**Table 2.**

*Sarcoma clinical trials of PARP inhibitors.*

#### *DNA Repair Defects in Sarcomas DOI: http://dx.doi.org/10.5772/intechopen.94881*

*DNA - Damages and Repair Mechanisms*

types of cancers [15, 57–60].

*2.2.1 ERCC1*

possible treatment approach for sarcoma patients.

**2.2 Nucleotide excision repair (NER) pathway**

completed clinical trials of PARP inhibitors in sarcoma compared to other tumors hinders us from making a definite conclusion (**Table 2**). Future preclinical and clinical studies will shed more lights on the effectiveness of PARP inhibition as a

NER is a DDR pathway responsible for repairing bulky DNA lesions induced by ultraviolet irradiation, carcinogens, and some chemotherapeutic agents such as cisplatin [57]. The involvement of NER pathway in DNA damage induced by chemotherapeutic drugs attracted researchers to investigate the association of NER activity with the response to these cytotoxic agents in various cancers. Although there are some controversies regarding the role of NER pathway in cancer, some studies showed direct correlations between NER activity and increased response to chemotherapy [15, 57]. Recent efforts in whole-genome sequencing and data analysis of The Cancer Genome Atlas have led to a better understanding of the roles of the molecules involved in this pathway and introduced NER genes as prognostic biomarkers of response to various DNA damaging chemotherapeutic in different

ERCC1 is the key component of NER pathway that has been investigated in a large number of studies due to its prognostic properties in cancer treatment [61–63]. The association between the expression of ERCC1 and response to trabectedin in STS was investigated in a recent translational study designed by Moura et al. [64]. Expression levels were evaluated using qRT-PCR in 66 patients with advanced STS who were treated with trabectedin. The results showed that the expression level of ERCC1 is correlated with patients' progression-free survival [PFS (the length of time during and after treatment that the disease does not get worse)] and overall survival. Patients who had higher expression levels of ERCC1 showed better responses to the trabectedin and had longer PFS rates [64]. Similarly, ERCC1 expression has reported to be associated with treatment response in other sarcomas such as osteosarcoma and leiomyosarcoma, highlighting the importance of this key NER protein as a predictable biomarker in sarcoma [65, 66]. Polymorphism of NER genes and the relation of different alleles with the treatment response has also been investigated in osteosarcoma, indicating the association of some polymorphisms with a higher risk of osteosarcoma development [67]. A study conducted by Obiedat et al., investigated the relationship between polymorphisms of ERCC1 and ERCC2 and response to cisplatin-based chemotherapy and clinical outcomes in osteosarcoma patients [68]. They analyzed the association between ERCC1

**Compound Phase Cancer type and trial details Clinical trail identifier**

(including Ewing sarcoma)

NCT01583543

NCT01286987

NCT00687687

Olaparib II Adult participants with recurrent/metastatic Ewing sarcoma

Iniparib II Advanced, persistent, or recurrent uterine carcinosarcoma

Talazoparib I Advanced or recurrent solid tumors

**148**

**Table 2.**

*Sarcoma clinical trials of PARP inhibitors.*

(C118T (rs11615) and C8092A (rs3212986)) and ERCC2 (A751C (rs171140) and G312A (rs1799793)) polymorphisms and clinical parameters including event-free survival (EFS) (the length of time after treatment that a patient lives without any complications or event that the treatment intended to prevent or delay) rates in 44 patients with osteosarcoma who were treated with cisplatin-based neoadjuvant chemotherapy [68]. The findings illustrated that there is a significant positive correlation between ERCC1 C8092 A genotypes and median EFS rate. In other words, the patients who carried allele C (CC & CA) had longer EFS rates than patients with AA genotype, highlighting the importance of ERCC1 polymorphism in osteosarcoma [68]. Taken together, these studies suggested that ERCC1 could be considered as a reliable predictive factor of the effectiveness of some DNA-damaging chemotherapeutic drugs in sarcoma patients, and different polymorphisms could be used as prognostic biomarkers for designing the best treatment strategy.
