Mike Martin

Laser Accelerated Radiotherapy: Is It On Its Way to the Clinic?

radiation. Loma Linda (Calif.) University Medical Center oncologists are using protons to treat early stage lung cancers, pituitary adenomas, pediatric orbital and ocular tumors, acoustic neuromas, benign meningiomas, and prostate cancer. To target therapy and minimize tissue damage, radiation oncologists exploit a proton beam characteristic called the Bragg peak. A Bragg curve plots how ionizing radiation loses energy as it travels through matter, in this case, tissue. For accelerated protons, the energy curve peaks sharply as the particle stops, releasing its power like a well-placed punch. This so-called Bragg peak effect provides “normal tissue sparing superior to other radiotherapies,” said Albert Einstein’s Kalnicki.

Comparing Invasive Species to Metastatic Cancers Inspires New Insights for Modelers

Evidence that power laws govern invasive species came from crop pathogen studies and computer simulations reported in such journals as Nature , Science , and Genetics . Marco and fellow authors Marcelo Montemurro, Ph.D., and Sergio Cannas, Ph.D., have studied biological invasions for years and suspected that the same laws govern tumor growth. They confi rmed their suspicions by comparing an Argentine forest including invasive species to noninvasive human glioma cells cultured either in live mice or in Matrigel, a patented gelatinous protein mixture secreted by mouse tumors. “Noninvasive cells from the center of the glioma” — which were used as an experimental control — “were genetically engineered to become invasive by expressing angiopoietin 2, a regulator that promotes tissue infiltration,” Marco explained. Likewise, aerial black-and-white photographs taken in 1970, 1987, and 1996 revealed the gradual spread of English elm ( Ulmus minor ), an ornamental European tree that invaded Argentina in the mid-20th century. From 1987 to 1997, 74 elm tree patches became 189 patches scattered across 17 acres. While Marco “would not say that trees native to the forest were a control,” she did identify two noninvasive species — Lithraea ternifolia and Fagara coco — as tantamount to “tissue surrounding a spreading tumor.”

Rewriting the Mathematics of Tumor Growth

A new theory about tumor growth makes oncology look a little like cosmology. Just as the universe accelerates as it expands, tumors become malignant at an accelerating speed, according to a team of scientists who have been probing the mathematics of tumor growth. Specifically, the researchers have discovered that tumor-driving mutations characteristic of nearly all cancer cells have a surprisingly small selective growth advantage of 0.4%. That advantage isn’t large enough to sustain tumor growth, which calls into question the long-held belief that tumors result from one or two mutations. “The most important take-away message from this research is that relying on genome studies to identify one wrong component is not the right approach,” said surgical oncologist Steven Libutti, M.D., director of the Montefiore–Einstein Center for Cancer Care at the Albert Einstein College of Medicine in New York. “Any individual mutation makes only a small contribution to the overall appearance of a cancer, and early mutations alone are probably not the only story.” Bert Vogelstein, M.D., a Howard Hughes Medical Institute investigator, led the team of researchers from six institutions around the world who mapped tumor growth rates. In a model best described as a sequential driver mutation theory, they suggest mutations that drive tumor growth—called driver mutations—multiply sequentially over time, each one slightly increasing the tumor growth rate through a process that depends on the average of three factors: driver mutation rate, the 0.4% average selective growth advantage, and cell division time. Other models describe tumor dynamics as an exponential function or according to a Gompertz curve that shows how tumor growth gradually rises and levels off over time. But this theory “is unique because it shows, for the first time, that a cancer cell with only one driver mutation will grow to only a certain size and then stop until another mutation happens,” said Iuliana Shapira, M.D., director of the cancer genetics department at North Shore University Hospital in Manhasset, N.Y., and was not part of the research team. With a combination of experimental data and computer simulations, the group applied their theory to hypothetical patients with glioblastoma multiforme, pancreatic adenocarcinoma, and familial adenomatous polyposis (FAP), which can become malignant. In computational tests of both the brain and pancreatic cancers, a second driver mutation appeared 8.3 years after the first. But the mutation rate accelerated, with only 4.5 more years passing until the third driver mutation emerged. Malignant progression in FAP follows a similar scenario. “For years, a benign tumor may grow slowly,” said team member Tibor Antal, Ph.D., a lecturer at Scotland’s University of Edinburgh School of Mathematics. “But when it starts gathering new mutations, the growth process speeds up and leads to a malignant cancer fast.” The idea that cancerous mutations progress with the disease, thereby creating cumulative damage—rather than simply being a one-time force that pushes a boulder down a hill—makes sense to Libutti, who was not a member of the research team. “Their research agrees with data showing that cancer is a long, complicated problem that can change with time and conditions,” Libutti explained. The sequential driver mutation theory may also help efforts to “personalize” cancer genomics, Shapira explained. “One could foresee the capability to estimate how many driver mutations fuel specific types of cancer, and how long a specific type of cancer was present in someone.”

Can Game Theory Explain Invasive Tumor Metabolism

“In the evolutionary sense, only traits that allow successful adaptations survive,” said Phillip Manno, M.D., chief of clinical oncology and hematology at the Nevada Cancer Institute in Las Vegas. “This idea can certainly be applied to cancer, in which cells acquire a needed phenotype to survive.” With the right mathematical approach, researchers can frame intercellular interactions that lead to phenotype acquisitions as survival games. Coming from a long tradition in sociology, economics, and more recently, biology, “game theory has been used successfully to study the evolutionary dynamics of populations made of different phenotypes in traditional ecosystems,” said Basanta. “We believe it can be used to study the evolutionary trajectories of cancer.” Some researchers consider carcinogenesis itself an evolutionary trajectory. In almost stepwise progression, cancer cells evolve by acquiring different phenotypes, including the ability to trigger blood vessel growth, invade surrounding tissue, me tastasize, and grow autono mously. As these phenotypes evolve, survival

Materials Scientists Join Oncologists To Explore Nano- and Microtherapeutics Materials Science and Oncology

In the past year, researchers have reported killing cancer cells with magnetically driven, spinning iron – nickel discs; iron – cobalt particles; and radio waves aimed at gold, cadmium, indium, and gallium particles. It’s all happened in preclinical studies so far. But the studies have drawn attention, partly because of their science-fiction – sounding methods and partly because they highlight a burgeoning partnership between two unlikely bedfellows: materials science researchers and clinical oncologists. “I’ve seen a dramatic increase over the last 3 – 4 years in the involvement of chemists, physicists, bioengineers, and materials scientists in clinical oncology,” said Steven Curley, M.D. , a surgical oncologist at the M. D. Anderson Cancer Center in Houston, who is working on the radio waves. Some of the partnerships are focused on nanoimaging devices ( see accompanying news story); others, on nano- or microtherapeutics. The treatments they are exploring are diverse but share a core concept: the pairing of biologically active molecules such as drugs and antibodies with biologically inert particles such as metals and polymers.

Does Homeostatic Pressure Explain Tumor Growth

T o the much-studied genetic and biochemical forces that govern cell growth, dysplasia, and metastasis, a burgeoning science — call it mechanical biology — is adding forces that might seem more applicable to airliners and skyscrapers. Shear, friction, stress, tension, and viscosity also play a role in oncogenesis, according to researchers exploring this interface between biology and physics. “To grow, a tumor must, most of the time, push normal tissue out of its natural position,” said Jacques Prost, Ph.D. , of the Curie Institute in Paris, a leader in the physical sciences research department where Pierre and Marie Curie discovered radium and Paul Langevin discovered sonar. “Mechanical forces are at work, hence the necessity of investigating their importance.” In a new report, Prost and his colleagues propose a mathematical model, based on existing clinical and laboratory data, that explains how a mechanical force that they call homeostatic pressure affects tumor growth and metastasis. Writing in the American Institute of Physics HFSP Journal, the physicists argue that analyzing cancer strictly on the basis of DNA abnormalities or chemical on – off switches cannot fully account for clinical and experimental data. The authors claim that their approach could lead to “a quantitative, experimentally accessible measure for the metastatic potential of early malignant growths.” “Genes do not move matter — physical mechanisms and processes do,” said Gabor Forgacs, Ph.D., a professor of biological physics and biomedical engineering at the University of Missouri, Columbia. Summing up the argument for investigating the physics of carcinogenesis, Forgacs said the Prost group’s analysis “illustrates how simple physical concepts like pressure can be applied to the ultimate intricate biological system: the tumor.”

How Do You Track Lung Tumor Motion? A Critical Question With Competing Answers

Martin Fuss, M.D. , remembers the old days when radiologists treated a large area to get at a small tumor. Back then, the bone-encased male prostate seemed like an immovable object, recalled Fuss, who directs the imageguided radiation therapy department at the Oregon Health Sciences University in Portland. But advanced imaging technology now makes it possible to spot the slightest movement, he said. “We’ve found that even the prostate can move.” These slight movements are critical to radiation therapists who can now take precise aim at tumors, sparing surrounding tissues. “Because we are now able to zero in very tightly on a tumor,” Fuss said, “motion is so much more important.” And nowhere more important than in the lung, where every breath can move a tumor. In radiation therapy, tracking lung tumor motion has become a hot area of research. Implanted devices are one way to track motion, but they require surgery and have been associated with a 20% – 50% greater risk of pneumothorax, or air in the pleural cavity, which can collapse or lead to infection of an already embattled lung. A better way, according to some experts, is to use anatomic surrogates — organs or structures, usually near the tumor, whose movements closely track tumor motion. Tracking tumor motion during radiation therapy is “one of the most important things we do,” said Stephen Feigenberg, M.D., a radiation oncologist at Fox Chase Cancer Center in Philadelphia. “Everyone is trying to fi gure out how to do it without implanted tracking devices. It would be wonderful to come up with a noninvasive approach, and that’s the appeal of anatomic surrogates.” Recently, two groups proposed different anatomic surrogates for lung tumor motion — the diaphragm and the carina, a cartilaginous ridge that divides the trachea into the primary bronchi. Their latest studies have ignited debate over which surrogate works best. In June, Steve Jiang, Ph.D., Laura Servino, Ph.D., and fellow researchers from the Center for Advanced Radiotherapy Technologies at the University of California, San Diego, published the results of a 2-year study that favors the diaphragm as a lung tumor motion surrogate. Their fi ndings appeared in the journal Physics in Medicine and Biology . In July 2008, radiation oncologists Suresh Senan, Ph.D., and Lineke van der Weide, heading a seven-person team from Amsterdam’s VU University Medical Center, published a study supporting the carina as anatomic surrogate in the International Journal of Radiation Oncology and Biological Physics . They confi rmed and extended those results in the same journal this June and presented their fi ndings, with some new caveats, at a meeting in early September.