My laboratory is focused on three specific areas of biology related to radiation exposure:
Biology of exposure to charged particles
Charged particles, in this case, are elemental particles stripped of their elections. They are by definition hadrons, which are particles that consist entirely of quarks. This definition also includes pi-mesons; however our biological interest includes exposures to protons as well as to heavier particles, including 12C, 16O, 18Ne, 28Si, 56Fe and 48Ti.
Our interest in exposure is two-fold. First, protons are trapped in magnetic belts that surround the earth. And protons are ejected from the sun at near-relativistic speeds in random directions. Such solar showers are known to interrupt communications on earth. These solar showers are also a hazard to astronauts on extended missions of low earth orbit, and in particular, those astronauts outside of the earth's magnetosphere on missions to the moon or Mars. Of particular concern to the manned space program is that higher particle masses create higher risk for carcinogenesis and other non-carcinogenic endpoints. For example, when mice are exposed to 56Fe particles at a nominal energy of 1000 MeV/n, the risk for radiation-induced hepatocellular carcinoma is possibly 50-fold that of an equivalent dose of X- or G-rays. This scenario is unacceptable to NASA. However, the error on such measures is also very large. NASA currently believes that without a better understanding of the risk, missions to Mars or extended stays on the moon may come with an unacceptable risk for fatal cancers.
To address these concerns, my laboratory, as part of two multi-project NASA Specialized Centers of Research (NSCOR), is addressing the risk for lung carcinogenesis after space radiation exposures. The first NSCOR uses non-oncogenically immortalized human bronchial epithelial cells (HBECs) generated in the laboratory of the NSCOR overall PI, John Minna, M.D. Our overall goal is to discern the radioresponse of HBECs to space radiation exposures. More specifically, we want to understand the oncogenic progression of HBECs and identify biomarkers of carcinogenic risk. We do not understand whether the oncogenic process from radiation exposure is different from that of cigarette or environmental mutagens. We do not know if radiation is a more effective initiator of lung cancer or works more effectively to promote lung cancer. Using HBECs isolated from 60 individuals we are examining the initial cellular and genomic response to representative ions found in space, such as Si and Fe. We are also determining the rate of cellular transformation after such exposures. Transformed cells are then tested for their ability to generate tumors in immune-compromised mice. Transformed clones and any subsequent tumors are being examined for genomic and epigenomic alterations as a function of time post-irradiation to identify biomarkers for the oncogenic process that can subsequently be validated in human tumor samples. Ultimately, we expect to account for inter-individual differences in risk for carcinogenesis after ionizing radiation, including the potential enhanced risk due to exposures to space radiation.
In the second NSCOR, we have partnered with collaborators at the University of Texas Medical Branch, Colorado State University, the University of Chicago, and Promega Corporation. We are determining the mechanisms for the induction of acute myelogenous leukemia (AML) as well as hepatocellular carcinoma (HCC). The induction of AML from radiation exposures is of particular interest to NASA because of the short latency time (2 – 5 years). It is conceivable that an individual could develop AML and succumb to the disease before the completion of a mission to Mars. We are using mouse models to determine the induction of these two cancers as a function of dose and radiation type and then determining the molecular changes that lead to the disease phenotype. We have also initiated a project to serially sample serum and plasma for miRNA to identify miRNA that may be indicative of disease onset.
Predictive factors for head and neck squamous cell carcinoma
The second specific area of biology is clinically oriented. Using genomic and epigenomic analysis we are determining predictive factors for clinical outcome in head and neck squamous cell carcinoma (HNSCC). This is a collaborative effort with clinicians and scientists at MD Anderson Cancer Center as well as physicians and scientists at UT Southwestern, and is funded by the National Cancer Institute and the Cancer Prevention Research Institute of Texas. We have identified a 39-gene signature for recurrence free and overall survival and have validated that gene signature in several independent patient cohorts where gene expression databases were available. In addition, we have identified several miRNA associated with distant metastasis and risk for local recurrence. We are now defining the targets and subsequently mechanisms by which these miRNA exert their influence on the ability of a tumor to metastasize or escape therapy. We are examining circulating miRNA for response to therapy and metastatic potential using a relatively non-invasive method. And lastly, we have also generated cell lines that form tumors to test biomarkers of response in vivo, and to test targeted therapeutic agents against genes or miRNA that may be key drivers of the oncogenic process.
Combined modality therapy
The third area of biology we are focused on is referred to as combined modality therapy. Our goal is to identify agents that we feel would work synergistically to enhance the response of tumor cells to radiation or to protect normal cells from radiation. This is a collaborative effort with small pharma and other commercial entities, as well as the National Cancer Institute. Because this work is supported by commercial entities we are not able to openly discuss, at this time, our initial results. However, our models include a series of lung cancer cell lines generously provided by John Minna, M.D. These cell lines will be used both in vitro as well as in vivo where needed. Our goal is to bring agents to clinical trials in lung and other cancers at UT Southwestern.
As described above, heavy particles are very effective at inducing carcinogenesis; however, this effect is generally at very low total doses and beyond that, cell killing is the dominant effect. In addition, there are physical differences to the energy deposition patterns with particles that allow for enhanced tumor targeting and sparing of normal tissues. Furthermore, heavier particles are more effective at killing hypoxic tumors than standard radiotherapy. Heavy particle radiotherapy began in the United States over 30 years ago; however, because of the expense the concept was abandoned. Since then, a number of heavy particle centers have been constructed in Europe and Asia and they are treating patients. Because of our extensive experience with particle biology we have launched a program to develop an advanced radiotherapy center at UT Southwestern that includes the construction of a proton therapy center as well as a heavy particle therapy center. This is partially in response to a formal call from the NCI to develop one or two heavy particle research centers in the U.S.
We intend to develop basic, translational and clinical research programs in physics, biology, and medicine that will contribute to the use of heavy particles for therapy. We are collaborating with the GSI Helmholtz Centre for Heavy Ion Research in Darmstadt, Germany; the heavy particle research center in Lanzhou, China; and the National Institute of Radiological Sciences in Chiba, Japan. This effort will require several years for implementation. Phase One, the proton center, will break ground soon.