Improving the Efficacy of Tumor Radiosensitization Through Combined Molecular Targeting

Abstract

Chemoradiation, either alone or in combination with surgery or induction chemotherapy, is the current standard of care for most locally advanced solid tumors. Though chemoradiation is usually performed at the maximum tolerated doses of both chemotherapy and radiation, current cure rates are not satisfactory for many tumor entities, since tumor heterogeneity and plasticity result in chemo-and radioresistance. Advances in the understanding of tumor biology, a rapidly growing number of molecular targeting agents and novel technologies enabling the in-depth characterization of individual tumors, have fuelled the hope of entering an era of precision oncology, where each tumor will be treated according to its individual characteristics and weaknesses. At present though, molecular targeting approaches in combination with radiotherapy or chemoradiation have not yet proven to be beneficial over standard chemoradiation treatment in the clinical setting. A promising approach to improve efficacy is the combined usage of two targeting agents in order to inhibit backup pathways or achieve a more complete pathway inhibition. Here we review preclinical attempts to utilize such dual targeting strategies for future tumor radiosensitization.

Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC Cells

“…Overall, our results point towards a mechanism for radiosensitization driven by the abrogation of the, in HPV-positive HNSCC cells extensive, G2 cell cycle arrest in combination with the induction of additional DNA damage in S/G2 through PARP inhibition. While differences may exist in detail, the described effectiveness in different entities and by application of various checkpoint inhibitors clearly point towards a very robust radiosensitization of proliferating tumor cells by this combinatorial approach ( 37 , 38 ). In contrast, normal fibroblasts, representing p53-proficient normal tissue cells, were only modestly affected in our study ( Figure 5D ), which indicates a fair degree of tumor specificity, especially given that many normal tissues do not or only slowly proliferate.…”

“…Apart from interfering with G2 arrest, the inhibition of Wee1, Chk1, or ATR can directly compromise the ability to perform HR (34)(35)(36) and the induction of replication stress, which is to a large extent caused by nucleotide shortage due to unrestrained CDK activity and enhanced origin firing (18), that may create an unfavorable environment for DNA repair in S phase. Given these potential S/ G2 phase-based mechanisms, it is easily imaginable that the combined inhibition of PARP and the S/G2 cell cycle checkpoints could be an especially effective treatment option for HPV-positive HNSCC cells, and its radiosensitizing effect has already been demonstrated in preclinical studies in a number of other cancer entities (37,38). Against this background, we tested the combined inhibition of PARP and the S/G2 cell cycle checkpoint in intrinsically DSB repair-compromised HPVpositive HNSCC cells using clinically relevant inhibitors, all of which are already being tested in combination with radiotherapy in clinical trials in HNSCC.…”

Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond

“…GBM is characterized by a high level of inherent radioresistance which is considered to derive from overexpression of DNA damage response (DDR) genes and basally increased DDR activity ( 6 , 8 , 9 , 45 , 46 ). In this context, the molecular chaperone HSP90 is of particular interest and represents a promising target for radiosensitization approaches, since several key regulators of the DDR are known to crucially depend on HSP90 folding assistance ( 70 – 75 ). However, in single-agent settings administration of HSP90 inhibitors was frequently associated with side effects of relevant severity, including gastrointestinal toxicity and hepatoxicity, because the concentrations needed to achieve anti-tumor effects—despite the relative selectivity for cancer versus normal cells—were rather high, and the employed substances exhibited suboptimal toxicity profiles and poor pharmacokinetic features ( 76 ).…”

miR‐200a/b/‐429 downregulation is a candidate biomarker of tumor radioresistance and independent of hypoxia in locally advanced cervical cancer

“…Successful establishment of a test would help to select patients for clinical trials on strategies to overcome tumor resistance, and to exclude patients with no expected benefit. Several exciting strategies are upcoming, like combination therapy with radiation and targeted radiosensitizers, including inhibitors of the PI3K‐AKT pathway and of cell–matrix interactions [ 57 ], or escalation of the radiation dose within normal‐tissue tolerance by proton therapy [ 58 ].…”