Improving radiotherapy in cancer treatment: Promises and challenges

Abstract

Effective radiotherapy for cancer has relied on the promise of maximally eradicating tumor cells while minimally killing normal cells. Technological advancement has provided state-of-the-art instrumentation that enables delivery of radiotherapy with great precision to tumor lesions with substantial reduced injury to normal tissues. Moreover, better understanding of radiobiology, particularly the mechanisms of radiation sensitivity and resistance in tumor lesions and toxicity in normal tissues, has improved the treatment efficacy of radiotherapy. Previous mechanism-based studies have identified many cellular targets that can affect radiation sensitivity, notably reactive oxygen species, DNA-damaging response signals, and tumor microenvironments. Several radiation sensitizers and protectors have been developed and clinically evaluated; however, many of these results are inconclusive, indicating that improvement remains needed. In this era of personalized medicine in which patients' genetic variations, transcriptome and proteomics, tumor metabolism and microenvironment, and tumor immunity are available. These new developments have provided opportunity for new target discovery. Several radiotherapy sensitivity-associated "gene signatures" have been reported although clinical validations are needed. Recently, several immune modifiers have been shown to associate with improved radiotherapy in preclinical models and in early clinical trials. Combination of radiotherapy and immunocheckpoint blockade has shown promising results especially in targeting metastatic tumors through abscopal response. In this article, we succinctly review recent advancements in the areas of mechanism-driven targets and exploitation of new targets from current radio-oncogenomic and radiation-immunotherapeutic approaches that bear clinical implications for improving the treatment efficacy of radiotherapy.

Keywords: DNA damage response; cancer genomics; hypoxia; immune check points; radiotherapy.

Figure 1. Schematic diagram showing the interrelationships among the four pillars of current cancer therapy, i.e., cyto-reductive surgery, chemotherapy, radiotherapy, and immunotherapy

Cyto-reductive surgery is used to debulk tumor mass for subsequent three other treatment types. Radiotherapy is used in combination with many other therapies as indicated in the overlapping areas.

Figure 2. Multiple features of radiation-induced cellular responses in cancer cells

Radiation induces radiolysis which “splits” H₂0 into radicals. This can occur throughout the cells, but for simplicity, only inside the nucleus is indicated. Radiation induces mitochondrial leakage of electrons which interact with O₂ to generate ROS. ROS can travel into nucleus to cause DNA damage and induce oxidative stress. Other cellular responses include immune modulators, checkpoint, cytokines, inflammation, and DNA damage responses, released tumor antigens and danger signals such as HMGB1 and calreticulin as described in the text.

Figure 3. Radiation-induced immune response in cancer therapy

Radiation induces release of tumor antigens which are captured and processed by antigen-presenting cells (APC) to activate cytotoxic T lymphocytes (CTL). CTL are recruited to attack tumor cells or metastatic cells to elicit abscopal effect. Radiation also upregulates PD-L1 and combination with anti-PD-L1 therapy enhances MHC and Fas expression on tumor cells and increases T-cell-mediated cytotoxicity including releases of cytokines and DAMP to elicit killing of primary and metastatic tumor cells.