ANTI-TUMOUR TREATMENTMarkers involved in resistance to cytotoxics and targeted therapeutics in pancreatic cancer
Introduction
Pancreatic cancer retains a poor prognosis among the gastrointestinal cancer, with a 5-year overall survival (OS) of less than 5%. Recently, a large population-based study from the California Cancer Registry involving a total of 10,612 patients with pancreatic adenocarcinoma selected reported a median survival of 3.5 months for patients who had no surgical resection and of 13.3 months for those who underwent initial surgery.1 The poor survival associated with pancreatic cancer stems in part from the advanced stage at diagnosis for the majority of cases. Therefore, pancreatic adenocarcinoma still represents a therapeutic challenge in oncology.
Chemotherapy is the only treatment option in metastatic pancreatic cancer, and has been recently validated as the standard treatment in the adjuvant setting, as well as in locally advanced disease, in which situations (chemo)radiotherapy is no longer a standard treatment. Chemotherapeutic agents that are widely used in pancreatic cancer mainly include DNA-damaging agents, such as fluorouracil, oxaliplatin and gemcitabine. Ten years ago, Burris et al. showed in the palliative setting that gemcitabine was more effective than fluorouracil in improving disease-related symptoms and offered a slight but significant improvement in survival.2 Since then, many novel therapies were tested, including targeted therapies. Among them, only erlotinib that targets the epidermal growth factor receptor (EGFR) has been shown to improve survival used in combination with gemcitabine compared to gemcitabine alone.3 Nevertheless, it remains challenging to predict which patient will benefit from treatment and which one will suffer from drug toxicity. The clinical response rate to gemcitabine alone or in combination remains modest, mainly due to the intrinsic chemoresistance of pancreatic cancer cells. Investigating mechanisms mediating chemoresistance is therefore of clinical interest in drug development of new agents.4 In this paper, we aimed reviewing markers of resistance to cytotoxic agents and to molecular targeted therapies that may further help selecting patients who are more likely to benefit from these treatments and give a new direction for personalized treatment.
Section snippets
DNA-damaging agents
Our genome is vulnerable to an outfit of DNA-damaging agents, of both endogenous and environmental origin. Counteracting potentially cytotoxic and mutagenic accidents require constant excision and replacement of damaged nucleotide residues. Failures in DNA repair enzymes or in normal apoptosis pathways contribute to carcinogenesis by allowing accumulation of gene mutations, genetic instability and transgression of cell cycle checkpoints that would normally induce programmed cell death.
Perspectives
Despite technological advances, innovative treatments, and significant discoveries, treatment of pancreatic cancer remains a challenge. Chemotherapy is purely palliative with minimal impact on survival. Drug efficacy is limited because of many different unrelated mechanisms, including abnormal membrane receptor transport, inefficient metabolic drug conversion or increased metabolite inactivation, enhanced DNA repair and alterations in the apoptotic pathways. Moreover, the role of
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Apoptotic activity and antitumor efficacy of PEGylated TNF-related apoptosis-inducing ligand (TRAIL) in a Mia Paca-2 cell-xenografted mouse model
2014, Biomedicine and PharmacotherapyCitation Excerpt :This cancer is so deadly that patients with locally advanced tumors have a median survival of only 6–10 months, and this is reduced to 3–6 months for patients with metastatic tumors [4]. Furthermore, the usages of conventional chemotherapeutics, such as, fluorouracil, gemcitabine, and cisplatin, and radiotherapy have not resulted in any extension of survival due to the insensitivity of pancreatic cancer to these treatments [2,5]. Accordingly, new therapeutic agents are required for the treatment of pancreatic cancer.