Francisco Javier Ramos

Anti-epidermal growth factor receptor monoclonal antibodies in cancer treatment

Although the prognosis of cancer remains poor recent advances in the diagnostic methods, new approaches in surgical procedures and the development of new therapeutic agents have had a significant impact in the outcome of cancer patients. A better understanding of the molecular pathways that characterize cell growth, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. The epidermal growth factor receptor (EGFR) mediated signal transduction has been one of the most studied pathways in carcinogenesis. The phosphorylation of EGFR activates multiple biological processes including apoptosis, differentiation, cellular proliferation, motility, invasion, adhesion, DNA repair and survival. Several therapies have been developed to inactivate the EGFR pathway including monoclonal antibodies against the extracellular domain of EGFR. In this review, the authors examine the development of monoclonal antibodies against EGFR and the effects of this blockage in cell cycle, as well as the most important trials with these monoclonal antibodies in several tumor types.

Phase I Pharmacokinetic and Pharmacodynamic Study of the First-in-Class Spliceosome Inhibitor E7107 in Patients with Advanced Solid Tumors

Purpose: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of E7107 administered as 5-minute bolus infusions on days 1, 8, and 15 in a 28-day schedule. Experimental Design: Patients with solid tumors refractory to standard therapies or with no standard treatment available were enrolled. Dose levels of 0.6 to 4.5 mg/m2 were explored. Results: Forty patients [24M/16F, median age 61 years (45–79)] were enrolled. At 4.5 mg/m2, dose-limiting toxicity (DLT) consisted of grade 3 diarrhea, nausea, and vomiting and grade 4 diarrhea, respectively, in two patients. At 4.0 mg/m2, DLT (grade 3 nausea, vomiting, and abdominal cramps) was observed in one patient. Frequently occurring side effects were mainly gastrointestinal. After drug discontinuation at 4.0 mg/m2, one patient experienced reversible grade 4 blurred vision. The maximum tolerated dose (MTD) is 4.0 mg/m2. No complete or partial responses during treatment were observed; one patient at 4.0 mg/m2 had a confirmed partial response after drug discontinuation. Pharmacokinetic analysis revealed a large volume of distribution, high systemic clearance, and a plasma elimination half-life of 5.3 to 15.1 hours. Overall drug exposure increased in a dose-dependent manner. At the MTD, mRNA levels of selected target genes monitored in peripheral blood mononuclear cells showed a reversible 15- to 25-fold decrease, whereas unspliced pre-mRNA levels of DNAJB1 and EIF4A1 showed a reversible 10- to 25-fold increase. Conclusion: The MTD for E7107 using this schedule is 4.0 mg/m2. Pharmacokinetics is dose-dependent and reproducible within patients. Pharmacodynamic analysis revealed dose-dependent reversible inhibition of pre-mRNA processing of target genes, confirming proof-of-principle activity of E7107. Clin Cancer Res; 19(22); 6296–304. ©2013 AACR.

EGFR and KRAS in colorectal cancer

The epidermal growth factor receptor (EGFR) is recognized as an important player in colorectal cancer (CRC) initiation and progression. This membrane-bound receptor tyrosine kinase (RTK) has therefore become a key target of therapeutic strategies designed to treat metastatic CRC, in particular with monoclonal antibodies (mAbs) against the extracellular domain of the receptor. KRAS is an effector molecule responsible for signal transduction from ligand-bound EGFR to the nucleus. Activating mutations in KRAS are recognized as a strong predictor of resistance to EGFR-targeted mAbs. Routine testing of all patients with CRC for KRAS mutations is now recommended; only those harboring wild-type (WT) KRAS should be candidates for such therapies, thus improving outcomes, and minimizing unnecessary toxicity and cost. Even though the identification of the importance of KRAS status has marked a turning point in the treatment of metastatic CRC (mCRC), it is becoming apparent that other critical elements in the complex signaling pathways related to EGFR may also contribute vital information that will aid in treatment decisions and ultimately benefit patients.

Oxaliplatin-based chemotherapy in the management of colorectal cancer

Oxaliplatin is the only third-generation platinum derivative compound that has found a place in the routine treatment of colorectal cancer (CRC). The appearance of oxaliplatin, as well as irinotecan, in the CRC treatment armamentarium has offered new standards for adjuvant treatment and greater hopes in metastatic disease. Moreover, the combination of oxaliplatin-based chemotherapy with new targeted drugs has improved response rates and survival of these patients. Despite these new approaches, the prognosis of CRC remains poor and a better understanding of the molecular pathways is needed to optimize the use of these new approaches. In this review, the authors examine the development of oxaliplatin as well as the main trials that have positioned oxaliplatin as a key drug in the treatment of CRC.

Understanding the Predictive Role of K-ras for Epidermal Growth Factor Receptor–Targeted Therapies in Colorectal Cancer

The prognosis of metastatic colorectal cancer (mCRC) remains poor regardless of the advances obtained in recent years with new therapeutic agents, surgical procedures, and diagnostic methods. New treatments directed to molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. Current use of irinotecan, oxaliplatin, and bevacizumab combined with the long-time standards 5-fluorouracil and leucovorin as first- or second-line treatment for patients with mCRC has resulted in median overall survival figures of > 20 months. Additional improvements in treatment are likely to be facilitated by the use of rationally selected therapeutic agents that target functionally important proteins in tumor cells, such as the epidermal growth factor receptor (EGFR). The activation of EGFR leads to the activation of intracellular effectors involved in intracellular signaling pathways such as the G protein K-Ras. The K-Ras oncoprotein controls transduction of signals required for proliferation, differentiation, and survival, mainly acting as guanosine diphosphate/guanosine triphosphate-regulated binary switches located at the inner surface of the plasma membrane. Monoclonal antibodies (MoAbs) designed to bind to the ectodomain of the EGFR have shown activity in chemorefractory mCRC and in the first-line setting. Cetuximab and panitumumab are MoAbs that bind to the EGFR and thereby inhibit cell proliferation, metastasis, and angiogenesis. Recent clinical data confirm that the efficacy of cetuximab and panitumumab is confined to patients bearing tumors with wild-type K-ras. K-ras mutation analysis may now be considered a new standard of care in the selection of patients for EGFR-targeted therapy.

The role of salvage treatment in advanced colorectal cancer

The selection of salvage therapy after first-line treatment failure for metastatic colorectal cancer patients has become more complex with the development of several active drugs in this setting. The addition of oxaliplatin and irinotecan to 5-fluorouracil in the first-line therapy has conditioned the election of the regimen used in second-line, becoming a standard of care the switch between both schedules at the time of disease progression. The recent introduction of new targeted drugs has complicated the scenario even more, allowing different possible combinations in first-, second-, third- and even fourth-line therapy. The role of hepatic arterial infusions has been reconsidered with the availability of new and more active cytotoxic drugs and has become an approach to be taken in mind in the management of these patients. With the possibility of active salvage therapy, surgery rescue approaches should be taken in account during all the course of the patients disease.

Update on Novel Strategies to Optimize Cetuximab Therapy in Patients with Metastatic Colorectal Cancer

The prognosis of metastatic colorectal cancer (mCRC) remains poor despite the advances made in recent years with new therapeutic agents, surgical procedures, and diagnostic methods. New treatments directed toward molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. Cetuximab is a chimeric monoclonal antibody that binds to the epidermal growth factor receptor and thereby inhibits cell proliferation, metastasis, and angiogenesis. Preclinical studies indicate that cetuximab induces synergistic antitumor activity when combined with chemotherapy or radiation. In pretreated patients with mCRC, cetuximab might restore sensitivity toward irinotecan and has therefore been registered for the treatment of patients with mCRC refractory to irinotecan. Moreover, cetuximab seems to add substantial benefit to standard oxaliplatin- and irinotecan-based combinations, resulting in high response rates in the first-line setting. Recent preclinical and clinical data have optimized cetuximab therapy. New targeted therapy combinations and the identification of biomarkers associated with disease control in patients treated with cetuximab are changing the current management of mCRC. Also, preliminary data suggest that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy.

New approaches and targets in advanced colorectal cancer

The prognosis of cancer remains poor in spite of the advances obtained in recent years with new therapeutic agents, new approaches in surgical procedures and new diagnostic methods. An emerging understanding of the molecular pathways that characterise cell growth, cell cycle, apoptosis, angiogenesis and invasion has led to the identification of novel targets for cancer therapy. Numerous proteins have been implicated as having a crucial role in colorectal cancer (CRC). The targets can be grouped according to their cellular localisation such as membrane receptor targets (epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), insulinlike growth factor receptor (IGFR), platelet-derived growth factor receptor (PDGFR), tumour necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R), and c-Met), intracellular signalling targets (Ras/Raf/MAPK pathway, phosphatidylinositol3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), src kinase and p53/Hdm2) and other protein kinases that regulate cell division including aurora kinases and polo-like kinases (Fig. 1). Emerging data from the clinical development of new drugs directed to these targets is providing novel opportunities in the treatment of patients with CRC that will probably translate into efficacy benefits in the coming years.

New approaches in systemic treatment of advanced colorectal cancer: the molecular targets era.

The prognosis of advanced colorectal cancer remains poor in spite of the advances obtained in recent years with new therapeutic agents, new approaches in surgical procedures and new diagnostic methods. New treatments directed to molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. In this review, the authors examine the most important trials with monoclonal antibodies and tyrosine kinase inhibitors in the treatment of advanced colorectal cancer.

Emerging strategies in the treatment of advanced esophageal, gastroesophageal junction, and gastric cancer: the introduction of targeted therapies

Upper gastrointestinal malignancies are major causes of morbidity and mortality worldwide. Despite the results of recent clinical trials with new chemotherapy strategies showing encouraging activity and efficacy, the prognosis of patients with advanced gastric, gastroesophageal junction and esophageal cancer remains poor. The demonstration in other tumor types of the effectiveness of anticancer drugs with a targeted mechanism of action, interfering with pathways involved in tumor growth and spread, has opened a new era in drug development. In patients with advanced colorectal cancer, the introduction of epidermal growth factor receptor (EGFR) inhibitors and antiangiogenic agents has resulted in a significant increase in antitumor activity and survival. These targeted agents are currently being also evaluated in other tumor types including these upper gastrointestinal malignancies. These targeted agents include, among others, EGFR inhibitors, antiangiogenic agents, cell-cycle inhibitors, apoptosis promoters, and matrix metalloproteinase (MMP) inhibitors. The emerging data from the clinical development of these compounds provide novel opportunities in the treatment of these common malignancies that will probably translate into clinical benefit for patients with these diseases. This review describes the preclinical rationale and the current status of the clinical development of these compounds in patients with gastroesophageal neoplasms.