Data summarized from Hegi et al. 2005.
1. Introduction
The current standard of care for the treatment of glioblastoma multiforme (GBM) includes the surgical resection of the tumor in combination with ionizing radiation and the DNA alkylating agent Temozolomide (TMZ). The introduction of TMZ into clinical use has improved patient outcomes [1, 2]. Stupp et al. showed that the addition of TMZ to radiotherapy lengthened the median survival in patients with GBM from 12.1 months to 14.6 months [2]. TMZ exerts an effect upon GBM cells by preferentially damaging the DNA of the rapidly growing tumor cells, ultimately resulting in their death. While the combined use of TMZ and ionizing radiation can increase overall survival, the long-term survival for GBM patients is still poor [3]. What has recently become apparent is that GBM tumors can develop several forms of resistance to the DNA damage-induced cell death caused by radiotherapy and TMZ treatments. In this way, GBM tumors can survive and generate new tumors when they should otherwise not survive. This review will discuss mechanisms of resistance to DNA damage-induced cell death in GBM tumors and will outline some DNA repair functions that can be targeted to potentially improve treatment outcomes.
Maintaining the integrity of the genome is essential for the health and survival of multicellular organisms. The continuous exposure of cellular DNA to potentially harmful environmental and internal insults necessitates redundant and overlapping DNA repair mechanisms. Several excellent reviews have extensively described the wide variety of DNA repair mechanisms used by cells in response to DNA damage [4-6]. Damage to DNA can result in cell cycle arrest to allow for DNA repair mechanisms to occur, or can stall replication forks during DNA replication causing senescence. Proliferating cells, like those in GBM tumors, are affected to a greater extent than quiescent cells following DNA damage, causing the cells to arrest at particular points within the cell cycle [7]. However, cancers such as GBMs are quite adept at repairing the DNA damage or over-riding the cell cycle checkpoints to allow cell proliferation to continue despite the damage.
GBM tumors respond to DNA damage induced by ionizing radiation and TMZ treatment through increased expression of DNA repair enzymes, including the proteins O-6-methylguanine-DNA methyltransferase (MGMT) and Poly (ADP-ribose) Polymerase 1 (PARP-1) [8]. Furthermore, tumors are able to eliminate chemotherapeutic compounds from cells through the increased expression and activity of ABC transporters, specifically ABC-1 [9]. Compounding this issue is the growing body of evidence indicating that a small population of slow-growing cancer stem cells reside within the GBM tumor (also called glioma-initiating cells) and are responsible for the subsequent recurrence of GBM tumors [10, 11]. Glioma initiating cells are particularly resistant to standard treatments, in part through the elevated expression of enzymes responsible for repair of DNA damage [12, 13]. Therefore, successful destruction of GBM tumors may require a combined approach utilizing standard treatments in combination with inhibition of DNA repair pathways. This approach to cancer treatment, called synthetic lethality, preferentially affects cancer cells by inhibiting several molecular processes necessary for tumor survival without significantly affecting normal tissues [14, 15]. This treatment approach utilizing the DNA repair enzymes MGMT and PARP-1 have been a focus of the research conducted at the Upper Michigan Brain Tumor Center, and this review will be supplemented with findings from our laboratory.
2. O-6-methylguanine-DNA methyltransferase
The transcription factor Sp1 functions in transcriptional regulation of the MGMT gene, and CpG methylation within the promoter sequence affects chromatin structure to affect Sp1 access to the promoter site [23]. Methylation of specific CpG clusters in the promoter is correlated with MGMT gene silencing [24]. However, the overall amount, location, and homogeneity of MGMT promoter methylation is variable in GBM [25]. Dunn et al. investigated 109 newly diagnosed GBMs, and found that 58 tumors had an elevated methylation status compared to non-neoplastic brain tissue (≥ 9% methylated). Furthermore, 19 of the tumors examined with a methylation status greater than 35% correlated with the highest 2-year survival rates [26]. It is not fully understood what determines MGMT promoter methylation levels, but recent evidence indicates that p53 may play a role. Using human lung cancer cells, Lai et al. showed that the knockdown of p53 increases MGMT promoter methylation in wild type p53 lung cancer cells [27] while Srivenugopal et al. reported that inducible p53 expression suppresses MGMT levels in a p53-null lung cancer cell line [28]. In contrast, published work by Wang et al. suggests that hypermethylation of CpG islands within the MGMT gene does not strictly correlate with reduced MGMT protein expression [29]. A number of studies have highlighted the variability in MGMT promoter methylation and MGMT gene expression levels indicating both a variability in MGMT activity within and between tumors [30]. More recently, Kanemoto et al. performed deep sequencing analyses of the entire MGMT promoter to develop a diagnostic assay for progression-free survival of GBM patients based upon hypermethylation of CpG islands. Despite the evidence that variability in MGMT promoter methylation does exist, the data confirm the general hypothesis that hypermethylation of the MGMT promoter does correlate with reduced MGMT enzyme activity [31].
The MGMT enzyme functions as both a transferase and acceptor of alkyl-groups. MGMT activity does not require cofactors or other enzymes, rapidly removes DNA adducts from the O6 position of guanine, and transfers them to an internal cysteine residue (Cys145) within the enzyme active site [32]. This reaction is stoichiometric and once the MGMT protein has been alkylated, it is inactivated and undergoes ubiquitin-mediated degradation [33].
Most alkylating agents used to therapeutically induce cell death target the O6-methylguanine adduct. While MGMT primarily repairs O6-methylguanine DNA adducts, it has the ability to repair adducts of greater size (i.e. O6-ethylguanine) as well as the minor alkylation product O4-methylthymine. MGMT-mediated repair pathways correct the damage caused by alkylating chemotherapeutic agents utilized in the treatment of gliomas, melanomas, carcinoid tumors, and lymphomas, such as carmustine, temozolomide, streptozotocin, procarbazine, and dacarbazine [32].
3. Inhibition of O-6-methylguanine-DNA methyltransferase
The key mechanism of resistance to alkylating agents in GBM is the presence of MGMT enzyme, and most human tumors exhibit high levels of MGMT expression and activity. As mentioned previously, elevated expression of MGMT is inversely correlated with survival [34, 40, 41]. Thus, suppression of MGMT activity could render cells more sensitive to alkylating agents, augmenting cytotoxicity.
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Patients | 46 | 46 |
Median progression free survival (months) | 5.9 | 10.3 |
Median overall survival (months) | 15.3 | 21.7 |
2 year survival (%) | 22.7 | 46 |
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Patients | 54 | 60 |
Median progression free survival (months) | 4.4 | 5.3 |
Median overall survival (months) | 11.8 | 12.7 |
2 year survival (%) | 0 | 13.8 |
In 2008, our lab used RNA interference
Although it is possible for siRNA to function efficiently using cells grown in culture, siRNA application within organisms is difficult. These siRNA macromolecules do not cross cell membranes easily and would make crossing the blood brain barrier problematic. Thus, novel delivery systems for siRNA are being investigated. One successful nanoparticle system being developed is the LipoTrust EX Oligo liposome delivery system [13]. Kato et al. reported that liposome delivery of siRNA to downregulate MGMT was effective in sensitizing GBM to TMZ in both
It is worth noting that individualized therapy based solely on MGMT promoter methylation alone may not always be advantageous. MGMT promoter methylation may not correlate with TMZ sensitivity and survival in some populations [73]. Although it has been reported that the level of MGMT mRNA and protein expression is correlated with promoter methylation status [74-76], this correlation does not hold true in all cases [73, 76-80]. Reports of GBMs with unmethylated MGMT promoter regions and low MGMT mRNA expression as well as GBMs with methylated MGMT promoter regions expressing high MGMT mRNA levels suggest that methylation-independent pathways may alter MGMT mRNA levels [74, 76, 77, 81]. Evidence suggests that mechanisms of post-transcriptional regulation alter MGMT protein expression since protein analysis of MGMT does not correlate with mRNA [76]. Recent data suggest that miRNA regulation of MGMT may explain these discrepancies and miRNAs are currently being investigated as therapeutic targets [70, 82, 83]. Because MGMT expression appears be predictive of progression free and overall survival [74], adequate assessment of tumors may need to include MGMT mRNA and/or protein expression.
4. Poly (ADP-ribose) polymerase 1
5. Inhibition of poly (ADP-ribose) polymerase 1
Cancer treatments utilizing ionizing radiation and DNA alkylating agents damage DNA, which if not repaired causes cell death. Inhibition of PARP-1 contributes to the sensitization of tumor cells to these treatments and is the basis for multiple preclinical and clinical studies with PARP inhibitors in combination with classical therapies [92].
6. Conclusions
Surgical resection, radiation and use of TMZ is currently the standard of care for GBM patients. The alkylating agent, TMZ, induces lesions at the N7 and O6 positions of guanine and N3 position of adenine. However, many of these tumors express MGMT which promptly corrects the most cytotoxic lesion, the O6-methylguanine adduct. Tumors expressing MGMT are, therefore, inherently resistant to TMZ. MGMT inhibition improves the response to TMZ, but MGMT inhibition as standard therapy is still in development. O6BG, although too toxic to give systemically, may find itself useful for future therapy if delivery to the central nervous system can be improved. Gene therapy, with the enhancement of the delivery of synthetic nucleotides like the LipoTrust and oncolytic viruses, may become the standard of care in the future. There are several other molecules targeting pathways that influence MGMT and many more will surely emerge.
The majority (~80%) of these TMZ-induced DNA alkyl adducts, N7-methylguanine and N3-methyladenine, are repaired by the BER system. After the mismatched base has been removed, PARP-1 plays a role in repairing DNA breaks by binding and recruiting other BER proteins. Because of its role in the BER system, PARP inhibitors also improve the response to TMZ. While the results from numerous clinical trials have been disappointing due to systemic toxicities, new inhibitors may improve outcomes.
Modulation of TMZ resistance through the MGMT and BER pathways is clinically viable. New combinations of existing strategies may prove to further compliment TMZ and augment its effectiveness. Although several approaches have been used to modulate PARP and MGMT pathways, molecular screening should be used to identify targets with the greatest therapeutic potential. For example, pre-treatment assessment for MGMT and EGFR expression would provide information regarding the susceptibility to TMZ and PARP inhibitors, respectively. With the growing understanding of the pathways involved with DNA repair, the design of novel strategies or the use of combinations of existing therapies may improve GBM outcome.
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