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Molecular Targeted Therapy
Rafael Rosell, Miquel Taron, Teresa Moran on behalf of the Spanish Lung Cancer Group
Catalan Institute of Oncology, Barcelona , Spain
The elucidation of the signal-transduction network that drives neoplastic transformation has led to rationally designed cancer therapeutics that target specific molecular events. The main goal of these novel targeted therapies is to significantly reduce our reliance on DNA-directed chemotherapeutic agents with low therapeutic indices as the mainstay of cancer treatment. However, targeted cancer drugs, regardless of their mechanism of action, frequently face similar hurdles to those that challenge traditional cytotoxic agents: insufficient efficacy, development of resistance and unacceptable safety profiles continue to hamper clinical progress.
Reports of a three-to-eight-week improvement in median survival in previously treated stage IV non-small-cell lung cancer (NSCLC) patients with targeted therapy or combined chemo- plus targeted therapy have been met with relatively enthusiastic response in the scientific community. However, we have not yet been able to inspire this same enthusiasm in patients and their families. In fact, the classic approach of pharmaceutically oriented phase III trials has so far yielded meager benefit in clinical outcome, and until recently, the influence of histological subtype, age and smoking status on outcome has not been taken into consideration. Moreover, no predictive markers of response or survival are being used in clinical practice or validated in prospective trials.
The role of meta-analyses in deciding which chemotherapy combinations will be more useful can no longer be based on simple clinical parameters. The tumor and host genome needs to be included along with the clinical characteristics of age, smoking history (particularly in the field of lung cancer), histology, ethnicity, metastatic sites and performance status. Overexpression of ERCC1 and other nucleotide excision repair (NER) genes is associated with repair of cisplatin-induced DNA damage and clinical resistance to cisplatin. Patients with low DNA repair capacity (low expression of NER genes) could respond significantly better to DNA-directed agents, such as cisplatin, used alone rather than in combination with antimicrotubules. Growing evidence indicates that the expression levels of NER genes have an opposite effect on cisplatin and antimicrotubules, as shown in the following figure.
We will center our review on four of these predictive markers that can be used to customize first-line treatment of stage IV NSCLC: XRCC3 241 MetMet polymorphism predicts dramatically better survival with gemcitabine/cisplatin; 14-3-3? serum DNA methylation is also associated with significantly improved survival with gemcitabine/cisplatin; serum DNA methylation of checkpoint with forkhead and ring domains (CHFR) confers a survival advantage with docetaxel/cisplatin that can be as high as threefold in specific subsets of patients; and in patients harboring EGFR mutations, oral reversible EGFR inhibitors can prolong survival two- or threefold in comparison with chemotherapy. In addition, novel mechanisms of resistance related to cisplatin-induced ERCC1 expression will be explained, as well as the role of FOXO3a in conferring sensitivity to paclitaxel and potential resistance to the chronic administration of erlotinib in patients with EGFR mutations, as shown in the figure below.
A wealth of data indicates that the ER signaling pathway plays a central role in lung cancer progression. We speculate that resistance to chronic administration of erlotinib is induced by increasing estrogen receptor (ER) signaling mediated by the activation of FOXO3a. This is a paradigm of targeted therapies, since if not more than one pathway is blocked, the potential targeted cancer drug can induce tumor growth. For example, FOXO3a is downstream of Akt; thus, at the time that erlotinib inhibits Akt, FOXO3a is released, which in turn stimulates the ER signaling pathway. Several studies have suggested that fulvestrant decreases the expression of estrogen-regulated genes (cyclin D1) and blocks estrogen-stimulated pathways.
In conclusion, simple molecular assays using genomic or cDNA from tumor or serum DNA can contribute substantially to the customization of cancer treatment. These techniques warrant being tested in clinical trials based on genetic markers.
Molecular Targeted Therapy
Rafael Rosell, Miquel Taron, Teresa Moran on behalf of the Spanish Lung Cancer Group
Catalan Institute of Oncology, Barcelona , Spain
The elucidation of the signal-transduction network that drives neoplastic transformation has led to rationally designed cancer therapeutics that target specific molecular events. The main goal of these novel targeted therapies is to significantly reduce our reliance on DNA-directed chemotherapeutic agents with low therapeutic indices as the mainstay of cancer treatment. However, targeted cancer drugs, regardless of their mechanism of action, frequently face similar hurdles to those that challenge traditional cytotoxic agents: insufficient efficacy, development of resistance and unacceptable safety profiles continue to hamper clinical progress.
Reports of a three-to-eight-week improvement in median survival in previously treated stage IV non-small-cell lung cancer (NSCLC) patients with targeted therapy or combined chemo- plus targeted therapy have been met with relatively enthusiastic response in the scientific community. However, we have not yet been able to inspire this same enthusiasm in patients and their families. In fact, the classic approach of pharmaceutically oriented phase III trials has so far yielded meager benefit in clinical outcome, and until recently, the influence of histological subtype, age and smoking status on outcome has not been taken into consideration. Moreover, no predictive markers of response or survival are being used in clinical practice or validated in prospective trials.
The role of meta-analyses in deciding which chemotherapy combinations will be more useful can no longer be based on simple clinical parameters. The tumor and host genome needs to be included along with the clinical characteristics of age, smoking history (particularly in the field of lung cancer), histology, ethnicity, metastatic sites and performance status. Overexpression of ERCC1 and other nucleotide excision repair (NER) genes is associated with repair of cisplatin-induced DNA damage and clinical resistance to cisplatin. Patients with low DNA repair capacity (low expression of NER genes) could respond significantly better to DNA-directed agents, such as cisplatin, used alone rather than in combination with antimicrotubules. Growing evidence indicates that the expression levels of NER genes have an opposite effect on cisplatin and antimicrotubules, as shown in the following figure.
We will center our review on four of these predictive markers that can be used to customize first-line treatment of stage IV NSCLC: XRCC3 241 MetMet polymorphism predicts dramatically better survival with gemcitabine/cisplatin; 14-3-3? serum DNA methylation is also associated with significantly improved survival with gemcitabine/cisplatin; serum DNA methylation of checkpoint with forkhead and ring domains (CHFR) confers a survival advantage with docetaxel/cisplatin that can be as high as threefold in specific subsets of patients; and in patients harboring EGFR mutations, oral reversible EGFR inhibitors can prolong survival two- or threefold in comparison with chemotherapy. In addition, novel mechanisms of resistance related to cisplatin-induced ERCC1 expression will be explained, as well as the role of FOXO3a in conferring sensitivity to paclitaxel and potential resistance to the chronic administration of erlotinib in patients with EGFR mutations, as shown in the figure below.
A wealth of data indicates that the ER signaling pathway plays a central role in lung cancer progression. We speculate that resistance to chronic administration of erlotinib is induced by increasing estrogen receptor (ER) signaling mediated by the activation of FOXO3a. This is a paradigm of targeted therapies, since if not more than one pathway is blocked, the potential targeted cancer drug can induce tumor growth. For example, FOXO3a is downstream of Akt; thus, at the time that erlotinib inhibits Akt, FOXO3a is released, which in turn stimulates the ER signaling pathway. Several studies have suggested that fulvestrant decreases the expression of estrogen-regulated genes (cyclin D1) and blocks estrogen-stimulated pathways.
In conclusion, simple molecular assays using genomic or cDNA from tumor or serum DNA can contribute substantially to the customization of cancer treatment. These techniques warrant being tested in clinical trials based on genetic markers.
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