Cancer research is beginning to uncover chemopreventive medicines that reduce the risk of developing certain cancers, and Dr. David Huso is evaluating the medicines’ effects on protecting against cancers that occur following low-does radiation exposure. He is currently testing tamoxifen, a prototype chemopreventive agent, for protection in a rapid, radiation-induced breast cancer model using exposures to the types of radiation likely to occur in space.
Overview
Chemoprevention and Radiation-Induced Neoplasms
Principal Investigator:
David L. Huso, D.V.M., Ph.D.
Organization:
Johns Hopkins University School of Medicine
Technical Summary
Chemoprevention is a pharmaceutical approach to arresting or reversing the process of carcinogenesis during cancers typically prolonged latent period (often 20 years or more) before invasion or metastasis occurs. Surging scientific and public interest in applying chemoprevention strategies to people in the general population that have been identified to carry even slight increases in the risk of developing cancer (e.g., genetic risk) is fueling the identification of exciting new chemopreventive agents. Some now argue that future development of chemopreventive agents offers greater potential for the long-term control of cancer than the more-widely studied and aggressively pursued chemotherapy agents.
The major long-term risk associated with radiation exposure received during space travel is predicted to be radiation-induced cancer. The cancer-causing effects of low-LET radiations such as X-rays, g-rays or electrons, typical of environmental Earth exposures, have been relatively well-established. However, radiation likely to be encountered in space includes mainly heavy ions and protons along with their secondaries. Much less is known about the biology and risks associated with these types of radiation. The doses of radiation likely to be received even for long missions are probably low, but cover a broad range and are very unpredictable due to solar events. Like other types of radiation, the increased cancer risk associated with proton and heavy ion exposure is troubling because many radiation-induced cancers do not appear until later in life. Therefore, a large amount of uncertainty exists in how best to assess and manage the radiation risks associated with space travel.
Two high priorities in preparation for long term missions are 1). providing a better understanding of both the short-term and long-term carcinogenic risks of heavy-ion or proton radiation, and 2). developing pharmaceutical countermeasures to mitigate the carcinogenic risk associated with low-dose and mid-dose exposures to these types of radiation. Currently there are three cancer chemopreventive strategies that have clearly proven efficacy in preventing human familial and sporadic cancers: 1). selective estrogen receptor modulators for prevention of breast cancer; 2). NSAIDs (nonsteroidal antiinflamatory drugs), which may prevent a variety of cancers, and; 3). retinoids for certain epithelial cancers. As countermeasures to the cancer risk associated with space travel, these chemopreventive approaches offer a particularly promising approach for countermeasure investigation because of: A). these compounds are currently being used as preventives for human cancers although they are untested against proton or heavy ion-induced cancer; B). there are difficulties associated with absolutely blocking radiation-induced mutagenic damage to DNA during prolonged space travel either with shielding or pharmaceuticals, and; C). the prolonged latency period of most radiation-induced cancers (especially at low doses) offers a prolonged time period to administer chemopreventives. This is important since the latency period is the time when the most successful chemopreventives exert their effects. For most cancers, compounds that modulate the regulation of cell growth and apoptosis (rather than blocking mutagenic damage to DNA) have to date shown particular promise in preventing overt cancer from developing in susceptible organs.
Organs are not equally sensitive to the carcinogenic effects of radiation. Tissues that appear to be at higher risk for developing radiation-induced neoplasms include the female breast, the gastrointestinal tract (colorectal cancer), the thyroid, the bone marrow/lymphoid system (leukemia) and the lung. Women have an increasing role in the space program. The female breast is particularly sensitive to the carcinogenic effects of radiation and therefore a relevant tissue in which to study chemoprevention of radiation-induced cancer. Chemoprevention of radiation-induced cancer in this sensitive target organ provides an excellent system in which to initially gain insights into the chemoprevention of radiation-induced cancer in general.
Over the past few years, tamoxifen has not only emerged as an effective chemopreventive against breast cancer, but it has also become the most widely prescribed anticancer drug in the world. It is a prototype of the group of pharmaceuticals called selective estrogen receptor modulators. Tamoxifen had been used for over 25 years for breast cancer treatment prior to its application as a chemopreventive. This level of acceptance for use in humans along with its proven chemopreventive efficacy against sporadic breast cancer provides a strong rationale for investigating its safety and efficacy against breast tumors induced by heavy ions and protons. As a potential countermeasure to the risks associated with prolonged space missions, the tamoxifen family of compounds have outstanding potential with a high level of readiness.
The class of compounds that includes tamoxifen, the selective estrogen receptor modulators (SERMs), are thought to have outstanding potential both in estrogen replacement therapy and as chemopreventive agents. Burgeoning research and development of new SERM compounds has led to many new and improved SERMs undergoing trials. Tamoxifen, however, remains the prototype SERM for breast cancer chemoprevention. Newer SERMs will hopefully further improve on tamoxifens effects while reducing its side effects.
SERMs are ligands for the estrogen receptor (ER) and modify carcinogenesis in breast epithelial cells by antagonizing ER signaling. However, in other tissues, SERMs can act as partial ER agonists and promote the beneficial effects of estrogens in, for example, the skeletal and cardiovascular systems. Interestingly, tamoxifen may also affect carcinogenesis in a number of organ systems by disrupting apoptosis regulation in proliferating cells. In spite of the widespread use of tamoxifen, very little is known about its lifetime effectiveness against radiation-induced neoplasms, particularly those induced by radiation likely to be encountered in space such as protons and heavy ions.
In vivo studies provide a powerful means for directly evaluating the effectiveness of particularly promising chemopreventives against cancers that may occur following radiation exposure. The rat mammary tumor model has been used extensively to analyze the carcinogenic effects of both chemical xenobiotics and physical agents. The Sprague-Dawley rat mammary-tumor model is particularly well-suited for studies in the low-dose range because this model is prone to develop induced mammary neoplasms early in life. Previous studies using the Sprague-Dawley model have shown that sublethal doses of radiation (X-rays, gamma rays and neutrons - not particularly relevant to space travel) induce mammary tumors, often within one year and with a linear dose-effect relationship. Thus the Sprague-Dawley rat mammary-carcinogensis model not only closely resembles human breast cancer biologically, but it also is a highly sensitive model in which to examine the effects of radiation exposure and for testing pharmaceutical countermeasures against radiation effects. Our initial studies have focused on the effects of whole-body, low-level, heavy-ion and proton radiation along with chemoprevention of similarly induced mammary tumors using the female Sprague-Dawley rat mammary-tumor model. The well-studied, widely prescribed protoypte SERM, tamoxifen, has been effectively and safely used in humans for chemotherapy for almost two decades. These advantages, along with an understanding of its molecular mechanism of action, suggest it would be an excellent candidate for successful long-term chemoprevention of specific proton and heavy ion-induced cancers. The prospect for successful long-term chemoprevention of this potentially important, late-appearing cancer, relevant to space radiation exposure, is indeed an exciting prospect.
Hypothesis and Aims
There is an uncertain but serious risk of cancer potentially associated with prolonged space travel. These risks cannot be addressed with shielding alone. Our first hypothesis is that modeling these risks can remove much of the uncertainty and would allow better management of some of the radiation risks associated with prolonged space missions. Our second hypothesis is that the increased cancer risk that may be associated with radiation in the space environment can be mitigated by chemopreventive countermeasures implemented during the long cancer latency period that follows radiation exposure. The cancer-causing effects of radiation as well as the safety and efficacy of chemopreventives have not been determined under conditions relevant to space. Animal models provide the best tools to test these hypotheses in relevant settings and should provide important insights into the chemoprevention of breast cancer in the general population.
Specific Aims
- To determine the relative risks associated with exposure to the types of radiation encountered in space using a sensitive in vivo model of radiation-induced cancer, and;
- To determine if pharmaceutical cancer chemopreventives could provide a safe and effective countermeasure approach to mitigate the cancer risk that may be associated with exposure to the types of radiation likely to be encountered in space.
Key findings
Although our studies are not complete, preliminary trends in our tamoxifen studies have pointed to a proof of principle for a strategy in which chemopreventive agents could play an important role in preventing breast cancer following exposure to radiation during space travel. Confirmation of these trends is still pending the completion of these studies. Since Dr. Huso took over as PI of the chemoprevention studies, considerable progress has been made in this area. Since cancer chemoprevention in general is still in its infancy as an emerging field, chemoprevention based on new targets and emerging compounds hold considerable promise for continued improvement of strategies to effectively mitigate risks associated with radiation and other predisposing factors for cancers. During the coming year, we plan to complete our studies on tamoxifen chemoprevention of radiation-induced cancer and analyze in detail the overall findings. The data should give new insights into the use of pharmaceuticals in the mitigation of radiation-induced cancer.
Our results, though preliminary, provide a glimpse of the enormous potential payoff that chemoprevention research could provide not only for the future health of astronauts exposed to radiation, but also in the general population in the battle against cancer. Regardless of the reason for an individual to be at increased risk for developing particular cancers, be it radiation exposure as in our studies (relevant to astronauts and space travel) or genetic and environmental factors (relevant to the general population), specific chemopreventive compounds and strategies can be identified and implemented to mitigate risks that predispose individuals to cancer. Much work remains to be done to fully realize the benefits of chemoprevention strategies specifically in the battle against radiation-induced cancer. Support for research into chemoprevention of radiation-induced neoplasms such as that provided by NSBRI benefits not only space exploration efforts, but what is learned in this important area also could provide unique insight into cancer chemoprevention for the general population.
This project's funding ended in 2005