Augmenting the therapeutic window of radiotherapy: A perspective on molecularly targeted therapies and nanomaterials

Abstract

Radiation therapy is a cornerstone of modern cancer therapy alongside surgery, chemotherapy, and immunotherapy, with over half of all cancer patients receiving radiation therapy as part of their treatment regimen. Development of novel radiation sensitizers that can improve the therapeutic window of radiation therapy are sought after, particularly for tumors at an elevated risk of local and regional recurrence such as locally-advanced lung, head and neck, and gastrointestinal tumors. This review discusses clinical strategies to enhance radiotherapy efficacy and decrease toxicity, hence, increasing the overall therapeutic window. A focus is given to the molecular targets that have been identified and their associated mechanisms of action in enhancing radiotherapy. Examples include cell survival and proliferation signaling such as the EGFR and PI3K/AKT/mTOR pathways, DNA repair genes including PARP and ATM/ATR, angiogenic growth factors, epigenetic regulators, and immune checkpoint proteins. By manipulating various mechanisms of tumor resistance to ionizing radiation (IR), targeted therapies hold significant value to increase the therapeutic window of radiotherapy. Further, the use of novel nanoparticles to enhance radiotherapy is also reviewed, including nanoparticle delivery of chemotherapies, metallic (high-Z) nanoparticles, and nanoparticle delivery of targeted therapies - all of which may improve the therapeutic window of radiotherapy by enhancing the tumor response to IR or reducing normal tissue toxicity.

Keywords: Nanomedicine; Radiation sensitizer; Radiation therapy; Targeted therapy.

Fig. 1.

Multiscale tissue, cellular, and molecular mechanisms of tumor resistance to ionizing radiation (IR). (top right) Radiotherapy in the kilovoltage (KV) to megavoltage (MV) range is localized to tumors in various locations and surrounding tissues. (top left) Resistance to IR at the cellular level mediated by intracellular signaling pathways related to cellular survival and proliferation including the MAPK (RAS/RAF/MEK/ERK) and PI3K/AKT/mTORC pathways. Epigenetic regulation by HDAC and DNMT induces chromatin remodeling and altered gene expression leading to enhanced DNA repair and survival following IR. DNA repair genes including DNA-PKcs, PARP, ATM, and ATR can efficiently repair IR-induced single-strand and double-strand breaks. (center) Multiple factors in the tumor microenvironment can hinder the response to IR. Angiogenesis induced by VEGF secretion promotes tumor growth and irregular vasculature which can result in radiation-resistant hypoxic regions. Local immunosuppressive factors including ’exhausted’ effector T cells, regulatory T cells, and myeloid-derived suppressor cells (MDSCs) lead to ineffective priming of adaptive immunity following IR. Metallic nanoparticles combined with IR may modulate the tumor stroma to counteract these inhibitory mechanisms. (bottom right) Metallic nanoparticles present in the cytoplasm and nucleus combined with radiotherapy amplify both indirect and direct DNA damage through increased secondary electron production and generation of free radicals, leading to increased immunological cell death and release of tumor-associated neoantigens.

Fig. 2.

Increasing the therapeutic window of radiotherapy. At any given dose, there is a probability of tumor control or adverse event, the separation between tumor control and adverse event is the therapeutic window (or therapeutic ratio). (A) Narrow therapeutic window can be increased by sensitizing tumors to radiation via various mechanisms, shifting tumor control curve to the left. (B) Increased therapeutic window after treatment with sensitizing drug.

Fig. 3.

In vivo AuNCs-enhanced radiotherapy of tumor-bearing mice [81]. (A) c(RGDyC)-AuNCs accumulate in α_vβ₃ integrin-positive cancer cells and interact with incident radiation intensively, generating secondary radiation, and leading to radiation enhancement effect. Radiotherapy was performed at 4 h after i.v. injection of saline, c(RADyC)-AuNCs or c(RGDyC)-AuNCs. At 0.1 mmol Au kg⁻¹. (B) Tumor volume growth curves of the mice after various treatments (n = 3). (C) Ex vivo weight of the tumors at 14 days after the treatments. Error bars, mean ± SD; *P < 0.05 (two-tailed Student’s t-test). Reprinted with permission from Elsevier.

Fig. 4.

EGFR-targeted (cetuximab) mesoporous silica nanoparticle (NP) platform for PLK1 siRNA (siPLK1) delivery (C-siPLK1-NP) [86]. (A) C-siPLK1-NPs bind to EGFR receptors and are internalized, resulting in the loss of EGFR and phosphorylated EGFR, which can normally reach the nucleus to repair DNA. This reduces the cell’s ability to repair the damage caused by radiation. Simultaneously, siPLK1 on the nanoparticles is released in the cytosol and incorporated in the RNA induced silencing complex (RISC) to mediate PLK1 mRNA cleavage, which reduces PLK1 protein expression and arrests the cells in G2/M where they are most sensitive to radiation damage. Therefore, the platform serves a dual role (by targeting PLK1 and EGFR) to sensitize NSCLC cells to radiation. (B) A549 cells were treated with C-siSCR-NP or C-siPLK1-NP (50 nM as siRNA) for 72 hr followed by 2–6 Gy irradiation and re-plated for clonogenic survival assay. (C and D) 5 million A549 tumor cells were inoculated in both flanks of SCID mice. Treatments (0.3 nmol siRNA per tumor, once a week) and radiation (2 Gy to the left tumor only; 72 hr post treatments with nanoparticles) were administered for 6 weeks (n = 7). Growth of (C) non-irradiated tumors and (D) irradiated tumors. Data presented as mean ± SEM; **P < 0.01, ***P < 0.001, ****P < 0.0001. Reprinted with permission from Elsevier.