February 2, 2016

Cornell Finds Success with Cancer-Inhibiting Protein

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A recent Cornell study demonstrates a promising method for killing cancer cells in the bloodstream. Observing prostate cancer in mice, researchers injected liposomes containing a protein called Tumor Necrosis Factor Related Apoptosis-Inducing Ligand that attach themselves onto white blood cells to destroy cancer cells spreading through the bloodstream.
The experiment, performed as a collaboration between the labs of Prof. Michael King, biomedical engineering, and Prof. Chris Schaffer, biomedical engineering, served as a followup to a study published in January 2014 on the use of TRAIL to attack tumor cells.
“In the 2014 paper, we first showed that the nanoscale liposomes, when injected into the bloodstream, can kill nearly all of the cancer cells in the blood.” King said, “We showed this with human blood samples flowing in laboratory experiments, and we also performed short-term mouse experiments.”
According to King, these experiments consisted of injecting male mice with human prostate cancer cells and the TRAIL-carrying liposomes, which attach to white blood cells, and observing changes within a two hour period. The effects on the prostate tumors were encouraging, but the next step was to see whether TRAIL would hold up for metastasis — the formation of new tumors distant from the original tumor, the reason for more than 90 percent of human cancer deaths.
Image shows circulating tumor cells

Image courtesy of Prof. Michael King

Image shows circulating tumor cells

“The key for human prostate cancer is to detect the cancer early. Most prostate cancer cases will respond to treatment,”King said. “But in a fraction of prostate cancer cases the regular therapies do not work, and that’s referred to as castration-resistant prostate cancer. If the tumor progresses to form metastases, there’s a low chance of survival.”
Once again, mice were used, but this time the cancer cells were allowed to metastasize. While cancer may take months or years to spread within a human, it only takes weeks for the rodents.
“We set out with the goal of demonstrating this technology in a more realistic animal model of cancer metastasis. The earlier study was focused on showing that you could kill cancer cells floating around in the mouse’s blood.” King said, “But what was never answered in that earlier study is whether the therapy can really prevent metastasis —the formation of new tumors that are distant from the original tumor. That’s the major clinical problem in human cancers. Over 90 percent of cancer deaths are due to metastasis. This is the unaddressed need that we set out to fix.”
For the 2016 study, mice were observed for a period of nine weeks after being implanted with prostate cancer cells. The experimental group was given TRAIL therapy three weeks after implantation, followed by additional treatment every three days after that (the length of time the protein remains in the blood). It worked.
“What we found in the current study is that we completely prevented the development of new tumors in these mice, and we even shrunk the original tumor in size, which was a pleasant surprise,” King said.
Beyond this study, the next step is to expand and adapt this technology to treat different types of cancer. One experiment underway seeks to mimic the way humans are currently treated for breast cancer, according to King. The plan is to initiate TRAIL treatment on mice, surgically remove breast tumor, and then continue treatment.
“Without our therapy, the mouse will develop metastases in the lung, and bone and other organs.” said King, “We think a few well-timed treatments before and after surgery could completely prevent the metastasis.”
Mice in the control groups ( “Buffer” and “ES”) showed widespread metastasis to internal organs. mice treated with E-selectin/TRAIL liposomes (“ES/T”) showed no spread of cancer to the other organs

Image courtesy of Prof. Michael King

Mice in the control groups ( “Buffer” and “ES”) showed widespread metastasis to internal organs. mice treated with E-selectin/TRAIL liposomes (“ES/T”) showed no spread of cancer to the other organs

The treatment is not entirely foolproof. Though TRAIL particles are effective on most kinds of cancer, including prostate cancer, colon cancer, melanoma, and breast cancer, there are some cancers that have a natural resistance to TRAIL, according to King. Fortunately, there are a wide variety of “co-drugs” that can be used in combination with TRAIL to make the resistant cancer cells sensitive to treatment, King said.
“Some of the TRAIL sensitizers are natural products, things you would find in a vitamin store. There are products that are isolated from chili peppers … and actually many conventional cancer drugs will sensitize cancer cells to trail, as will a low dosage of aspirin. These are things that can be done with minimal risk,“ King said. “In my opinion, [the TRAIL] approach is applicable to most kinds of cancer.”
The ultimate goal is to progress to human clinical trials, according to King, and his lab has been recently receiving blood samples from metastatic cancer patients from various hospitals, allowing the nanoparticles to be tested on “real, circulating tumor cells.” According to King, this is the closest thing to experimenting on humans the team can hope for before enough data is collected to proceed to clinical trials.
“We’re really pleased about the results we’re getting.” King said, “The students and grad students working on the team are really excited, and we hope to continue to advance this technology.”

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