Role of angiogenesis inhibitors in colorectal cancer: sensitive and insensitive tumors.

Angiogenesis is a key factor in the carcinogenesis process. In oncological practice, angiogenesis inhibition, mainly through the blockade of the VEGF family and its receptors, has been robustly demonstrated to produce clinical benefits and, in specific disease subsets such as colorectal cancer, to extend the overall survival of treated patients. VEGF is a multifunctional growth factor that mediates its functions through cognate receptors on endothelial cells and it has been discovered for its capability to induce macromolecule hyperpermeability in veins and venules. Several approaches have been taken to target angiogenesis in cancer: drugs that target one or more soluble ligands of the VEGF family, drugs that selectively inhibit one or more receptors of the VEGF receptor family, and drugs that inhibit VEGF receptor(s) among other, non VEGF-related targets. At present, two compounds have shown significant clinical activity, bevacizumab, Avastin® and aflibercept, Zaltrap®, and only one of these (bevacizumab) has so far been registered for use in clinical practice. In the present review, we explore and summarize the main features of the angiogenetic process, concerning in particular a common and potentially lethal disease as colorectal cancer. We overview the molecular pathways that characterize angiogenesis, focusing on VEGF family, the current applications and limitations of its blockade in oncology, and the hypothetical future perspectives of anti-angiogenic therapy.

Patient-tailored treatments with anti-EGFR monoclonal antibodies in advanced colorectal cancer: KRAS and beyond.

Personalized medicine emphasizes the practice of considering individual patient characteristics as opposed to that centered on standards derived from epidemiological studies which, by definition, do not take into account the variability of individuals within a given population. When applied to oncology, personalized medicine is an even more complex concept because it extends the variability beyond the individual patient to the individual tumor. Indeed, the great genotypic and phenotypic variability (both in primary and metastatic sites of cancer) the development of targeted therapies, and the growing availability of biological assays complicate the scenario of personalized medicine in the oncological field. In this paper we review the results of anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) therapy in metastatic colorectal cancer (mCRC) in the context of tumor biology, delineating the future prospects of patient-tailored medicine in this area. In particular, we deal with EGFR inhibition by Cetuximab, a chimeric mouse human IgG1 mAb, and panitumumab, a fully human IgG2 mAb. We discuss the clinical impact of anti-EGFR mAbs on wild-type (WT) KRAS mCRC, also taking into account the feasibility of novel multi-marker approaches to treatment decision-making, aimed at increasing the predictive power of pre-therapy biomarkers. Experimental topics and fields of ongoing research, such as targeting microRNAs (miRNAs) with novel anticancer drugs and epigenetics in CRC are also addressed.

DNA damage response pathways and cell cycle checkpoints in colorectal cancer: current concepts and future perspectives for targeted treatment.

Although several drugs have been designed in the last few years to target specific key pathways and functions in colorectal cancer (CRC), the backbone of CRC treatment is still made up of compounds which rely on DNA damage to accomplish their role. DNA damage response (DDR) and checkpoint pathways are intertwined signaling networks that arrest cell cycle, recognize and repair genetic mistakes which arise during DNA replication and transcription, as well as through the exposure to chemical and physical agents that interact with nucleic acids. The good but highly variable activity of DNA damaging agents in the treatment of CRC suggests that intrinsic alterations in DDR pathways and cell cycle checkpoints may contribute differentially to the way cancer cells react to DNA damage. In the present review, our aim is to depict the recent advances in understanding the molecular basis of the activity of DNA damaging agents used for the treatment of CRC. We focus on the known and potential drug targets that are part of these complex and intertwined pathways. We describe the potential role of the checkpoints in CRC, and how their pharmacological manipulation could lead to chemopotentiation or synergism with currently used drugs. Novel therapeutic agents playing a role in DDR and checkpoint inhibition are assessed. We discuss the possible rationale for combining PARP inhibition with DNA damaging agents, and we address the link between DDR and EGFR pathways in CRC.

CHEK2 genomic and proteomic analyses reveal genetic inactivation or endogenous activation across the 60 cell lines of the US National Cancer Institute.

CHEK2 encodes a serine/threonine kinase (Chk2) activated by ATM in response to DNA double-strand breaks. On the one hand, CHEK2 has been described as a tumor suppressor with proapoptotic, cell-cycle checkpoint and mitotic functions. On the other hand, Chk2 is also commonly activated (phosphorylated at T68) in cancers and precancerous lesions. Here, we report an extensive characterization of CHEK2 across the panel of 60 established cancer cell lines from the NCI Anticancer Screen (the NCI-60) using genomic and proteomic analyses, including exon-specific mRNA expression, DNA copy-number variation (CNV) by aCGH, exome sequencing, as well as western blot analyses for total and activated (pT68-Chk2) Chk2. We show that the high heterogeneity of Chk2 levels in cancer cells is primarily due to its inactivation (owing to low gene expression, alternative splicing, point mutations, copy-number alterations and premature truncation) or reduction of protein levels. Moreover, we observe that a significant percentage of cancer cells (12% of the NCI-60 and HeLa cells) show high endogenous Chk2 activation, which is always associated with p53 inactivation, and which is accompanied by downregulation of the Fanconi anemia and homologous recombination pathways. We also report the presence of activated Chk2 (pT68-Chk2) along with histone γ-H2AX in centrosomes.