Many cancer researchers can claim to have devised “smart bombs.” What has been missing is the stealth bomber – a delivery system that can slip through the body’s radar defenses.
Oncolytic viruses, or viruses that preferentially kill cancer cells, have been discussed and tested for decades. An oncolytic virus against melanoma was approved by the FDA in 2015. But against metastatic cancers, they’ve always faced an overwhelming barrier: the human immune system, which quickly captures viruses injected into the blood and sends them to the liver, the body’s garbage disposal.
Researchers at Emory and Case Western Reserve have now circumvented that barrier. They’ve re-engineered human adenovirus, so that the virus is not easily caught by parts of the innate immune system.
A cryo-electron microscopy structure of the virus and its ability to eliminate disseminated tumors in mice were reported on November 25 in Science Translational Medicine.
“The innate immune system is quite efficient at sending viruses to the liver when they are delivered intravenously,” says lead author Dmitry Shayakhmetov, PhD. “For this reason, most oncolytic viruses are delivered directly into the tumor, without affecting metastases. In contrast, we think it will be possible to deliver our modified virus systemically at doses high enough to suppress tumor growth — without triggering life-threatening systemic toxicities.”
A new discovery by Emory researchers in certain lung cancer patients could help improve patient outcomes before the cancer metastasizes.
The researchers in the renowned Marcus Laboratory identified that highly invasive leader cells have a specific cluster of mutations that are also found in non-small cell lung cancer patients. Leader cells play a dominant role in tumor progression, and the researchers discovered that patients with the mutations experienced poorer survival rates.
The findings mark the first leader cell mutation signature identified in patients and could prove key in teasing out high-risk patients, allowing oncologists to develop a treatment plan early on before the disease has progressed.
“It has been a lot of fun to see the research go from the basic science side inside the lab to hopefully having an actual clinical impact,” says Brian Pedro, an MD/PhD student in Emory’s Medical Scientist Training Program. “Our data suggest that if you have one or more of these mutations, then we could potentially intervene early and improve patient outcomes.”
Stopping leader cells before they metastasize has long been a goal of researchers at the Winship Cancer Institute. “That is what we strive for as researchers,” Pedro says. “We are optimistic that this could be a promising clinical tool.”
The researchers specifically found the novel mutation cluster on chromosome 16q and compared the survival rates of those who had the mutations with those who did not. The results showed the patients who had the mutations had poorer survival rates across all stages.
Pedro says more investigation is needed to figure out why the mutations lead to poorer outcomes. He adds that he hopes the mutation signature can prove useful for cancer types beyond lung cancer.
Research from Adam Marcus’ and Mala Shanmugam’s labs was published Tuesday in Nature Communications – months after we wrote an article for Winship Cancer Institute’s magazine about it. So here it is again!
At your last visit to the dentist, you may have been given a mouth rinse with the antiseptic chlorhexidine. Available over the counter, chlorhexidine is also washed over the skin to prepare someone for surgery. Winship researchers are now looking at chlorhexidine and its chemical relative alexidine for another purpose: stopping cancer metastasis.
While the researchers don’t envision using chlorhexidine mouthwash as an anti-cancer measure directly, their findings suggest ways to combine other drugs, already in clinical trials, in ways that could deplete the cells needed for metastasis.
When used as an antiseptic, chlorhexidine is basically a detergent that blasts bacteria apart, scientists think. As leads for potential anti-cancer agents, chlorhexidine and its relatives appear to have a different effect. They interfere with mitochondria, the miniature power plants in our cells. Cancer cells trying to metastasize and invade other tissues seem to need their mitochondria more—especially the cells that are leading the way. Read more
What does it take to be a leader – of cancer cells?
Adam Marcus and colleagues at Winship Cancer Institute are back, with an analysis of mutations that drive metastatic behavior among groups of lung cancer cells. The findings were published this week on the cover of Journal of Cell Science, and suggest pharmacological strategies to intervene against or prevent metastasis.
Marcus and former graduate student Jessica Konen previously developed a technique for selectively labeling “leader” or “follower” lung cancer cells in culture, using lasers that turn a fluorescent protein from green to red. The leaders are more adventurous and invasive, but the followers support the leaders and help them survive. Check out our prize-winning video and their 2017 Nature Communications paper.
The magenta cells have leader-specific mutated Arp3 protein, while the green cells are unmodified followers.
The new research harnesses their technique to track the mutations that are specific to leader or follower cells. It was a collaboration with the lab of Paula Vertino, formerly at Winship and now at University of Rochester. Cancer Biology graduate students Elizabeth Zoeller and Brian Pedro led the work, with sophisticated genomics from Ben Barwick.
One of the leader-specific mutations was in Arp3, part of a protein complex that promotes the protrusion of cellular blobs, facilitating migration. The researchers took the mutated Arp3 protein from leader cells and forced its production in follower cells. In the cover image, the magenta cells on the outside are the ones with the mutated Arp3 protein, while the green cells are unmodified. Read more
When cancer cells split off from a tumor to seed deadly metastases, they are thought to travel as clusters or packs, a phenomenon known as collective invasion. The members of an invasive pack are not all alike, scientists at Winship Cancer Institute of Emory University have learned.
Lung cancer cells making up an invasive pack have specialized roles as leaders and followers, which depend on each other for mobility and survival, the scientists report in Nature Communications.
The differences between leaders and followers — and their interdependence — could be keys for future treatments aimed at impairing or preventing cancer metastasis, says senior author Adam Marcus, PhD, associate professor of hematology and medical oncology at Winship Cancer Institute and Emory University School of Medicine.
“We’re finding that leader and follower cells have a symbiotic relationship and depend on each for survival and invasion,” he says. “Because metastatic invasion is the deadliest aspect of cancer, our goal is to find agents that disrupt that symbiotic relationship.”
Marcus and former graduate student Jessica Konen, PhD began by observing how a mass of lung cancer cells behaves when embedded in a 3-D protein gel. The cells generally stick together, but occasionally, a few cells extend out of the mass like tentacles, with the leader cell at the tip.
“We saw that when the leader cell became detached or died unexpectedly, the followers could no longer move,” says Konen, now a postdoctoral fellow at MD Anderson. “In one particular movie, we saw a leader cell come out away from the rest of the cells, and then seem to realize that nobody was following him. He actually did a 180, and went back to grab cells to bring with him.” Read more
As Sancheti explains, an advantage of minimally invasive approaches (sometimes called VATS for video-assisted thoracic surgery) is that surgeons do not open the patient’s chest, avoiding pain and potential complications and reducing length of stay in the hospital.
Among thoracic surgeons, the shift to this type of approach has taken place in the last few years — unevenly. Here’s a graph from one recent publication from Felix Fernandez, MD and colleagues, showing the percent of stage I lung cancer surgeries — compiled for individual surgeons in the Society of Thoracic Surgeons — that are minimally invasive from 2011-2014. The average is about 63 percent, but it varies widely.
Attention medical journalists: if you want to ask questions like “Are these minimally invasive lung surgery approaches really good for long term patient outcomes?”, Fernandez is your guy. As the numbers come in, he is leading a team that is analyzing them. Read more
Cancer biologists Jessica Konen and Scott Wilkinson,Â in Adam Marcus’ lab, recently published a paper on the function of LKB1, a gene that is often mutated in lung cancer cells. [Number three behind K-ras and p53.]
Mesenchymal shape is defined as having a length more than twice the width. Amoeboid looks more like the cell on the right: rounded up. Thanks to Jessica Konen for photo.
Konen and Marcus were featured in a prize-winning video that our team produced last year, which discusses how they developed a technique for isolatingÂ “leader cells”Â — lung cancer cells that migrate and invade more quickly — from a large groupÂ and studying those cells’ properties more intensively.
TheÂ Molecular Biology of the Cell paper covers a related topic: how LKB1 mutation affects cell shape. In particular, losing LKB1 converts lung cancer cells from a “mesenchymal” morphology to an “amoeboid” morphology.Â Read more
PeopleÂ touched by a brain tumor — patients,Â their families or friends — may have heard of the drug Gliolan or 5-ALA, which is taken up preferentially byÂ tumor cells and makes them fluorescent. The idea behind it is straightforward: if the neurosurgeon can seeÂ the tumor’s boundaries better during surgery, he or she can excise it more thoroughly and accurately.
A hand-held device to detect glowing brain tumors could allow closer accessÂ to the critical areaÂ than a surgical microscope
Biomedical engineer Shuming Nie and colleagues recently described their development of a hand-held spectroscopic deviceÂ for viewing fluorescent brain tumors. This presents aÂ contrast withÂ the current tool, a surgical microscope — see figure.
Nie’s team testedÂ their technologyÂ on specimens obtained from cancer surgeries.Â Their paper in Analytical Chemistry reports:
The results indicate that intraoperative spectroscopy is at least 3 orders of magnitude more sensitive than the current surgical microscopes, allowing ultrasensitive detection of as few as 1000 tumor cells.Read more
Parietin, shown to have anticancer activity in the laboratory, is a dominant pigment in Caloplaca lichens. Note: this study did not assess the effects of eating lichens or rhubarb. Photo courtesy of www.aphotofungi.com
Parietin, also known as physcion, could slow the growth of and kill human leukemia cells obtained directly from patients, without obvious toxicity to human blood cells, the authors report. The pigment could also inhibit the growth of human cancer cell lines, derived from lung and head and neck tumors, when grafted into mice.
A team of researchers led by Jing Chen, PhD, discovered the properties of parietin because they were looking for inhibitors for the metabolic enzyme 6PGD (6-phosphogluconate dehydrogenase). 6PGD is part of the pentose phosphate pathway, which supplies cellular building blocks for rapid growth. Researchers have already found 6PGD enzyme activity increased in several types of cancer cells.
“This is part of the Warburg effect, the distortion of cancer cells’ metabolism,” says Chen, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. “We found that 6PGD is an important metabolic branch point in several types of cancer cells.” Read more
Doctors are using a â€œdivide and conquerâ€ strategy against lung cancer, and in some corners of the battlefield, itâ€™s working. A few mutations â€“ genetic alterations in the tumor that donâ€™t come from the patientâ€™s normal cells — have been found for which drugs are effective in pushing back against the cancer.
However, most lung tumors do not have one of these mutations, and response rates to conventional chemotherapy in patients with advanced lung cancer are poor. Generally, only around 20 percent of patients show a clinical response, in that the cancer retreats noticeably for some time.
Johann Brandes and colleagues at Winship Cancer Institute have been looking for biomarkers that can predict whether an advanced lung tumor is going to respond to one of the most common chemotherapy drug combinations, carboplatin and taxol.
â€œThe availability of a predictive test is desirable since it would allow patients who are unlikely to benefit from this treatment combination to be spared from side effects and to be selected for other, possibly more effective treatments,â€ Brandes says.
Brandesâ€™ teamâ€™s data comes from looking at patients with advanced lung cancer at the Atlanta VAMC from 1999 to 2010. In a 2013 paper in Clinical Cancer Research, the team looked at a protein called CHFR. It controls whether cells can reign in their cycles of cell division while being bombarded with chemotherapy.
In this group being treated with carboplatin and taxol, patients who had tumors that measured low in this protein lived almost four months longer, on average, than those who had tumors that were high (9.9 vs 6.2 months).
His team takes a similar approach in a new paper published in PLOS One. Postdoc Seth Brodie is the first author of the PLOS One paper; he is also co-first author of the CHFR paper along with Rathi Pillai. Read more