imetelstat and cediranib

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide. Recently, it has been found that about 40 % of patients with CRC have mutations in the K-RAS gene. Several clinical trials have showed that patients with metastatic colorectal cancer (mCRC) who present tumour-promoting mutations in signalling pathways involving the epidermal growth factor receptor (EGFR), which includes activating K-RAS mutations, do not respond to anti-EGFR drugs such as panitumumab and cetuximab. Hence, K-RAS status is now considered an important negative predictive factor for response to anti-EGFR drugs. Moreover, K-RAS status seems to have also a prognostic role in CRC, but this fact is somewhat controversial. Activity of antiangiogenic agents seems not to be influenced by K-RAS gene status. Tumour angiogenesis has attracted interest in attempts to improve the management of mCRC. The vascular endothelial growth factor (VEGF) pathway is fundamental to the regulation of angiogenesis, and research has focused on developing agents that selectively target it. In this way, the anti-VEGF antibody bevacizumab in combination with chemotherapy has provided important clinical benefits in terms of response rate, progression-free survival and overall survival to patients with mCRC. Efficacy data of bevacizumab in K-RAS wild-type patients seem to be comparable with the efficacy data observed with anti-EGFR therapies in a cross-trial comparison. Although there is a lack of prospective and randomized data in this setting, the combination of chemotherapy plus antiangiogenic agents could be considered as an effective alternative for the treatment of mCRC with independence of K-RAS gene status. Here, we review the available data we have in the literature of the use of antiangiogenic strategies in the treatment of mCRC nowadays.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; ErbB Receptors; Fluorouracil; Genes, ras; Humans; Imidazoles; Indazoles; Indoles; Irinotecan; Niacinamide; Oligonucleotides; Organoplatinum Compounds; Oxaliplatin; Pharmacogenetics; Phenylurea Compounds; Prognosis; Protein-Tyrosine Kinases; Pyridines; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Signal Transduction; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

Functional blood vasculature is essential for tumor progression. The main signalization pathways that play a key role in the survival and growth of tumor vessels originate from the VEGF-, PDGF- and FGF tyrosine kinase receptors. In the past decade, significant results have been published on receptor tyrosine kinase inhibitors (RTKIs). In this paper, the mechanisms of action and the results so far available of experimental and clinical studies on multi-target antiangiogenic TKIs are discussed. On the one hand, notable achievements have been made recently and these drugs are already used in clinical practice in some patient populations. On the other hand, the optimal combination and dosage of these drugs, selection of the apropriate biomarker and better understanding of the conflicting role of PDGFR and FGFR signaling in angiogenesis remain future challenges.

Topics: Angiogenesis Inhibitors; Animals; Axitinib; Benzenesulfonates; Humans; Imidazoles; Indazoles; Indoles; Neoplasms; Neovascularization, Pathologic; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Receptor Protein-Tyrosine Kinases; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Sunitinib

Angiogenesis is essential for tumor growth and metastasis. The main regulators of the process are the signaling cascades of VEGF-, PDGF- and FGF receptors. Inhibition of these pathways holds potential therapeutic benefit not only for cancer patients, but also for the treatment of other diseases. This paper summarizes the experimental and clinical results of studies available so far on the multi-target tyrosine kinase inhibitor nintedanib (BIBF 1120). According to these studies, nintedanib effectively inhibits VEGFR-, PDGFR- and FGFR signalization and thus the proliferation and survival of cell types which highly express these receptors (i.e. endothelial and smooth muscle cells and pericytes). In vitro studies and in vivo xenograft experiments have provided promising results. In the clinical setting, BIBF 1120 seems to be effective and well tolerated in various tumor types, such as lung, prostate, colorectal and hepatocellular carcinoma, as well as in gynecological tumors. The main adverse events are gastrointestinal toxicities and the reversible elevation of liver enzyme levels. Nintedanib might also be combined with paclitaxel, carboplatin, pemetrexed and docetaxel. There are several ongoing clinical trials testing the efficacy of BIBF 1120.

Topics: Animals; Antineoplastic Agents; Axitinib; Benzenesulfonates; Carcinoma, Hepatocellular; Clinical Trials as Topic; Colorectal Neoplasms; Digestive System; Enzyme Inhibitors; Female; Genital Neoplasms, Female; Humans; Imidazoles; Indazoles; Indoles; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Prostatic Neoplasms; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Quinazolines; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Xenograft Model Antitumor Assays

Despite advances in surgery, radiation therapy, and chemotherapy, patients with cancer have a poor prognosis. Sustained aberrant tumor angiogenesis and metastasis is a major obstacle for effective cancer treatment. Just a few years ago, few would argue that one of the key success stories of the modern cancer medicine were the anti-angiogenic drugs targeting the vascular endothelial growth factor (VEGF) signaling pathway approved by FDA. This initial success inspired many researchers to search for new anti-angiogenic targets and drugs with the hope that one day, anti-angiogenic therapy might really become the panacea for cancer patients. Unfortunately, the limited clinical benefits achieved with anti-angiogenic drugs conflicts with the widely accepted notion that angiogenesis is a key event in tumor progression. Emerging data indicate that unique characteristics of the tumor vasculature within the tumor microenvironment may hold the key for success of anti-angiogenic therapy. In particular, the molecular and cellular alterations that sustain aberrant tumor angiogenesis in the face of angiogenic inhibitors represents novel targets for rationally designing and improving current anti-angiogenic strategies.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Drug Resistance, Neoplasm; Humans; Indazoles; Indoles; Neoplasms; Neovascularization, Pathologic; Niacinamide; Oligonucleotides; Phenylurea Compounds; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Sorafenib; Sulfonamides; Sunitinib; Tumor Microenvironment

Despite developments in conventional (chemo)radiotherapy and surgery, survival of non-small cell lung cancer (NSCLC) patients remains poor. Treatments with targeted molecular drugs offer novel therapeutic strategies. Bevacizumab, a recombinant anti-vascular endothelial growth factor (VEGF) antibody, is the antiangiogenic drug at the most advanced stage of development in the therapy of NSCLC. However, a number of questions and future challenges relating to the use of bevacizumab in NSCLC remain. Furthermore, novel agents targeting the pre-existing NSCLC vasculature (i.e. vascular disrupting agents, VDAs) or multiple tyrosine kinase inhibitors have emerged as unique drug classes delivering promising results in several preclinical and clinical studies. Herein, we review the most recent data using these novel targeted agents either alone or in combination with chemotherapy in NSCLC.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Axitinib; Benzenesulfonates; Bevacizumab; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Indazoles; Indoles; Lung Neoplasms; Niacinamide; Oligonucleotides; Phenylurea Compounds; Piperidines; Pyridines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Sorafenib; Sulfonamides; Xanthones

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality in the United States. Therapeutic agents that target the underlying biology of this disease are necessary to improve outcomes. Angiogenesis plays a central role in NSCLC tumor growth and metastases. The vascular endothelial growth factor pathway (VEGF) as a therapeutic target was recently validated in NSCLC. Since then, a multitude of early phase clinical trials that incorporate the use of angiogenesis inhibitors, either as single agents or in combination with cytotoxic chemotherapy, have been conducted in advanced, refractory NSCLC. This article reviews these clinical trials with attention to toxicity, efficacy, and direction of further study. The data from these trials suggest that optimal use of anti-angiogenic agents in NSCLC is more likely in combination with standard cytotoxic agents, however the most effective combination with the least toxicity is yet to be determined.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Benzenesulfonates; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Indoles; Neovascularization, Pathologic; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Protein-Tyrosine Kinases; Pyridines; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sunitinib; Treatment Outcome