Using the body’s own defenses to track down and kill escaping cancer cells during surgeries

TRAIL-coated leukocytes, which adhere to white blood cells, can kill escaping cancer cells during surgeries. (Vanderbilt University)

Cellular soldiers created using the body’s own defenses can track down and kill escaping cancer cells during surgeries, preventing metastasis and saving lives, a Vanderbilt University biomedical engineer has discovered, particularly in cases of triple negative breast cancer.

Michael King, J. Lawrence Wilson Professor of Engineering and chair of the biomedical engineering department, and his team attached two proteins to the surface of lipid nanoparticles: TNF-related apoptosis-inducing ligand – or TRAIL – and the adhesion receptor E-selectin. The injected nanoparticles then adhere to white blood cells, and the introduction of these TRAIL-coated leukocytes into the bloodstream before, during and after tumor removal kills all cancer cells loosed as a result.

“Collisions between the TRAIL-coated leukocytes and cancer cells in the bloodstream are happening constantly,” King said. “We’ve tested this both in the bloodstream and in hundreds of blood samples from cancer patients being treated in clinics across the country. In all cases, within two hours, the viable cancer cells are cleared out. This has worked with breast, prostate, ovarian, colorectal and lung cancer cells.”

Not only can the method work during surgeries, King said, but potentially with patients who already suffer metastatic cancer in multiple sites and who have no worthwhile treatment options. Because all the components of the TRAIL-coated leukocytes occur naturally in the body, it increases the potential for a quicker path from the bloodstreams of mouse models to human trials.

Surgical intervention in breast cancer is a known cause of metastatic growth and accelerated tumor relapse, either because of cancer cells shed during the process, inflammation at the wound site or a combination of the two factors. Chemotherapy is the most widely used treatment for the resulting metastasis, but still, the five-year survival rate for triple negative breast cancer sits well below 30 percent.

The group’s past experiments with TRAIL-coated leukocytes were effective in blocking metastasis, but required multiple repeated injections to sustain their beneficial effect. King said this new breakthrough overcomes those issues by designing three simple doses to coincide with the surgical procedure.

Learn more: Cellular soldiers designed to kill cancer cells that get loose during surgery, stop metastasis

 

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Novel imaging system could help boost survival rates for ovarian cancer

Researchers at MIT and MGH have developed an image-guided surgical system that could help surgeons better visualize and remove tiny ovarian tumors. Fluorescent carbon nanotubes are used as probes to bind to the tumors, making them easier to see.
Image courtesy of the researchers

More effective surgery could boost survival rates for ovarian cancer.

Ovarian cancer is usually diagnosed only after it has reached an advanced stage, with many tumors spread throughout the abdomen. Most patients undergo surgery to remove as many of these tumors as possible, but because some are so small and widespread, it is difficult to eradicate all of them.

Researchers at MIT, working with surgeons and oncologists at Massachusetts General Hospital (MGH), have now developed a way to improve the accuracy of this surgery, called debulking. Using a novel fluorescence imaging system, they were able to find and remove tumors as small as 0.3 millimeters — smaller than a poppy seed — during surgery in mice. Mice that underwent this type of image-guided surgery survived 40 percent longer than those who had tumors removed without the guided system.

“What’s nice about this system is that it allows for real-time information about the size, depth, and distribution of tumors,” says Angela Belcher, the James Mason Crafts Professor of Biological Engineering and Materials Science at MIT, a member of the Koch Institute for Integrative Cancer Research, and the recently appointed head of MIT’s Department of Biological Engineering.

The researchers are now seeking FDA approval for a phase 1 clinical trial to test the imaging system in human patients. In the future, they hope to adapt the system for monitoring patients at risk for tumor recurrence, and eventually for early diagnosis of ovarian cancer, which is easier to treat if it is caught earlier.

Belcher and Michael Birrer, formerly the director of medical gynecologic oncology at MGH and now the director of the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, are the senior authors of the study, published online in the journal ACS Nano on April 22.

Neelkanth Bardhan, a Mazumdar-Shaw International Oncology Fellow at the Koch Institute, and Lorenzo Ceppi, a researcher at MGH, are the lead authors of the paper. Other authors include MGH researcher YoungJeong Na, MIT Lincoln Laboratory technical staff members Andrew Siegel and Nandini Rajan, Robert Fruscio of the University of Milan-Bicocca, and Marcela del Carmen, a gynecologic oncologist at MGH and chief medical officer of the Massachusetts General Physicians Organization.

Glowing tumors

Because there is no good way to detect early-stage ovarian cancer, it is one of the most difficult types of cancer to treat. Of 250,000 new cases diagnosed each year worldwide, 75 percent are in an advanced stage. In the United States, the five-year combined survival rate for all stages of ovarian cancer is 47 percent, only a slight improvement from 38 percent three decades ago, despite the advent of chemotherapeutic drugs such as cisplatin, approved by the FDA in 1978 for ovarian cancer treatment. In contrast, the five-year combined survival rate for all stages of breast cancer has steadily improved, from around 75 percent in the 1970s to over 90 percent now.

“We desperately need better upfront therapies, including surgery, for these (ovarian cancer) patients,” Birrer says.

Belcher and Birrer joined forces to work on this problem through the Bridge Project, a collaboration between the Koch Institute and Dana-Farber/Harvard Cancer Center. Belcher’s lab has been developing a novel type of medical imaging based on light in the near-infrared (NIR) spectrum. In a paper published in March, she reported that this imaging system could achieve an unprecedented combination of resolution and penetration-depth in living tissue.

In the new study, Belcher, Birrer, and their colleagues worked with researchers at MIT Lincoln Laboratory to adapt NIR imaging to help surgeons locate tumors during ovarian cancer surgery, by providing continuous, real-time imaging of the abdomen, with tumors highlighted by fluorescence. Previous analyses have shown that survival rates are strongly inversely correlated with the amount of residual tumor mass left behind in the patient during debulking surgery, but many ovarian tumors are so small or hidden that surgeons can’t find them.

To make the tumors visible, the researchers designed chemical probes using single-walled carbon nanotubes that emit fluorescent light when illuminated by a laser. They coated these nanotubes with a peptide that binds to SPARC, a protein that is overexpressed by highly invasive ovarian cancer cells. This probe binds to the tumors and makes them fluoresce at NIR wavelengths, allowing surgeons to more easily find them with fluorescence imaging.

The researchers tested the image-guided system in mice that had ovarian tumors implanted in a region of the abdominal cavity known as the intraperitoneal space, and showed that surgeons were able to locate and remove tumors as small as 0.3 millimeters. Ten days after surgery, these mice had no detectable tumors, while mice that had undergone the traditional, non-image-guided surgery, had many residual tumors missed by the surgeon.

By three weeks after the surgery, many of the tumors had grown back in the mice that underwent image-guided surgery, but those mice still had a median survival rate that was 40 percent longer than that of mice that underwent traditional surgery.

No other imaging system would be able to locate tumors that small during a surgical procedure, the researchers say.

“You can’t have a patient in a CT machine or an MRI machine and have the surgeon perform this surgical debulking procedure at the same time, and you can’t expose the patient to X-ray radiation for multiple hours of the long surgery. This optics-based imaging system allows us to do that in a safe manner,” Bardhan says.

Alessandro Santin, a professor of obstetrics and gynecology and clinical research program leader at the Yale University School of Medicine, described the results as “intriguing.”

“These data support the potential use of this novel imaging system in the intraoperative setting for the optical detection of residual malignant tissue at the time of surgical staging, and/or cytoreductive surgery in ovarian cancer patients,” says Santin, who was not involved in the study.

Monitoring patients

For most ovarian cancer patients, tumor debulking surgery is followed by chemotherapy, so the researchers now plan to do another study where they treat the mice with chemotherapy after image-guided surgery, in hopes of preventing the remaining tiny tumors from spreading.

“We know that the amount of tumor removed at the time of surgery for patients with advanced-stage ovarian cancer is directly correlated with their outcome,” Birrer says. “This imaging device will now allow the surgeon to go beyond the limits of resecting tumors visible to the naked eye, and should usher in a new age of effective debulking surgery.”

Now that they have demonstrated that this concept can be successfully applied to imaging during surgery, the researchers hope to begin adapting the system for use in human patients.

“In principle, it’s quite doable,” Siegel says. “It’s purely the mechanics and the funding at this point, because this mouse experiment serves as the proof of principle and may actually have been more challenging than building a human-scale system.”

The researchers also hope to deploy this type of imaging to monitor patients after surgery, and eventually to develop it as a diagnostic tool for screening women at high risk for developing ovarian cancer.

“A major focus for us right now is developing the technology to be able diagnose ovarian cancer early, in stage 1 or stage 2, before the disease becomes disseminated,” Belcher says. “That could have a huge impact on survival rates, because survival is related to the stage of detection.”

Learn more: Imaging system helps surgeons remove tiny ovarian tumors

 

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Synthetic biomarkers could be used to diagnose ovarian cancer months earlier than now possible

A high-magnification micrograph of an ovarian clear cell carcinoma. The images show, focally, the characteristic clear cells with prominent nucleoli and the typical hyaline globules. A high-magnification micrograph of an ovarian clear cell carcinoma. The images show, focally, the characteristic clear cells with prominent nucleoli and the typical hyaline globules. Image: Nephron/CC BY-SA 3.0

New technology can detect tiny ovarian tumors

Most ovarian cancer is diagnosed at such late stages that patients’ survival rates are poor. However, if the cancer is detected earlier, five-year survival rates can be greater than 90 percent.

Now, MIT engineers have developed a far more sensitive way to reveal ovarian tumors: In tests in mice, they were able to detect tumors composed of nodules smaller than 2 millimeters in diameter. In humans, that could translate to tumor detection about five months earlier than is possible with existing blood tests, the researchers say.

The new test makes use of a “synthetic biomarker” — a nanoparticle that interacts with tumor proteins to release fragments that can be detected in a patient’s urine sample. This kind of test can generate a much clearer signal than natural biomarkers found in very small quantities in the patient’s bloodstream.

“What we did in this paper is engineer our sensor to be about 15 times better than a previous version, and then compared it against a blood biomarker in a mouse model of ovarian cancer to show that we could beat it,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, and the senior author of the study.

This approach could also be adapted to work with other cancers. In this paper, which appears in the April 10 issue of Nature Biomedical Engineering, the researchers showed they can detect colorectal tumors that metastasized to the liver.

The paper’s lead authors are postdoc Ester Kwon and graduate student Jaideep Dudani.

Synthetic biomarkers

Bhatia first reported the strategy of diagnosing cancer with synthetic biomarkers in 2012. This method measures the activity of protein-cutting enzymes called endoproteases, which are made by tumors to help recruit blood vessels and invade surrounding tissues so the cancer can grow and spread.

To detect this sort of enzyme, the researchers designed nanoparticles coated with small protein fragments called peptides that can be cleaved by particular proteases called MMPs. After being injected into a mouse, these particles passively collect at the tumor site. MMPs cleave the peptides to liberate tiny reporter fragments, which are then filtered out by the kidney and concentrated in the urine, where they can be detected using various methods, including a simple paper-based test.

In a paper published in 2015, the researchers created a mathematical model of this system, to understand several factors such as how the particles circulate in the body, how efficiently they encounter the protease, and at what rate the protease cleaves the peptides. This model showed that in order to detect tumors 5 millimeters in diameter or smaller in humans, the researchers would need to improve the system’s sensitivity by at least one order of magnitude.

In the current study, the researchers used two new strategies to boost the sensitivity of their detector. The first was to optimize the length of the polymer that tethers the peptides to the nanoparticle. For reasons not yet fully understood, when the tether is a particular length, specific proteases cleave peptides at a higher rate. This optimization also decreases the amount of background cleavage by a nontarget enzyme.

Second, the researchers added a targeting molecule known as a tumor-penetrating peptide to the nanoparticles, which causes them to accumulate at the tumor in greater numbers and results in boosting the number of cleaved peptides that end up secreted in the urine.

By combining these two refinements, the researchers were able to enhance the sensitivity of the sensor 15-fold, which they showed was enough to detect ovarian cancer composed of small tumors (2 millimeters in diameter) in mice. They also tested this approach in the liver, where they were able to detect tumors that originated in the colon. In humans, colon cancer often spreads to the liver and forms small tumors that are difficult to detect, similar to ovarian tumors.

“This is important work to validate novel strategies for the earlier detection of cancer that are not dependent on biomarkers made by cancer cells. [The method] instead forces the generation of artificial biomarkers at the tumor site, if any tumor indeed exists within the body,” says Sanjiv Sam Gambhir, chair of the department of radiology at Stanford University School of Medicine, who was not involved in the study. “Such approaches should eventually help change the way in which we detect cancer.”

Earlier diagnosis

Currently, doctors can look for blood biomarkers produced by ovarian tumors, but these markers don’t accumulate in great enough concentrations to be detected until the tumors are about 1 centimeter in diameter, about eight to 10 years after they form. Another diagnostic tool, ultrasound imaging, is also limited to ovarian tumors that are 1 centimeter in diameter or larger.

Being able to detect a tumor five months earlier, which the MIT researchers believe their new technique could do, could make a significant difference for some patients.

In this paper, the researchers also showed that they could detect disease proteases in microarrays of many tumor cells taken from different cancer patients. This strategy could eventually help the researchers to determine which peptides to use for different types of cancer, and even for individual patients.

“Every patient’s tumor is different, and not every tumor will be amenable to targeting with the same molecule,” Bhatia says. “This is a tool that will help us to exploit the modularity of the technology and personalize formulations.”

The researchers are now further investigating the possibility of using this approach on other cancers, including prostate cancer, where it could be used to distinguish more aggressive tumors from those that grow much more slowly, Bhatia says.

Learn more: New technology can detect tiny ovarian tumors

 

 

 

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Stanford Researchers Create “Evolved” Protein that May Stop Cancer from Spreading

Jennifer Cochran and Amato Giaccia led a team of researchers who have developed an experimental therapy to treat metastatic cancer. (Photo: Rod Searcey)

Jennifer Cochran and Amato Giaccia led a team of researchers who have developed an experimental therapy to treat metastatic cancer. (Photo: Rod Searcey)

Experimental therapy stopped the metastasis of breast and ovarian cancers in lab mice, pointing toward a safe and effective alternative to chemotherapy.

A team of Stanford researchers has developed a protein therapy that disrupts the process that causes cancer cells to break away from original tumor sites, travel through the bloodstream and start aggressive new growths elsewhere in the body.

This process, known as metastasis, can cause cancer to spread with deadly effect.

“The majority of patients who succumb to cancer fall prey to metastatic forms of the disease,” said Jennifer Cochran, an associate professor of bioengineering who describes a new therapeutic approach in Nature Chemical Biology.

Today doctors try to slow or stop metastasis with chemotherapy, but these treatments are unfortunately not very effective and have severe side effects.

The Stanford team seeks to stop metastasis, without side effects, by preventing two proteins – Axl and Gas6 – from interacting to initiate the spread of cancer.

Axl proteins stand like bristles on the surface of cancer cells, poised to receive biochemical signals from Gas6 proteins.

When two Gas6 proteins link with two Axls, the signals that are generated enable cancer cells to leave the original tumor site, migrate to other parts of the body and form new cancer nodules.

To stop this process Cochran used protein engineering to create a harmless version of Axl that acts like a decoy. This decoy Axl latches on to Gas6 proteins in the bloodstream and prevents them from linking with and activating the Axls present on cancer cells.

In collaboration with Professor Amato Giaccia, who leads the Radiation Biology Program in the Stanford Cancer Center, the researchers gave intravenous treatments of this bioengineered decoy protein to mice with aggressive breast and ovarian cancers.

Mice in the breast cancer treatment group had 78 percent fewer metastatic nodules than untreated mice. Mice with ovarian cancer had a 90 percent reduction in metastatic nodules when treated with the engineered decoy protein.

“This is a very promising therapy that appears to be effective and nontoxic in preclinical experiments,” Giaccia said. “It could open up a new approach to cancer treatment.”

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Targeting cancer with a triple threat

The new MIT nanoparticles consist of polymer chains (blue) and three different drug molecules — doxorubicin is red, the small green particles are camptothecin, and the larger green core contains cisplatin. Image courtesy of Jeremiah Johnson

MIT chemists design nanoparticles that can deliver three cancer drugs at a time.

Delivering chemotherapy drugs in nanoparticle form could help reduce side effects by targeting the drugs directly to the tumors. In recent years, scientists have developed nanoparticles that deliver one or two chemotherapy drugs, but it has been difficult to design particles that can carry any more than that in a precise ratio.

Now MIT chemists have devised a new way to build such nanoparticles, making it much easier to include three or more different drugs. In a paper published in the Journal of the American Chemical Society, the researchers showed that they could load their particles with three drugs commonly used to treat ovarian cancer.

“We think it’s the first example of a nanoparticle that carries a precise ratio of three drugs and can release those drugs in response to three distinct triggering mechanisms,” says Jeremiah Johnson, an assistant professor of chemistry at MIT and the senior author of the new paper.

Such particles could be designed to carry even more drugs, allowing researchers to develop new treatment regimens that could better kill cancer cells while avoiding the side effects of traditional chemotherapy. In the JACS paper, Johnson and colleagues demonstrated that the triple-threat nanoparticles could kill ovarian cancer cells more effectively than particles carrying only one or two drugs, and they have begun testing the particles against tumors in animals.

Longyan Liao, a postdoc in Johnson’s lab, is the paper’s lead author.

Putting the pieces together

Johnson’s new approach overcomes the inherent limitations of the two methods most often used to produce drug-delivering nanoparticles: encapsulating small drug molecules inside the particles or chemically attaching them to the particle. With both of these techniques, the reactions required to assemble the particles become increasingly difficult with each new drug that is added.

Combining these two approaches — encapsulating one drug inside a particle and attaching a different one to the surface — has had some success, but is still limited to two drugs.

Johnson set out to create a new type of particle that would overcome those constraints, enabling the loading of any number of different drugs. Instead of building the particle and then attaching drug molecules, he created building blocks that already include the drug. These building blocks can be joined together in a very specific structure, and the researchers can precisely control how much of each drug is included.

Each building block consists of three components: the drug molecule, a linking unit that can connect to other blocks, and a chain of polyethylene glycol (PEG), which helps protect the particle from being broken down in the body. Hundreds of these blocks can be linked using an approach Johnson developed, called “brush first polymerization.”

“This is a new way to build the particles from the beginning,” Johnson says. “If I want a particle with five drugs, I just take the five building blocks I want and have those assemble into a particle. In principle, there’s no limitation on how many drugs you can add, and the ratio of drugs carried by the particles just depends on how they are mixed together in the beginning.”

Varying combinations

For this paper, the researchers created particles that carry the drugs cisplatin, doxorubicin, and camptothecin, which are often used alone or in combination to treat ovarian cancer.

Each particle carries the three drugs in a specific ratio that matches the maximum tolerated dose of each drug, and each drug has its own release mechanism. Cisplatin is freed as soon as the particle enters a cell, as the bonds holding it to the particle break down on exposure to glutathione, an antioxidant present in cells. Camptothecin is also released quickly when it encounters cellular enzymes called esterases.

The third drug, doxorubicin, was designed so that it would be released only when ultraviolet light shines on the particle. Once all three drugs are released, all that is left behind is PEG, which is easily biodegradable.

This approach “represents a clever new breakthrough in multidrug release through the simultaneous inclusion of different drugs, through distinct chemistries, within the same … platform,” says Todd Emrick, a professor of polymer science and engineering at the University of Massachusetts at Amherst who was not involved in the study.

Working with researchers in the lab of Paula Hammond, the David H. Koch Professor of Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, the team tested the particles against ovarian cancer cells grown in the lab. Particles carrying all three drugs killed the cancer cells at a higher rate than those that delivered only one or two drugs.

Johnson’s lab is now working on particles that carry four drugs, and the researchers are also planning to tag the particles with molecules that will allow them to home to tumor cells by interacting with proteins found on the cell surfaces.

Johnson also envisions that the ability to reliably produce large quantities of multidrug-carrying nanoparticles will enable large-scale testing of possible new cancer treatments. “It’s important to be able to rapidly and efficiently make particles with different ratios of multiple drugs, so that you can test them for their activity,” he says. “We can’t just make one particle, we need to be able to make different ratios, which our method can easily do.”

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