Cancer

A recent discovery by Van Andel Research Institute (VARI) scientists enables the prediction of patient sensitivity to proposed drug therapies for glioblastoma - the most common and most aggressive malignant brain tumor in humans.

The study, published in the Proceedings of the National Academy of Science, investigated glioblastoma models characterized by cell signaling activation and gene amplification for their susceptibility to inhibitors of both the human MET oncogene and the epidermal growth factor receptor (EFGR).

An oncogene is a gene with the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels. High MET levels often occur in human tumors, and cells with inappropriate MET signaling produce activity that potently affects the spread of cancer. This signaling is implicated in most types of human cancers and high MET expression often correlates with poor prognosis. Mutations affecting EGFR expression or activity are also linked to cancer.

"Because oncogene MET and EGFR inhibitors are in clinical development against several types of cancer, including glioblastoma, it is important to identify predictive markers that indicate patient subgroups suitable for such therapies," said VARI Research Scientist Qian Xie, Ph.D., lead author of the study.

"Studies have shown that targeting MET signaling can have potent antitumor effects," said Co-Author George F. Vande Woude, Ph.D., Head of the VARI Laboratory of Molecular Oncology. "Therefore, it is important to understand the mechanisms leading to HGF/MET sensitivity and to identify the patient subgroups most likely to benefit from MET-targeted therapeutics."

Dr. Vande Woude's career can be characterized by the uniquely broad scope of his work with MET and its molecular partner hepatocyte growth factor (HGF) - from the original cloning and characterization of the gene, through explaining the role of the HGF/ MET signaling pathway in human cancers, and then to applying that knowledge toward the identification of inhibitors of this important cancer pathway. Because MET and HGF play such an integral role in the process of cell survival, growth, blood vessel formation, and metastasis, they are a significant target in the development of anti-cancer drugs.

Dr. Vande Woude is also the co-author of an article published last week in Nature Reviews Cancer entitled "Targeting MET in cancer: rationale and progress," which updates the progress of MET and HGF as targets in the development of anti-cancer drugs.

"Progress in understanding this vital process has led to the successful development of blocking antibodies and a large number of small-molecule MET kinase inhibitors," said Vande Woude. "Results from recent clinical studies demonstrate that inhibiting MET signaling in several types of solid human tumors has major therapeutic value."

Treatment with three relatively new "targeted" cancer drugs has been linked to a slightly elevated chance of fatal side effects, according to a new analysis led by scientists at Dana-Farber Cancer Institute. They added that the risk remains low, but should be taken into account by physicians and patients.

The incidence of fatal complications was 1.5 percent in patients who received any of the three drugs, which block the vascular endothelial growth factor (VEGF) tyrosine kinase receptors in cancer cells, according to the study published February 6 in the Journal of Clinical Oncology. This is compared to a 0.7 percent incidence in patients given standard treatments or placebos.

The study looked at three drugs: sorafenib (Nexavar), sunitinib (Sutent), and pazopanib (Votrient). Sorafenib is approved to treat kidney and liver cancer, sunitinib to treat kidney cancer and gastrointestinal stromal tumor (GIST), and pazopanib to treat kidney cancer.

The authors of the study, led by Dana-Farber's Toni Choueiri, MD, suggest that physicians give full consideration of the potential risk before using the targeted drugs with patients at slightly high risk for bleeding or heart attacks - the most common fatal adverse events seen in clinical trials. They also recommended that physicians and patients be aware of the risks and to consider if those patients need to be closely monitored.

"There is no doubt for the average patient, these drugs have benefits and are FDA-approved for these indications," said Choueiri. "While the absolute incidence of these fatal side effects is very small, the relative risks are higher and patients and practitioners need to be aware of it."

For example, he said, it might be necessary to temporarily stop treating a patient with the drug or to cancel an elective surgery while a patient is taking one of these drugs. Choueiri added that these drugs should be used cautiously in patients who have had heart attacks. "The patient should be given all the information, and then he or she can balance the pros and cons in deciding whether to take the next step into treatment."

Choueiri said he believed the study is the first meta-analysis of published controlled trials to show a significantly increased risk of death from treatment with these VEGF-tyrosine kinase inhibitors. The majority of patients who died suffered fatal bleeding; the second most common cause was heart attack or heart failure; liver failure was also seen.

The 10 clinical trials subjected to the meta-analysis included 4,679 patients treated with the drugs.

Vascular endothelial growth factor receptor is a tyrosine kinase molecule that responds to chemical signals secreted by tumors to encourage the formation of new blood vessels for the purpose of providing nutrients to support tumor growth. However, humans need vascular endothelial growth factor (VEGF) at low levels to maintain critical to several physiologic processes in the body, including wound-healing, cardiac homeostasis, and formation of new blood vessels in normal tissues. As a result, blocking VEGF to treat cancer can interfere with these normal functions, increasing the odds of adverse effects

Scientists working with Professor Bernd Kaina of the Institute of Toxicology at the Medical Center of Johannes Gutenberg University Mainz have demonstrated for the first time that certain cells circulating in human blood - so-called monocytes - are extremely sensitive to reactive oxygen species (ROS). They were also able to clarify the reason for this: ROS are aggressive forms of oxygen that are generated during states of "oxidative stress" and play a significant role in various diseases. However, ROS are also naturally produced by cells of the immune system, in particular by macrophages, in response to exposure to pathogens. Macrophages are, similar to dendritic cells, generated by monocytes, which happens when monocytes leave the blood stream and enter the tissue. The scientists show that both macrophages and dendritic cells are resistant to ROS, as opposed to their precursor cells, the monocytes. The Mainz team attributes this hypersensitivity of monocytes to multiple defects in DNA repair that are apparent in these cells. They assume that a sophisticated mechanism for regulating the immune response and preventing excessive ROS production is behind this phenomenon, which was observed for the very first time. Their work has been published in the leading scientific journal Proceedings of the National Academy of Sciences.

It is generally known that one of the undesirable effects of ionizing radiation and drugs used to treat cancer is an impairment of the immune system, which ceases to function properly. However, it is still unclear which immune system cells respond most sensitively following radio- and chemotherapy, and which cells are resistant. "This is the question we addressed in our current research project," explains Professor Dr. Bernd Kaina, Director of the Institute of Toxicology at the University Medical Center in Mainz. "We were able to demonstrate that human monocytes are hypersensitive to reactive oxygen species (ROS), while macrophages and dendritic cells derived from monocytes by cytokine maturation are resistant." The scientists observed this extreme sensitivity of monocytes after exposure to radiation, chemicals, and even oxidized low-density lipoprotein (oxLDL), which plays a role in atherosclerosis. All of the above resulted in the formation of intracellular ROS, which damages the DNA and leads to cell death or even malignant transformation. Specific immune system cells, particularly the macrophages, produce ROS in response to an invasion of the body by pathogens. Ideally, production of ROS should cease once the pathogens have been eliminated. There also need to be limitations on the quantity of ROS produced, as these can damage healthy cells in inflamed tissue as well. In fact, chronic infections, in which ROS are continuously being produced, are frequently linked to an increased susceptibility to cancer.

Why do monocytes react so sensitively to ROS? Kaina's team has successfully determined the cause of the hypersensitivity of monocytes to oxidative stress: The monocytes were unable to repair DNA following ROS-induced damage to their genetic substance. This is because these cells produce very low levels of certain important repair proteins called XRCC1, ligase III, PARP-1, and DNA-PK in medical jargon. "Monocytes are in fact defective as far as two important DNA repair systems are concerned, i.e. base excision repair and DNA double-strand break repair," explains Kaina. "Thus far, a general repair defect of this nature has been observed neither in the cells of the human body nor in experimental in vitro systems."

Professor Kaina assumes that the repair defect in monocytes plays an important role in the regulation of the immune response: To prevent excessive production of ROS by macrophages in the inflamed tissue and an overactivation of the immune response, monocytes, as precursor cells of the ROS-producing macrophages, undergo increased and selective destruction due to their extreme sensitivity to ROS. In turn, fewer monocytes mean fewer macrophages and consequently lower levels of ROS - all in all a sophisticated way of regulating the monocyte/macrophage/dendritic cell system. It is clear that this has potential clinical implications: In the case of chronic inflammatory diseases in particular, the body is in a state of imbalance and excessive amounts of ROS are produced, which results in damage to the genetic substance of the healthy cells and is a contributing factor to the onset of cancer. It is possible that this vicious circle could be interrupted by the selective elimination of monocytes in the inflamed tissue