Moving Forward in the Next Decade: Radiation Oncology Sciences for Patient-Centered Cancer Care.

In a time of rapid advances in science and technology, the opportunities for radiation oncology are undergoing transformational change. The linkage between and understanding of the physical dose and induced biological perturbations are opening entirely new areas of application. The ability to define anatomic extent of disease and the elucidation of the biology of metastases has brought a key role for radiation oncology for treating metastatic disease. That radiation can stimulate and suppress subpopulations of the immune response makes radiation a key participant in cancer immunotherapy. Targeted radiopharmaceutical therapy delivers radiation systemically with radionuclides and carrier molecules selected for their physical, chemical, and biochemical properties. Radiation oncology usage of "big data" and machine learning and artificial intelligence adds the opportunity to markedly change the workflow for clinical practice while physically targeting and adapting radiation fields in real time. Future precision targeting requires multidimensional understanding of the imaging, underlying biology, and anatomical relationship among tissues for radiation as spatial and temporal "focused biology." Other means of energy delivery are available as are agents that can be activated by radiation with increasing ability to target treatments. With broad applicability of radiation in cancer treatment, radiation therapy is a necessity for effective cancer care, opening a career path for global health serving the medically underserved in geographically isolated populations as a substantial societal contribution addressing health disparities. Understanding risk and mitigation of radiation injury make it an important discipline for and beyond cancer care including energy policy, space exploration, national security, and global partnerships.

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials.

There is an urgent need to improve reproducibility and translatability of preclinical data to fully exploit opportunities for molecular therapeutics involving radiation and radiochemotherapy. For in vitro research, the clonogenic assay remains the current state-of-the-art of preclinical assays, whereas newer moderate and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models. Elucidating effects on the cancer stem cells (CSC, and CSC-like) and developing biomarkers for defining targets and measuring responses are also important. In vivo studies are necessary to confirm in vitro findings, further define mechanism of action, and address immunomodulation and treatment-induced modification of the microenvironment. Newer in vivo models include genetically engineered and patient-derived xenograft mouse models and spontaneously occurring cancers in domesticated animals. Selection of appropriate endpoints is important for in vivo studies; for example, regrowth delay measures bulk tumor killing, whereas local tumor control assesses effects on CSCs. The reliability of individual assays requires standardization of procedures and cross-laboratory validation. Radiation modifiers must be tested as part of clinical standard of care, which includes radiochemotherapy for most tumors. Radiation models are compatible with but also differ from those used for drug screening. Furthermore, the mechanism of a drug as a chemotherapeutic agent may be different from its interaction with radiation and/or radiochemotherapy. This provides an opportunity to expand the use of molecular-targeted agents. Clin Cancer Res; 22(13); 3138-47. ©2016 AACR.

Role of tumor necrosis factor-alpha and TRAIL in high-dose radiation-induced bystander signaling in lung adenocarcinoma.

In the present study, ionizing radiation (IR)-induced bystander effects were investigated in two lung cancer cell lines. A549 cells were found to be more resistant to radiation-conditioned medium (RCM) obtained from A549 cells when compared with the H460 exposed to RCM procured from H460 cells. Significant release of tumor necrosis factor-alpha (TNF-alpha) was observed in A549 cells after IR/RCM exposure, and the survival was reversed with neutralizing antibody against TNF-alpha. In H460 cells, significant release of TNF-related apoptosis-inducing ligand (TRAIL), but not TNF-alpha, was observed in response to IR, RCM exposure, or RCM + 2Gy, and neutralizing antibody against TRAIL diminished clonogenic inhibition. Mechanistically, TNF-alpha present in RCM of A549 was found to mediate nuclear factor-kappaB (NF-kappaB) translocation to nucleus, whereas the soluble TRAIL present in RCM of H460 cells mobilized the nuclear translocation of PAR-4 (a proapoptotic protein). Analysis of IR-inducible early growth response-1 (EGR-1) function showed that EGR-1 was functional in A549 cells but not in H460 cells. A significant decrease in RCM-mediated apoptosis was observed in both A549 cells stably expressing small interfering RNA EGR-1 and EGR-1(-/-) mouse embryonic fibroblast cells. Thus, the high-dose IR-induced bystander responses in A549 may be dependent on the EGR-1 function and its target gene TNF-alpha. These findings show that the reduced bystander response in A549 cells is due to activation of NF-kappaB signaling by TNF-alpha, whereas enhanced response to IR-induced bystander signaling in H460 cells was due to release of TRAIL associated with nuclear translocation of PAR-4.

Rasagenthi lehyam (RL) a novel complementary and alternative medicine for prostate cancer.

PURPOSE: The use of complementary and alternative medicine (CAM) in cancer has been increasing. The therapeutic modalities which originated from India, viz., Ayurveda and Siddha, have phytotherapy as their fundamental basis and, therefore, produce few side effects. They are among the most ancient medicinal systems and are still being practiced in India and elsewhere, to cure cancer and other diseases. Many Siddha practitioners in the southern parts of India prescribe rasagenthi lehyam (RL) as a drug for cancer. RL contains 38 different botanicals, many of which have been shown to possess therapeutic efficacy, and 8 inorganic compounds, all prepared into a paste in a palm sugar and hen's egg base. The efficacy of RL in killing prostate cancer cells in vitro was investigated in this study to determine whether RL could be recommended as a CAM for prostate cancer. METHODS: In order to scientifically validate the anticancer activity of RL on prostate cancer, a methanolic extract of RL was serially extracted with four organic solvents, and the extracts were tested for clonogenic inhibition and induction of apoptosis in PC-3 prostate cancer cells, with and without irradiation. n-Hexane, ethyl acetate and chloroform extracts of RL effectively killed PC-3 cells. RESULTS: The IC(50) values of n-hexane, ethyl acetate and chloroform extracts of RL were 3.84 microg/ml, 3.68 microg/ml and 75 ng/ml, respectively. All three extracts induced apoptosis in PC-3 cells. Further, all the three extracts when combined with radiation, caused enhanced effect on killing of PC-3 cells. Among the three extracts, the chloroform extract showed the most significant radiation-sensitizing effect. CONCLUSION: RL, either in its original formulation prepared under strict quality control or its chloroform extract, could potentially be an alternative medicine for prostate cancer, and also a sensitizing agent in the context of radiation therapy for prostate cancer, as a complementary medicine. A more directed study could lead to the identification of the active principle(s) in the chloroform extract of RL for use in prostate cancer therapy.