Current Cancer Drug Targets - Volume 16, Issue 3, 2016

The main aim of current cancer research is to find a way to selectively affect the tumor cells, while leaving normal cells intact. Ataxia telangiectasia and Rad3-related kinase (ATR), a member of the phosphatidylinositol-3-related protein kinases (PIKK), represents a candidate target for achieving this goal. ATR kinase is one of the main kinases of the DNA damage response signaling pathway and responds to DNA damage caused by replication stress and various genotoxic agents (i.e. chemotherapy, ionizing radiation, ultraviolet light). ATR activation triggers cell cycle checkpoints, DNA repair and apoptosis, but also resistance of tumor cells to DNA damaging agents, through stress support under replication stress. Thus, the inhibition of ATR leads to increased effectiveness of cancer therapy and in addition enables highly selective targeting of cancer cells through synthetic lethal interactions. Despite this great potential, only a few potent and selective inhibitors of ATR kinase have been developed to date. However, those which have been developed provide great promise, and are under evaluation in many current preclinical and clinical trials. The purpose of this review is to summarize the potential of ATR inhibitors and the medicinal chemistry efforts which resulted in their identification.

It was estimated that small cell lung cancer (SCLC) accounts for about one Sixth of all lung cancer cases. Patients with SCLC are usually diagnosed in advanced stage of disease. Unfortunately at this stage, prognosis is very poor. Bevacizumab is a monoclonal antibody against VEGF, which inhibits the angiogenesis in malignant tumors. Although Bevacizumab has been approved for firstline use in advanced non-SCLC, the first report has been available for its use in SCLC. In this review, we summarized all available data on the use of Bev in SCLC patients. Finally, future directions are discussed.

Background: Twenty percent of patients with Acute Myeloid Leukemia (AML) carry a translocation between chromosomes 21 and chromosome 8 resulting in the formation of a chimeric oncoprotein AML1-ETO. The patients with this translocation although have a favourable prognosis, but the 5-year survival is only about 50%. It is anticipated that identification of novel therapeutic targets in t(8;21) positive AML will lead to treatment options that improve patient survival. Areas covered: The oncoprotein and the proteins required to maintain its stability and functionality are the first obvious therapeutic targets. Further, newer technologies like combining gene expression and DNA occupancy profiling assays, gene expression–based high-throughput screening, etc have led to identification of proteins or pathways that are required by AML1-ETO for leukemogenesis and the agents that modulate these proteins to be considered good candidates for targeted molecular therapy. Various FDA approved drugs and secondary metabolites derived from traditional medicinal plants have been shown to possess anti-proliferative effect on t(8:21) harboring leukemic cell lines. Conclusion: In order to improve the therapeutic regime for AML patients with t(8;21), efforts are required to translate the success achieved in identification of potent candidates for targeted therapy into clinical setup in the best possible combination.

Despite the enormous number of anticancer drugs presently available in the clinic, treatment failure due to drug resistance is very frequent. The identification of mechanisms of resistance to different drugs is necessary, in order to identify ways to prevent and circumvent such resistance. Indeed, the identification of novel therapeutic targets to overcome cancer drug resistance remains one of the major challenges in drug discovery and development. The methods employed to identify drug resistance mechanisms and novel therapeutic targets depend greatly on the establishment of cancer drug resistant cell lines. The establishment of such drug resistant cell lines is laborious and time-consuming and various different approaches have been described. This manuscript reviews the methodologies that have been used to create cancer drug resistant cell lines and to identify their mechanisms of resistance. In addition, this review highlights the most frequent drug resistance mechanisms found in cancer cells.

Invasion leading to the formation of metastasis is one of the hallmarks of cancer. Analysis of different human cancers has led to the identification of the PPFIA1 gene encoding the protein liprin-α1, a possible player in cancer. The PPFIA1 gene is amplified in malignant tumors, including about 20% of breast cancers. Also the liprin-α1 protein is found overexpressed in tumors. Liprin-α1 belongs to the liprin family of cytosolic scaffold proteins that includes four liprin-α, two liprin-β members, and liprin-γ/kazrinE. In this review we will discuss the available evidence on the role of different members of the liprin family in distinct aspects of tumor cell migration and invasion. Evidence from in vitro studies indicates that the widely expressed liprin-α1 protein regulates the migration and invasion of human breast cancer cells. Liprin-α1 affects cell migration and invasion by regulating the organization of lamellipodia and invadopodia, two structures relevant to cell invasion. In the cell liprin-α1 forms a complex with liprin-β1, ERC1/ELKS and LL5 proteins, which localizes at the front of migrating cells and positively regulates lamellipodia stability, and integrin–mediated focal adhesions. On the other hand, liprin-β2 appears to play a role as tumor suppressor by inhibiting breast cancer cell motility and invasion. The available data indicate that liprins are central players in the regulation of tumor cell invasion, therefore representing interesting targets for anti-metastatic therapy.

Cervical carcinomas are almost universally associated with high-risk human papillomavirus (HPV) infections, and are a leading cause of cancer death in women worldwide. Since the late 1990s, when a spate of studies reported the benefit of cisplatin-based chemotherapy, there had been a dearth of clinical trials in cervical cancer (CC). More effective therapies in locally advanced and recurrent or metastatic CC are an urgent clinical need. In the era of molecular oncology one should look beyond conventional chemoradiation and chemotherapy for locally advanced and advanced CC. The fact that the initiating oncogenic insult, infection with a high-risk HPV and viral oncoprotein expression is common to almost all CC offers unique opportunities for disease control. Diverse biologic pathways with an implication in the development and progression of CC are being explored. For the first time, increase in overall survival has recently been obtained for advanced CC patients with a target drug, the antiangiogenic agent bevacizumab, and durable complete responses after HPV-targeted adoptive T cell therapy in metastatic CC patients were achieved. In this review, we will summarize molecular aspects of HPV infection focusing on potential targets to stop the carcinogenic process, present updated drug development data, and discuss challenges and prospects for the future.

Clinical treatment response achievable with conventional chemotherapy in high-grade osteosarcoma (OS) is severely limited by the presence of intrinsic or acquired drug resistance, which in previous studies has been mainly addressed for overexpression of ABCB1 (MDR1/P-glycoprotein). This study was aimed to estimate the impact on OS drug resistance of a group of ATP binding cassette (ABC) transporters, which in other human tumors have been associated with unresponsiveness to the drugs that represent the backbone of multidrug treatment regimens for OS (doxorubicin, methotrexate, cisplatin). By using a group of 6 drug-sensitive and 20 drug-resistant human OS cell lines, the most relevant transporter which proved to be associated with the degree of drug resistance in OS cells, in addition to ABCB1, was ABCC1. We therefore evaluated the in vitro activity of the orally administrable ABCB1/ABCC1 inhibitor CBT-1® (Tetrandrine, NSC-77037). We found that in our OS cell lines this agent was able to revert the ABCB1/ABCC1-mediated resistance against doxorubicin, as well as against the drugs used in second-line OS treatments that are substrates of these transporters (taxotere, etoposide, vinorelbine). Our findings indicated that inhibiting ABCB1 and ABCC1 with CBT-1®, used in association with conventional chemotherapeutic drugs, may become an interesting new therapeutic option for unresponsive or relapsed OS patients.

Anti-angiogenesis therapy is one major approach of cancer therapies nowadays. Unfortunately, anti-angiogenesis therapy targeting VEGF-A was recently stumbled by the drugresistance that results from adaptive mechanisms, such as intratumor hypoxia. To obtain a more efficient therapeutic response, we created and identified a novel chimeric fusion of VEGF121 and VEGF165, which was connected by Fc region of human IgG1 to enhance dimerization. We found that the treatment of VEGF121-VEGF165 chimeric protein reduces proliferation, migration, invasion, and tube formation in endothelial and/or cancer cells through competing VEGF165 homodimer in a paracrine and an autocrine manner. Furthermore, the fusion protein attenuated autocrine VEGFR2-HIF-1α-VEGF165/Lon signaling through PI3KAKT- mTOR pathway in cancer cells. In conclusion, our data demonstrated that the chimeric VEGF121-VEGF165 arrests the tube formation of endothelial cells and interferes with tumor cell growth, migration and invasion, suggesting that it could be a potential drug as an angiogenesis antagonist in cancer therapy. The VEGF121-VEGF165 targets not only paracrine angiogenic cascade of endothelial cells but also autocrine PI3K-AKT-mTOR-mediated VEGFR2-HIF-1α- VEGF165/Lon signaling that drives drug resistance in tumor cells. Our study will open up the patient opportunities to combat drug resistance to antiangiogenic therapy.