2013:
2012:
2011:
- Assessment of Melanoma-Specific Novel Markers in the U.S. Military Population
- Highlights of a Noninvasive Genetic Test for Colon Cancer Screening
2013
Environmental Exposures and Cancer Risk
Posted March 12, 2013
Dr Robert C. Lantz, University of Arizona
In a Fiscal Year (FY) 2009 Concept award begun by Dr Mark Whitten and, after his retirement, continued by Dr Robert C. Lantz (with Ms Cindy Fastje and Dr Paul Sheppard) of the University of Arizona studied the carcinogenic potential of JP-8 (a type of jet fuel) and tungsten (a heavy metal) in a murine model. Both JP-8 and tungsten are toxicants that military members and their families might be exposed to when living near air fields, bases, and installations. To delve into the possible risks, Dr Lantz and his collaborators worked to tease out the multiple factors which might lead to increased cancer risk. In previous studies, the researchers had been able to show that in utero exposure to tungsten followed by postnatal exposure to a specific lung virus (respiratory syncytial virus- RSV) led to the development of diseases in mice that were similar to human leukemia. The FY09 Peer Reviewed Cancer Research Program Concept award evaluated the effects of in utero exposures to tungsten or to JP-8 and exposure to different viruses. After exposures, analysis was performed at several different ages to determine the levels of white blood cells and weight of the spleen, an organ that is responsible for producing the white blood cells. For animals that were exposed to a virus and the toxicants during in utero development (first hypothesis), Dr Lantz and his collaborators did not find any significant differences between unexposed animals and the treated animals.
For the second hypothesis, in utero exposure to tungsten followed by postnatal infection with RSV. The results were different and showed leukemia-like alterations in mice. This data has been published in Fastje, C.D., Harper, K., Sheppard, P.R., Witten, M.L. In Utero Exposure to Sodium Tungstate and Post-Natal Exposure to Respiratory Syncytial Virus Results in Hematological/Immunological Disease in Mice: Implications for Childhood Leukemia. Chemico-Biological Interactions. 2012;196(3):89-95. These result support a multi-step carcinogenic pathway illustrating that toxicant exposure in utero followed by postnatal infection with virus and not in concert during in utero development is critical to understanding the cancer risks. However, these alterations were not seen when animals were exposed to either tungsten or jet fuel in utero followed by postnatal exposure to the Epstein-Barr virus (Fig 1).
These results indicate that the responses are specific for the type of viral infections after birth and the sequence of exposure. This indicates that there may be differences in the responses based on the types of virus and/or the cell types that they infect. The overall response therefore, may be specific for particular viral interactions and is not just a general effect of the JP-8 jet fuel or tungsten on inflammatory responses. The results demonstrate that environmental exposures during fetal development and long term exposures after birth play a significant role in health outcomes, particularly in the risk of cancer development.
Dr Lantz and his research group plan to identify possibly cellular and/or molecular targets of the toxicants and viral particles. By accomplishing this, they hope to find ways to intervene to reduce or eliminate the effect of toxicants on cancer risk as well as finding early ways to detect alterations that might lead to cancer development.Fig 1. Spleenic mass following in utero exposure to tungsten and postnatal exposure Epstein-Barr Virus. Data are from 35 day old animals. No significant differences were seen.
2012
Gold-Containing Nucleosides as Noninvasive Ablation Agents
Posted March 20, 2012
Anthony Berdis, Ph.D., Case Western Reserve University, Cleveland, OH
About 12 million people are affected with some type of cancer. Radiation therapy (RT) is an effective cancer treatment along with surgery and chemotherapy; at least 50 percent of cancer patients receive RT at some point during their cancer treatment. RT uses ionizing radiation (IR) such as x-rays to damage deoxyribonucleic acid (DNA) or genetic material within the tumor cells leading to cell death. However, most IR methods are not specific to cancer cells; i.e., the procedure may also damage normal cells or transform them into cancer cells as the damaged DNA gets inappropriately processed. Therefore, as with other cancer therapies, there are side effects associated with RT.
In an effort to optimize and potentiate RT by combining it with radiosenstizing compounds , Dr. Anthony Berdis received a Fiscal Year 2009 Peer Reviewed Cancer Research Program Concept Award to develop a novel class of chemosensitizer for IR by introducing gold (I) into sulfur-containing nucleosides, an anti-leukemia agent. Attaching gold (I) to a nucleoside analog improves selectivity and efficacy of IR therapy in several significant ways:
- As a biocompatible metal, gold (I) can have potent anti-cancer effects.
- Attachment of nucleoside with gold (I) improves specificity towards cancer cells in comparison to non-cancer cells by bringing the compound directly to cancer cells.
- Gold(I) containing nucleosides also produces beneficial pharmacological effects by targeting kinases (enzymes catalyzing phosphorylation of substrates).
- Reactivity of gold-carbon and gold-sulfur bonds towards radiation amplifies cytotoxity of radiation and improves efficacy of IR therapy.
Dr. Berdis and colleagues synthesized and tested several gold (I) containing compounds on different cancer cells lines such as HeLa (ovarian) and HCT116 (colon) cancer cells. They determined two compounds (labeled as compound 3 and compound 4) hold promising capability to increase the cancer-cell killing activity of IR. The cytotoxity of IR is due to the inability of cancer cells to repair double-strand DNA breaks (DSBs), the most lethal form of DNA damage caused by IR. HeLa cells treated with RT alone showed a survival curve reflecting cells capable of repairing damaged DNA created by the IR exposure. However, in cells treated with either compound 3 or compound 4 for 24 hours followed by RT, the repairing phase is absent, indicating an increase in the cytotoxicity of IR treatment.
Dr. Berdis also elucidated the cellular mechanism for potentiating the anti-cancer effects of the gold (I) containing compounds. H2AX is a protein which gets phosphorylated and activated in response to DSBs formed by IR exposure. As the figure demonstrates, in the absence of compound 3, H2AX gets phosphorylated to repair DSB, while in the presence of compound 3, H2AX phosphorylation is inhibited. The DSBs are thus not repaired, resulting in cell death. On the other hand, compound 4 treatment inhibits DSBs repair process in the step after activation of H2AX.
Therefore, the accumulative results of this proof-of-concept study suggest combination of gold (I) containing compounds with IR, as a potent therapeutic strategy for tumor ablation, may have a major impact on cancer research. Dr. Berdis continues to pursue these studies with more advanced experiments to move the combination therapy of gold (I)-containing compounds and IR chemostrategy forward.
Schematic illustration showing proposed model of gold (I) containing nucleosides to potentiate the therapeutic effects of IR by inhibiting DNA repair
2011
Assessment of Melanoma-Specific Novel Markers in the U.S. Military Population
Posted May 5, 2011
Mohammed Kashani-Sabet, M.D., California Pacific Medical Center, San Francisco, California
Sancy Leachman, M.D., Ph.D., University of Utah, Salt Lake City, Utah
Although it remains one of the rarer types of skin cancer, melanoma is linked to about 75% of skin cancer-related deaths. Exposure to the sun or ultraviolet radiation (UVR) has been identified as one of the strongest environmental risk factors for melanoma development. In addition to sun/UVR exposure, genetic and molecular factors have been recognized as important components associated with the onset and progression of the disease. Since the accurate diagnosis of melanoma based on histopathological evaluation can be very challenging, the development of more sensitive and specific diagnostic tools is necessary.
Recipients of a Fiscal Year 2009 Collaborative Translational Science Award, Drs. Mohammed Kashani-Sabet and Sancy Leachman are proposing to examine a number of genetic markers of melanoma susceptibility, and to validate multi-marker diagnostic and prognostic assays for melanoma. The groundwork for this study is based on the identification of molecular markers that are differentially expressed at various stages of melanoma. With extensive expertise in the clinical care of melanoma patients, melanoma genetic epidemiology, cancer pathology, and progression markers, a group of talented clinicians and scientists have joined forces to assess known risk factors for melanoma among the active duty military population utilizing serum samples from the U.S. Military. Military personnel are extensively exposed to UVR as a result of their deployment assignments. Accurate assessment of risk and diagnostic factors for melanoma will help in identifying service men and women at higher risk of developing melanoma; this study may yield a simple melanoma risk assessment model that could be translated into the clinic. Additionally, the efficacy of melanoma-specific pre-selected multi-marker molecular diagnostic and prognostic assays, based on immunohistochemistry and quantitative polymerase chain reaction (PCR) platforms, will be validated within the U.S. Military population.
If successful, this study will benefit the melanoma community and the military population with clinically translatable molecular tools that can be used for the assessment of melanoma susceptibility, diagnosis, and prognosis.
Links:
Public and Technical Abstracts: Molecular Determinants of Melanoma Susceptibility and Progression
Highlights of a Noninvasive Genetic Test for Colon Cancer Screening
Dr. Su discusses her work on developing a non-invasive genetic urine test for colorectal cancer.
Posted March 10, 2011
Dr. Ying-Hsiu Su, Drexel University
Colorectal cancer (CRC) remains the second leading cause of cancer deaths in the United States (more than 57,000 projected deaths in 2009) despite the availability of sensitive screening tests such as colonoscopy. The inconvenience of the test and the risks involved contribute to the low adherence rate (40%) among U.S. adults. Our goal is to develop a noninvasive urine screening test for the early detection of adenoma and CRC that will enable more precise identification of individuals within the population who require colonoscopies. Such a test would enhance screening for CRC, reduce the cost to society of performing expensive, invasive diagnostic examinations that yield a majority of negative results, and ultimately save lives through early detection.
We successfully detected CRC-associated K-ras mutations in the urine of patients with CRC that are genetically heterogeneous. A single marker is unlikely to have sufficient sensitivity and specificity to be used as a stand-alone screening test. A panel of urine biomarkers that includes both genetic and epigenetic DNA alterations should provide a test with high sensitivity and specificity for CRC. In the past year, we have successfully developed a sensitive assay for detecting one of the most promising CRC DNA markers, aberrant hypermethylation of the vimentin gene, in the urine of patients with CRC. We performed a blinded study in which we used our assay to detect hypermethylated vimentin in 20 CRC tissue and 20 CRC urine samples identified only by barcodes. We did not know which tissue matched to which urine sample. As a control for healthy subjects, we also examined 20 urine DNA samples from subjects with no known neoplasia.
Using our assay, we detected methylated vimentin gene in 80% of CRC tissue samples and in 75% of urine samples with a concordance of 70% between marker-positive tissues and their matched urine samples. Ten percent of urine samples from control subjects contained a low level of methylated vimentin.
The results of this project indicate that, in addition to genetic mutation markers, epigenetic methylated DNA markers could also be used for a urine test. Work is in progress to develop a technology platform for screening a panel of CRC markers to develop a CRC screening test that would be acceptable to the high-risk population, thereby improving compliance. The availability of a noninvasive urine test would enhance the willingness of patients to undergo CRC screening, and CRC could be detected at an early, curable stage.
A manuscript describing the work is being prepared for publication.
