GBM radiosensitizers: dead in the water…or just the beginning?

Abstract

Abstract:The finding that most GBMs recur either near or within the primary site after radiotherapy has fueled great interest in the development of radiosensitizers to enhance local control. Unfortunately, decades of clinical trials testing a wide range of novel therapeutic approaches have failed to yield any clinically viable radiosensitizers (1). However, it is well-recognized that temozolomide chemotherapy is administered concurrently with radiotherapy specifically as a radiosensitizer. Furthermore, it can be argued that many of the previous radiosensitizing strategies, for GBM and many other tumor types were not backed by firm pre-clinical evidence supporting a synergistic or additive interaction (2). Another poorly understood variable is lack of blood-brain barrier penetration as potential limitation for treatment efficacy, as until recently most clinical trials did not assess the actual drug levels in GBM tumors. Finally, despite an understanding that DNA repair status was an important variable for radiotherapy treatment responses dating back to the 1970's, the actual DNA repair pathways and proteins were only fully elucidated in the last decade. Here, we present recent progress in the use of small molecule DNA damage response inhibitors as GBM radiosensitizers. In addition, we discuss the latest progress in targeting hypoxia and oxidative stress for GBM radiosensitization. Introduction. The finding that most GBMs recur either near or within the primary site after radiotherapy has fueled great interest in the development of radiosensitizers to enhance local control. Unfortunately, decades of clinical trials testing a wide range of novel therapeutic approaches have failed to yield any clinically viable radiosensitizers (1). However, it is well-recognized that temozolomide chemotherapy is administered concurrently with radiotherapy specifically as a radiosensitizer. Furthermore, it can be argued that many of the previous radiosensitizing strategies, for GBM and many other tumor types were not backed by firm pre-clinical evidence supporting a synergistic or additive interaction (2). Another poorly understood variable is lack of blood-brain barrier penetration as potential limitation for treatment efficacy, as until recently most clinical trials did not assess the actual drug levels in GBM tumors. Finally, despite an understanding that DNA repair status was an important variable for radiotherapy treatment responses dating back to the 1970's, the actual DNA repair pathways and proteins were only fully elucidated in the last decade. Here, we present recent progress in the use of small molecule DNA damage response inhibitors as GBM radiosensitizers. In addition, we discuss the latest progress in targeting hypoxia and oxidative stress for GBM radiosensitization. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation

Radiosensitizing high-Z metal nanoparticles for enhanced radiotherapy of glioblastoma multiforme

“…Since GBM is considered as a radioresistant tumor [3] and most of the recurrence occurs in the radiotherapy field [4], radiosensitization of the tumor is an important target to improve the outcome in patients with GBM. Therefore, multiple radiosensitizing strategies are actively under development, including PI3K pathway inhibitors [5], DNA repair inhibitors [6], hyperthermia [7], aldehyde dehydrogenase inhibitors [8], and high atomic number (high-Z) metal nanoparticles (NPs) [9].…”

N6-Isopentenyladenosine Enhances the Radiosensitivity of Glioblastoma Cells by Inhibiting the Homologous Recombination Repair Protein RAD51 Expression

“…However, most tumors recur at the primary site or in its proximity following radiotherapy, which prompted the search for new therapeutic strategies aimed at increasing tumor radiosensitivity enhancing the efficacy of RT. Most of these approaches focused on drugs able to inhibit the DNA repair process, such as TMZ itself, which acts as a radiosensitizer, inducing DNA damage that includes also highly toxic DNA double-strand breaks (DSBs), and delaying the resolution of phosphorylated histone H2AX (γH2AX) foci, through inhibition of DNA repair (4,5). N 6 isopentenyladenosine (iPA), a member of the cytokinin family, is a naturally modified nucleoside formed by an adenosine harboring an isopentenyl group at N-6 position.…”

The Role of 2-Oxoglutarate Dependent Dioxygenases in Gliomas and Glioblastomas: A Review of Epigenetic Reprogramming and Hypoxic Response

“…Carbogen was tested in combination with nicotinamide, which is believed to prevent transient cessations in blood flow, thus inhibiting the development of acute hypoxia ( 154 ). Drugs have been developed to improve oxygen delivery (eg trans sodium crocetinate, TSC) ( 155 ), to normalize the tumor vasculature (e.g., anti-VEGF bevacizumab) ( 156 ), or to reduce oxygen consumption rate via mitochondrial poisons (e.g., anti-parasitic drugs atovaquone, ivermectin, proguanil, mefloquine, and quinacrine) and tested in patients with GBM ( 157 ). Overall, the results of these clinical trials have been disappointing and none of the approaches have been adopted into clinical practice, and actual oxygen measurements were largely lacking.…”