PL02-04

Today, cisplatin (and its analogs, carboplatin and oxaliplatin) remain the scaffolding of chemotherapy in many solid tumors including lung, head and neck, bladder, ovarian, and colon carcinomas. After several decades of clinical trials, a therapeutic plateau has been reached using standard chemotherapy in most solid tumors. A re-evaluation of strategies to improve clinical outcomes is needed.
 The DNA repair mechanism is one of the crucial molecular pathways potentially involved in resistance to platin-based chemotherapy. Alkylating agents such as platinum components form DNA-adducts that induce DNA lesions that are directly responsible for the cytotoxicity. The excision repair cross-complementation group 1 (ERCC1) is a highly conserved nuclease in mammals that performs the excision of these cytotoxic DNA-adducts during a process called Nucleotide Excision Repair (NER). The ERCC1 gene is one of the 16 genes that encode the proteins of the NER complex and together with its XP group F (XPF) partners, performs an essential late step in the NER process responsible for the 5-prime incision. Many cancer cells have the ability to resist against the effects of chemotherapy through increased capacity of DNA-repair, in particular through the activation of the NER pathway due to high levels of ERCC1. NER functions by a "cut-and-paste" mechanism in which cisplatin damage recognition, local opening of the DNA helix around the lesion, damage lesion and gap-filling occur in successive steps.
 Numerous studies have reported the importance of ERCC1 expression in the repair mechanism of cisplatin-induced DNA adducts in human ovarian cancer cells, in primary gastric tumors, in colorectal and esophageal cancer. ERCC1 mRNA ? expression has been negatively associated with response to cisplatin or oxaliplatin chemotherapy in gastric and colon cancer. High tumor tissue levels of ERCC1 mRNA in ovarian and gastric cancer patients have been associated with cisplatin resistance. Recently, ERCC1 protein expression was studied in resected NSCLC tumors from 761 patients from the International Adjuvant Lung Trial (IALT). Patients with ERCC1 negative tumors who were randomized to chemotherapy had significantly prolonged survival compared to those who were randomized to observation (test for interaction, P<0.009; HR=0.65; 95% CI [0.50-0.86]). In contrast, there was no survival difference between treated and none-treated patients among ERCC1 positive patients (HR=1.14; 95% CI [0.84-1.55]). It was concluded that NSCLC patients with completely resected ERCC1 negative tumors seem to be stronger candidates for adjuvant cisplatin-based chemotherapy than those with resected ERCC1 positive tumors.
 Based on these results, two areas of development can be envisioned. First, future platinum-based chemotherapy (or even radiotherapy) could be chosen according to pharmacogenomic criteria such as ERCC1 expression on tumor tissue. Second, pharmacological modulation of ERCC1 may allow increasing the efficacy of platinum-derivatives in ERCC1-positive tumors. Different approaches are currently being investigated to modulate ERCC1 expression or function. It may be possible to target protein-protein interaction within the NER machinery. In that regard ERCC1-XPF, ERCC1-XPA and ERCC1-DNA interactions are areas of investigation. Various compounds have been shown to decrease either ERCC1 protein levels or its mRNA levels, among them SU5416, lactacystin (a proteasome inhibitor), and interleukin-1 alpha. Detailed analysis of the molecular mechanism of such modulations is however lacking.
 Preclinical and clinical data clearly show that ERCC1 is a potential anti-cancer drug target. However pharmacological modulation of ERCC1 clearly presents major challenges for drug discovery. It might appear that the inhibition of ERCC1 combined with platinum use would lead to increased toxicity in normal tissues without a clear improvement of the therapeutic index.

AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics-- Oct 22-26, 2007; San Francisco, CA