Current Signal Transduction Therapy - Volume 5, Issue 3, 2010

Recent improvements in radiation oncology have been the most dramatic in human oncology and have yielded many fruitful outcomes in treatments for cancer patients. Improvements in physical technology have led us to a new world of treating targets from any direction using intensity-modulated radiation therapy, stereotactic body radiation therapy, and image-guided radiation therapy. Moreover, in the field of radiation biology, various important facts have been confirmed. Radiation therapy affects the chain of signal transduction within cells, between cells and outside of cells. Finally, the cancer cell dies. Hypoxia-inducible factor 1 (HIF-1α) is a biomarker of hypoxic cells [1, 2]. Harada et al., discussed the correlation between HIF-1α and radioresistance, suggesting a positive correlation between the two. In the near future, progress in molecular imaging will allow us to detect hypoxic cells and apply intensity-modulated radiation therapy combined with anti-HIF-1α molecular drugs. Proliferation of cancer cells is also very important in this field. Akimoto et al., discussed the correlation between EGFR and cancer proliferation. Overexpression of EGFR has been proven to be correlated with radioresistance. Recently, an anti-EGFR molecular targeted drug (cetuximab) combined with radiation therapy has been shown to achieve better prognosis than radiation therapy alone for head and neck cancer [3]. Angiogenesis is necessary for cancer cells to survive. Furthermore, lung injury from radiation therapy has been correlated with angiogenesis. Amano et al., reviewed angiogenesis and radiation on the basis of their group study. The effect of radiation is usually limited to the field of irradiation. However, rarely, the application of radiation shows an effect outside this field, as the so-called abscopal effect [4]. Shiraishi et al., discussed the mechanisms of abscopal effects on the basis of their studies and the literatures. Their review article suggested that radiation therapy combined with drugs inducing abscopal effects are likely to become commonplace in the near future. Oka et al., reviewed various aspects of signal transduction and radiation in brain tumors. In particular, glioblastoma was noted as the most radioresistant brain tumor, requiring exacerbation of the effects of radiation using signal transduction therpay. The combination of radiation therapy and hyperthermia is very important, and many studies have examined this issue. Ohnishi et al., discussed radiation therapy combined with hyperthermia in terms of the guardian of the genome, the p53- pathway. Heavy ion radiation therapy shows a high-LET and a sharpened dose distribution. Heavy ion radiation therapy can be lethal to radioresistant cancer cells due to the unique mode of signal transduction. However, this unique signal transduction has remained unclear. Further studies are required in the field of signal transduction. Takahashi et al., reviewed this field. Finally, a new era of signal transduction in radiation oncology is beginning.

Recent advances in radiotherapy technology now enable us to deliver a booster dose of radiation to small target fractions in a malignant tumor. To fully exploit this technology in cancer therapy, it is necessary to clarify the location and dynamics of radioresistant cells in heterogeneous tumor microenvironments. Tumor cells in which the transcriptional activity of hypoxia-inducible factor 1 (HIF-1) is extremely high are recognized as potential targets, because HIF-1 has been strongly associated with tumor angiogenesis, invasion, metastasis, and poor prognosis after radiation therapy. In this review, we focus on recent advances in our understanding of [1] the molecular mechanism underlying the regulation of HIF-1's transcriptional activity, [2] the influence of radiation-induced alterations of the tumor microenvironment on intratumor HIF-1 activity, [3] HIF-1-mediated tumor radioresistance, and [4] an optimal treatment protocol for the combination of a HIF-1 inhibitor and radiation therapy.

Molecular target-based drugs have been expected as promising drugs in cancer treatment, and clinical trials using combined radiation therapy plus molecular target-based drugs have been performed to evaluate the feasibility and efficacy of this approach. In order to obtain maximum radiotherapeutic gain, a detailed understanding of the mechanism underlying the interaction between radiation and these drugs is indispensable. Preclinical data have already demonstrated synergistic enhancement of radiation-induced cell killing by several molecular target-based drugs, such as EGFR inhibitors. Among these, the effect of drugs targeted against receptor tyrosine kinase and its signal transduction pathways on the radiosensitivity has been intensively investigated. In this review, established and potential molecular targets for potentiation of radiation-induced cell killing are summarized, especially focusing on EGFR and its signal transduction pathways; also, clinical trials of combined radiation therapy plus molecular-target drug therapy are summarized.

Solid tumors require angiogenesis for their growth and to form metastatsis. Many new cancer therapies are directed against tumor vessels. Radiation therapy is one of the most widely used treatments for a wide variety of tumors, and is thought to act by directly targeting clongenes, as well as was induce apoptosis of endothelial cells, and reduce angiogenesis. Vascular targeting agents are aimed specifically at the existing tumor vasculature. Anti-angiogenic agents target angiogenesis or new growth of tumor vessels. Recent preclinical studies have suggested that radiotherapy in combination with antiangiogenic agents enhances the therapeutic ratio of ioninzing radiation alone. Targeting tumor vasculature has strong biological rationale in radiation therapy and preclinical studies consistently show an increase in radiationsensitization with combined treatment. This review article explores the complex interaction between radiation therapy and antiangiogenic agents. Furthermore we discuss the efficacy of combined radiotherapy and AT1-R antagonist (TCV-116) on tumor associated angiogenesis.

The abscopal effect is a potentially important phenomenon as a topic for basic research on tumor control and clinical oncology. Although it has been described in various malignancies, it is a rarely recognized clinical event. This phenomenon may arise mainly as a result of an activated immune system mediated through cytokines. Until recently, the abscopal effect referred to distant effects observed after local radiation therapy. However, some investigators argue that the term should now be used interchangeably with the “distant bystander effect.” From several aspects, including the distant bystander effects of other local therapies, we discuss the poorly researched but potentially intriguing abscopal effect that follows radiation therapy. Recently, experimentally-induced abscopal effects have been reported. Those reports show favorable inhibition of tumor growth not only at the irradiated site, but also at areas distant from the irradiated site using experimental protocols designed to induce reproducible abscopal effects. If consistent induction of the abscopal effect could be potentiated by intravenous administration of an immunostimulant, oncologists will seize upon the application of this effect for clinical use. Though the abscopal effect is still extremely controversial in view of the data now available, it can be hoped that translational research may offer a new concept for cancer therapy, namely, chemokine administration following local irradiation, leading to development of novel therapies for the treatment of advanced or metastatic cancer.

Primary central nervous system (CNS) tumors account for only 2% of all adult cancers and the annual incidence of primary malignant brain cancer was 7.3 per 100,000 person-years. Malignant gliomas are the most common primary CNS tumors in adults accounting for 78% of all primary malignant CNS tumors. Glial neoplasms represent about 40% of all primary CNS tumors, over three quarters being malignant. The median survival of patients with glioblastoma was 14.6 months after tereatment. Although recent basic and clinical research of malignant gliomas has improved, there is limitation of the outcome of the patients with malignant gliomas. Treatment strategy of tumor resection and radiotherapy for this tumor is still important and a recent advance in the use of concurrent chemo-radiation has improved survival in a large fraction of patients. New approaches using these signal transductional and gene researches are developing and may promise for further survival gains in the near future.

In order to achieve a high efficacy in cancer therapies which use radiation and/or hyperthermia, it is necessary to study and understand two important signal transduction pathways which can depress cell survival signals and simultaneously enhance cell death signals. Recent progress in molecular biology has provided information about these molecules and the associated mechanisms involved in their signaling and functioning. Targeting therapies have thus been examined to look for those which can affect genes capable of inducing a high efficiency in killing cancer cells after exposures to radiation and/or hyperthermia therapies. Target genes which function in cell survival signal transduction pathways, DNA repair, and protein repair are of primary interest. In contrast, apoptosis- and necrosis-inducing factors have an important role in leading to cell death in response to therapies. In this review, results from recent research efforts in Nara University are discussed.

High linear energy transfer (LET) radiotherapy has an excellent dose distribution and relative biological effectiveness (RBE). As the RBE of particle beams for therapy is important in terms of determining the dose prescription, we have to evaluate an accurate and reliable assessment method. Recently, several particle therapy facilities will open; however, the dose estimation is still not uniform. We have to confirm the quality assurance procedures among several facilities. Excellent local effect has been already achieved by treatment of monotherapy of carbon ion radiotherapy. The efficacy of carbon ion radiotherapy has been confirmed by taking advantage of the physical and biological properties. In addition, we have to gain the higher survival rate for locally advanced tumor with potentially metastasis. This paper reviews briefly background of carbon ion radiotherapy, biophysical characters, biological characters, and several radiobiological factors. The potential benefit of multimodality treatment will be also discussed to further improve therapeutic outcomes.