Many Lung Cancer Tumors May Prove Harmless, Study Finds

Research suggests CT scan screening might lead to needless worry, treatment in these cases

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Copper intake makes tumors breathe

Nov. 14, 2013 — Copper imbalances have been associated with a number of pathological conditions, including cancer. Publishing in PNAS scientists at EPFL have found that copper in drinking water -- given at the maximum levels permitted in public water supplies -- accelerated the growth of tumors in mice. On the other hand, reducing copper levels reduced tumor growth. The study strongly suggests that copper is an essential factor for the growth of tumors in humans as well.

Copper is a key player in cell growth. In order to proliferate, cells require energy, which they produce and store in the form of a molecule called ATP. Like all cells, tumor cells produce energy in two different ways: respiration, which requires oxygen, and glycolysis, which does not. Of the two, respiration is the more efficient way to make ATP. However it involves a number of enzymes, and one of the most important ones requires copper for its activity.

In a study led by Douglas Hanahan, researcher at EPFL and holder of the Merck Serono Chair in Oncology, scientists sought to examine the role of copper in cancer. To do this, they used genetically engineered mice with pancreatic neuroendocrine tumors. "This study was motivated by our previous puzzling observation; namely that cancers, unlike healthy tissues, are especially sensitive to changes in systemic copper levels," said Seiko Ishida, the lead author of the paper.

Their research provides direct evidence that copper can enhance the proliferation of cancer cells. "The biggest surprise was that a small amount of copper added to drinking water accelerated the growth of tumors, indicating that copper is an essential nutrient for them, said Ishida.

Teaming up with Johan Auwerx, also at EPFL, the researchers found that copper insufficiency resulted in a lower activity of the respiration enzyme in tumors. PET scans also revealed that copper-deficient tumors took higher levels of glucose, suggesting that their cells were compensating more and more by using glycolysis rather than respiration for their energy. But despite this, ATP levels did not fully recover, and tumors did not grow further.

Importantly, the researchers do not think that copper causes cancer. Exposure of healthy mice to the same amount of copper via drinking water for up to two years did not result in an increased incidence of cancer. The authors suggest that copper levels could be monitored in cancer patients. They propose that minimizing copper in the patient's system may be beneficial in cancer therapy, especially when combined with drugs that block glycolysis. This two-step strategy would starve cancer cells -- which tend to require much higher amounts of energy than normal cells -- by limiting their two major pathways for ATP production.

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Biomaterial-delivered chemotherapy could provide final blow to brain tumors

Nov. 12, 2013 — A polymer originally designed to help mend broken bones could be successful in delivering chemotherapy drugs directly to the brains of patients suffering from brain tumors, researchers at The University of Nottingham have discovered.

Their study, published in the journal PLOS ONE, shows that the biomaterial can be easily applied to the cavity created following brain cancer surgery and used to release chemotherapy drugs over several weeks.

The targeted nature of the therapy could also reduce the toxic effects of chemotherapy drugs on healthy parts of the body, potentially reducing the debilitating side-effects that many patients experience after cancer treatment.

Dr Ruman Rahman, of the University's Children's Brain Tumour Research Centre (CBTRC), who led the study, said: "Our system is an innovative method of drug delivery for the treatment of brain tumors and is intended to be administered immediately after surgery by the operating neurosurgeon."

"Ultimately, this method of drug delivery, in combination with existing therapies, may result in more effective treatment of brain tumors, prolonged patient survival and reduced morbidity."

Brain tumors are the major cause of cancer-related death in children and adults up to the age of 40. Most relapses occur when surgeons are unable to remove all of the cancerous cells during surgery -- something which can be particularly challenging in very young children and babies and by the very nature of a type of adult brain cancer called glioblastoma.

Although alternative systems for delivery of drugs directly to the brain have been developed, they are used infrequently because their success has been limited. This new drug delivery system is the first that can be molded to the shape of the brain tumor cavity and the first to deliver several different drugs over a clinically meaningful period of time.

The Nottingham polymer formulation is made from two types of micro-particles called PLGA and PEG and has been developed and patented by leading tissue engineer Professor Kevin Shakesheff, based in the University's School of Pharmacy. A powder at room temperature, it can be mixed to a toothpaste-like consistency with the addition of water.

The unique properties of the polymer lie in its ability to set into a rigid structure only when it reaches body temperature (37 degrees), a feature perfectly tailored for use in medical therapies. It was originally developed as a scaffold on to which new bone cells could be grown to speed up the knitting back together of broken bones.

Dr Ruman Rahman at the CBTRC and Dr Cheryl Rahman from the School of Pharmacy spotted the potential for the polymer to deliver chemotherapy drugs directly to patients' brain tumors. The work was performed at the CBTRC with neurosurgeon Mr Stuart Smith and neuro-oncologist Professor Richard Grundy. The cavity left by the removal of a tumor would be lined with the polymer while in paste form, which would start to solidify and gradually release the chemotherapy drugs after the incision has been closed. This would directly target any residual cells not initially removed during surgery.

In the lab, the Nottingham scientists were able to successfully demonstrate the slow-release properties of the material by placing paste loaded with three commonly used chemotherapy drugs into a solution of saline and measuring the quantities of the drugs given out by the material over time.

To establish whether the material itself is safe to use on patients in this form of therapy, they used it to create a 3D model onto which they were able to grow brain tumor cells and healthy brain blood vessel cells without any toxicity. They then simulated surgery on a sheep's brain from an abattoir by molding the paste around a brain cavity and warming the brain to human body temperature to harden the polymer.

The brain was then scanned using CT and MRI technology to demonstrate that it is still possible to distinguish the polymer from normal brain tissue on a routine brain scan, an aspect crucial for doctors when dealing with follow-up care for brain tumor patients who have undergone surgery.

The team also dealt with concerns that the material could disintegrate and release its chemotherapy contents too quickly during the subsequent radiotherapy which many cancer patients undergo following surgery. By placing the biomaterial loaded with chemotherapy drugs into a head cavity of a medical training dummy and subjecting it to the same duration and intensity of radiotherapy used for brain tumor patients they were able to successfully demonstrate the robust integrity of the structure.

Finally they showed that a chemotherapy drug called etoposide could be effective at killing brain cancer cells in a mouse when released from the polymer formulation. The next stage of the research will be to extend the study in mice with brain tumors to test whether animals with the drug-loaded polymers survive longer. The team are also investigating the release of other chemotherapeutic drugs that hold promise, supported by a recent grant award from Sparks.

As the research used a biomaterial and chemotherapy drugs already approved for medical use, many of the usual ethical approval hurdles to allow further investigation have already been cleared.

The first clinical test, anticipated in 3 years' time, will be to devise a multi-centre phase 0 clinical trial which would involve testing the therapy on a small number of patients for whom other clinical treatments have not been successful and would otherwise only be offered palliative care.

"This is a very exciting development and holds considerable promise for the treatment of malignant brain tumors in the near future" commented Professor Grundy, Co-Director of the CBTRC.

The study was funded by a grant from the Joseph Foote Trust, now part of the Brain Tumour Charity and a Nottingham Advanced Research Fellowship from The University of Nottingham.

Andy Foote, Chair of Trustees at The Brain Tumour Charity, said: "We are proud to have funded this research, which we hope will lead to an exciting new treatment in area where options are sorely lacking. Research into brain tumors receives a fraction of the funding than that of more common cancers and it is our priority to redress the balance. This is essential as figures show that advances in treatment, achieved through the dedicated work of committed researchers over the years such as Dr Rahman and all of the team at the CBTRC, have had a beneficial effect."

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Cancer cells supported by normal cells in and near tumors

Sep. 19, 2013 — Cold Spring Harbor Laboratory -- Investigators at Cold Spring Harbor Laboratory (CSHL) today report important progress in research aimed at finding ways to fight cancer by targeting the local environment in which tumors grow and from which they draw sustenance.

The targeting of interactions between cancer cells and their environment together with the traditional tactic of directly targeting cancer cells with drugs or radiation is an important new front in the fight against cancer.

The study was conducted by two CSHL scientists from different disciplines who joined forces in the Laboratory's tradition of collaborative research. Mikala Egeblad, Ph.D., is an expert in the analysis of interactions between cancer cells and normal cells, and Scott Powers, Ph.D., is an expert in applying genome-wide "big-picture" methods to the study of cancer.

Together, they decided to make the first systematic effort to catalog the repertoire of interactions between cancer cells and their environment and to determine how many of these interactions were involved in promoting cancer. In previous studies, different types of cancers and different types of normal cells were utilized; this work brought to light a bewildering array of potential targets. This made it difficult to know how best to proceed with the development of new therapies directed against the tumor environment.

Powers and Egeblad determined that even when focusing only on the signals between breast cancer cells and just one single cell type in the local environment (called fibroblasts), the majority of these signals promoted cancer. Interestingly, each signal that was closely studied had a different impact on breast tumors: one contributed to cancer cell survival, another to proliferation, and a third to inflammation and the growth of local blood vessels (both of which support tumors). Further experiments showed that when several of these signals were blocked at once, the inhibiting effect on tumor growth was greater than when individual signals were blocked.

"This tells us that tumor and normal cells interact as a complex network and that the hope of finding a 'single most important interaction' for therapeutic targeting is misguided," Powers commented. "When dealing with something that is this biologically complex, it is really important to assess the entire set of signals involved, rather than just one."

Dr. Egeblad added: "The good news from our study is that we can probably make much better progress at fighting cancer by targeting multiple interactions between tumors and their local environment."

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Proteins identified that may help brain tumors spread

Sep. 20, 2013 — Scientists at the University of Alabama at Birmingham have identified a molecular pathway that seems to contribute to the ability of malignant glioma cells in a brain tumor to spread and invade previously healthy brain tissue. Researchers said the findings, published Sept. 19, 2013, in the journal PLOS ONE, provide new drug-discovery targets to rein in the ability of these cells to move.

Gliomas account for about a third of brain tumors, and survival rates are poor; only about half of the 10,000 Americans diagnosed with malignant glioma survive the first year, and only about one quarter survive for two years.

“Malignant gliomas are notorious, not only because of their resistance to conventional chemotherapy and radiation therapy, but also for their ability to invade the surrounding brain, thus causing neurological impairment and death,” said Hassan Fathallah-Shaykh, M.D., Ph.D., associate professor in the UAB Department of Neurology. “Brain invasion, a hallmark of gliomas, also helps glioma cells evade therapeutic strategies.”

Fathallah-Shaykh said there is a great deal of interest among scientists in the idea that a low-oxygen environment induces glioma cells to react with aggressive movement, migration and brain invasion. A relatively new cancer strategy to shrink tumors is to cut off the tumor’s blood supply – and thus its oxygen source – through the use of anti-angiogenesis drugs. Angiogenesis is the process of making new blood vessels.

“Stop angiogenesis and you shut off a tumor’s blood and oxygen supply, denying it the components it needs to grow,” said Fathallah-Shaykh. “Drugs that stop angiogenesis are believed to create a kind of killing field. This study identified four glioma cell lines that dramatically increased their motility when subjected to a low-oxygen environment – in effect escaping the killing field to create a new colony elsewhere in the brain.”

Fathallah-Shaykh and his team then identified two proteins that form a pathway linking low oxygen, or hypoxia, to increased motility.

“We identified a signaling protein that is activated by hypoxia called Src,” said Fathallah-Shaykh. “We also identified a downstream protein called neural Wiskott-Aldrich syndrome protein (N-WASP), which is regulated by Src in the cell lines with increased motility.”

The researchers then used protein inhibitors to shut off Src and N-WASP. When either protein was inhibited, low oxygen lost its ability to augment cell movement.

“These findings indicate that Src, N-WASP and the linkage between them – which is something we don’t fully understand yet – are key targets for drugs that would interfere with the ability of a cell to move.” said Fathallah-Shaykh. “If we can stop them from moving, then techniques such as anti-angiogenesis should be much more effective. Anti-motility drugs could be a key component in treating gliomas in the years to come.”

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Uncovering cancer's inner workings by capturing live images of growing tumors

Sep. 17, 2013 — Scientists seeking new ways to fight cancer often try to understand the subtle, often invisible, changes to DNA, proteins, cells, and tissue that alter the body's normal biology and cause disease. Now, to aid in that fight, a team of researchers has developed a sophisticated new optical imaging tool that enables scientists to look deep within tumors and uncover their inner workings. In experiments that will be described at Frontiers in Optics (FiO), The Optical Society's (OSA) Annual Meeting, Dai Fukumura and his colleagues will present new optical imaging techniques to track the movement of molecules, cells, and fluids within tumors; examine abnormalities in the blood vessel network inside them; and observe how the tumors were affected by treatments.

These techniques, created by Fukumura and his long-term collaborators at Massachusetts General Hospital and Harvard Medical School, combine two different high-tech optical imaging methods that were custom-built for the research. One is called multiphoton laser-scanning microscopy (MPLSM), which is an advanced fluorescence imaging technology that is now commercially available at the high end of the microscope market. The other is called optical frequency domain imaging (OFDI), which images tissues by their light scattering properties. According to Fukumura, OFDI is gaining popularity in the optical imaging field but has yet to become commercially available.

"MPLSM overcomes many of the limitations from which conventional microscopy and confocal microscopy suffer, and OFDI provides robust large volume imaging data," Fukumura said.

Fukumura will present their research at FiO 2013, taking place Oct. 6-10 in Orlando, Fla. There, he will describe how his unique technique can image tumors inside and out, and show detailed pictures of live tumors -- images that he and colleagues call "astonishing."

He added that while the new combined approach would be too expensive to be used for routine diagnostic purposes, it promises to help researchers better understand the intricate workings of human cancer and aid in drug discovery to treat cancer. "These optical imaging approaches can provide unprecedented insights in the biology and mechanisms of cancer," he said.

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