship of the study. “Our decoy receptor seems in mice to not only to be very efficacious but also safe.”
Giaccia said, “We basically came up with a better glove, with a much stronger ability to catch the baseball — in this case, Gas6.”
Gas6 is a molecule that binds and activates Axl, the surface receptor that plays a key role in cell survival, growth and migration.
In many forms of cancer, Axl is over-expressed and binds Gas6 very strongly, which makes it difficult for the development of therapeutics to target this complex.
However, Giaccia and his team developed a decoy receptor that binds to Gas6 around 350 times better than Axl does.
When given to mice, the decoy took out the Gas6 molecules from the system and blocked them from activating Axl, suppressing cell growth and migration and stopping cancer growth.
“Our molecule has a higher affinity for Gas6, so it is more effective in taking it out,” said Giaccia.
To create the decoy receptor, called MYD1-72, they used yeast as a vessel to express different mutations of the Axl protein.
They then labelled Gas6 with a fluorescent molecule so that they could detect which mutated Axl protein it best bound with. Once they found the most effective mutation, they tested it against other promising therapies that target the Axl pathway and that are currently in clinical trials: BGB324 and foretinib.
MYD1-72 and foretinib were both able to reduce tumour size and metastasis, but foretinib showed toxicity in the mice. BGB324 showed little in the way of harmful effects on the mice, but did not reduce tumour burden. The researchers further tested their new decoy receptor on pancreatic and ovarian cancer in mice.
In ovarian cancer models, they tested the efficacy of MYD1-72 both alone and in conjunction with a DNA-damaging agent called doxorubicin that is commonly used for treatment.
They found that alone, MYD1-72 reduced tumour burden by 95 percent. In combination with doxorubicin, most mice ended up with almost complete tumour reduction.
In mice with more aggressive forms of ovarian cancer, MYD1-72 alone decreased tumour weight by 51 percent, whereas doxorubicin decreased tumour weight by 91 percent. When used together, the researchers measured a 99 percent reduction of tumour weight.
In pancreatic cancer, they also found that MYD1-72 in combination with a DNA-damaging agent called gemcitabine showed greater tumour reduction.
Alone, MYD1-72 did not make any impact on the mice’s tumour burden. Mice treated with MYD1-72 and gemcitabine together had a three times higher survival rate than mice not on any treatment.
These results suggested that a combination therapy of their decoy receptor and DNA-damaging agents could result in significantly lower levels of tumour burden.
“We are actively working to push this into clinical trials,” said Miao. “But we are also interested in looking at how our molecule affects other types of cancers.”
They hope to continue studies on how this decoy receptor could enhance treatments for other types of cancer, such as leukaemia.”These pre-clinical models in mice are pretty robust as we’ve shown in a number of different tumour settings and now in ovarian cancer and pancreatic cancer,” said Giaccia. “But we need to ultimately test this in human cancers.”
[hr] Source: JCI