Matching targets for selective cancer therapy

In the absence of a single specific and essential anticancer drug target, selective anticancer effects can be achieved by hitting least two targets. By revealing matching targets and desirable properties for drug analogs, this approach could radically change the path of drug discovery.     

Viral delivery for gene therapy against cell movement in cancer

Viral delivery for cancer gene therapy is a promising approach, where traditional radiotherapy or chemotherapy to limit proliferation and movement of cancer cells has met resistance. Based on the new understanding of the biology of the viral vectors, therapeutic viral vectors for cancer gene therapy have been improved for greater safety and efficacy as well as transitioned from being non-replicating to replication-competent. Traditional oncolytic vectors have focused on eliminating tumor growth, while novel vectors simultaneously target epithelial-to-mesenchymal transition (EMT) in cancer cells, which could further prevent and reverse the aggressive tumor progression. In this review, we highlight the illustrative examples of cancer gene therapy in clinical trials as well as preclinical data and include proposals on methods to further enhance the safety and efficacy of oncolytic viral vectors in cancer gene therapy.     

Enzyme and proton-activated prodrugs for a selective cancer therapy

This review is a survey of two approaches for a selective anticancer therapy that are based on a specific cleavage of specially designed non-toxic prodrugs with the liberation of a cytotoxic compound either by antibody-enzyme conjugates targeted to tumor-associated antigens or by acid-catalyzed hydrolysis of the prodrugs due to the increased concentration of hydronium ions in malignant tissue under hyperglycemic conditions. Herein, the design, synthesis and the biological testing of prodrugs are described.     

Exploring death receptor pathways as selective targets in cancer therapy

A recent and innovative strategy in cancer therapy is the activation of apoptosis in tumour cells specifically expressing death receptors (DR) belonging to the tumour necrosis factor (TNF) receptor superfamily and including several members known since the early ‘90. Among these, those largely studied for clinical purpose are TNF, CD95, and TRAIL receptors. Promising results are expecting from ongoing phases I/II clinical trials proving the therapeutic efficacy of DR agonistic antibodies and/or recombinant proteins alone or in association to classic and novel chemotherapeutic drugs. However, two key issues need extensive studies, before clinical and safe applications of DRs as effective anticancer drugs can be accepted: i. DR-based cancer therapy must be selective and effective against a broad range of cancers and reduce excessive systemic toxicity toward normal cells and tumour resistance after recurrent treatments; ii. an improved knowledge of mechanisms of alternative signalling triggered by DR ligands and leading to cell survival and apoptotic resistance. Activation of survival pathways regulated by key factors, such as NF-κB, JNK, p38, ERK and PI₃K are the focus of several studies revealing the dark side of DR signalling. The present review focuses on new insights in the signalling and clinical application of TNF, CD95 and TRAIL receptors.     

Gene therapy approaches for the selective killing of cancer cells

This review describes gene therapy strategies that take advantage of defective signal transduction pathways to selectively kill cancer cells without adversely affecting normal cells. The distinctive features of cancer cells currently exploited by gene therapy include mitosis, cell permissiveness to infection, specific protease activity, and the activity of the p53, Rb/E2F and wnt/catenin signal transduction pathways. In most cases, proof of concept has been obtained in vitro and in vivo, but only a few approaches made it to the clinic. Overall, the clinical success rate has been disappointing and it is concluded that the gene therapy of cancer requires more innovation and hard work before its potential can be fully realized.     

Viral vectors for gene therapy: past, present and future

Gene delivery has been attempted in both experimental and clinical settings. These studies have shown that therapeutic gene transfer is possible, but it has not yet arrived as a practicable therapeutic intervention. This is due in large part to the inability of the vectors used to convey genetic material to a desired location in sufficient quantity and for long enough time to be effective. Current research on viral vectors for gene therapy has focused on reengineering viruses currently being tested as delivery agents, modifying the host to facilitate viral gene transfer and developing new viruses for use in gene transfer. It is too early to know which of these approaches will be effective; however, these ongoing studies are likely to make available in the future an array of gene delivery vehicles with different strengths and weaknesses. It is reasonable to expect that several of the vectors now being studied will prove useful for some therapeutic applications.     

Bevacizumab: antiangiogenic cancer therapy

Angiogenesis, the process of new blood vessel formation, is an essential step in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a key mediator in this process, and elevated levels of this cytokine are observed in solid tumors and are correlated with worse clinical outcomes. Research has therefore focused on developing agents that target angiogenic factors such as VEGF in order to inhibit tumor growth. One such agent is bevacizumab, a humanized monoclonal antibody generated by engineering the VEGF-binding residues of a murine neutralizing antibody into the framework of a normal human immunoglobulin G. Bevacizumab recognizes VEGF receptors 1 and 2 and thus can neutralize the biologically active forms of VEGF that interact with these receptors. In addition, bevacizumab has shown antiangiogenic and antitumor activity in several cancer types, recently gaining approval from the FDA for use in combination with fluorouracil-based chemotherapy as a first-line treatment for metastatic cancer of the colon or rectum.     

Systemic therapy for advanced pancreatic cancer: individualising cytotoxic therapy

Introduction: Pancreatic cancer is an aggressive solid tumour associated with a high risk of local invasion and metastatic spread. In the absence of validated screening approaches, many patients present with advanced, incurable disease. Despite advances in treatment, the prognosis for patients with advanced pancreatic cancer remains poor. The benefits of surgical resection and radiation are unproven in this setting and, as patients generally present with distant metastases, systemic therapy forms the mainstay of treatment. The importance of selecting the optimal cytotoxic therapy remains to be critical to improving outcome and retaining quality of life. This review sets out to compare the current therapies available for advanced pancreatic cancer.

Areas covered: This review examines the evolution of the systemic management of advanced pancreatic cancer, with a particular focus on the landmark Phase III trials identified from an extensive PubMed and Google scholar literature search. The article summarises the cytotoxic agents in use and the results of two decades of clinical trials to culminate in an almost doubling of survival in clinical trials.

Expert opinion: In the concluding expert opinion, the challenges interpreting and translating trial results into clinical practice are discussed, where patients are often older and of worse performance status. In the future, novel biomarkers might be used to tailor therapy.     

Mitochondrial delivery of mastoparan with transferrin liposomes equipped with a pH-sensitive fusogenic peptide for selective cancer therapy

Mastoparan (MP), a potent facilitator of mitochondrial permeability transition (PT), could be used as an antitumor agent, if it were encapsulated in a tumor selective delivery system. We recently developed transferrin-modified liposomes (Tf-L) with a pH-sensitive fusogenic peptide (GALA), which delivers an encapsulated fluorescent marker into cytosol efficiently. In this study, we encapsulated MP into Tf-L with GALA for the selective delivery to mitochondria of tumor cells. The MP showed potent PT activity at concentrations above 25 microM in a homogenate of K 562 cells as well as in isolated mitochondria in the presence of phosphate. Tf-L equipped with cholesteryl GALA can release encapsulated sulforhodamine B, while Tf-L failed, as evidenced by confocal laser scanning microscopy. The MP, which was delivered with Tf-L with GALA, released cytochrome c (cyt c) from mitochondria to the cytosol, while free MP released cyt c not only to the cytosol but also extracellulary. These results demonstrate the utility of MP in Tf-L with GALA for cancer therapy.     

RET inhibition: implications in cancer therapy

Introduction: The RET gene encodes a receptor tyrosine kinase essential for ontogenesis of the enteric nervous system and kidney. Following identification of RET, it was found that somatic rearrangements of this gene, conventionally designated as RET/PTC, are frequently present in papillary thyroid carcinoma. Subsequently, activating germ line point mutations of RET were identified as being responsible for the hereditary medullary thyroid carcinoma syndromes MEN2A, MEN2B and FMTC. RET rearrangements have recently been identified in a small fraction of lung adenocarcinomas.

Area covered: The authors review the current field concerning the RET gene and protein, its involvement in cancer and the preclinical and clinical studies which highlight its role as a potentially important therapeutic target for several cancers.

Expert opinion: Many multitargeted inhibitors which crossreact with RET have been developed and investigated in clinical trials targeting many cancer indications. In particular, VEGFR/PDGFR inhibitors, widely explored as antiangiogenics, have been intensively studied in thyroid carcinoma patients. Notwithstanding the efficacy observed with such agents, their common clinical activity in thyroid carcinoma is of short duration and includes frequent and severe side effects, limiting their therapeutic action. These findings are discussed and the need for improved, more specific RET-targeting drugs is highlighted.     

Pancreatic cancer: advances in medical therapy

Progress in the treatment of pancreatic cancer has been notably slow and modest in contrast to other cancers of the GI tract over the last 5 years. Pancreatic cancer still continues to be a devastating illness that is marked by the appearance of early metastatic disease, despite curative surgery and the relative chemoresistance of the disease. However, small incremental benefits have been seen, and point to areas of research and development over the subsequent years. Developments in adjuvant chemotherapy and the use of gemcitabine in combination with other cytotoxic agents or with biological agents have changed clinical practice. Given its poor outlook and the paucity of active therapies, even modest gains can lead to regulatory approval and, therefore, pancreatic cancer represents a common target for pharmaceutical companies. Newer agents are in development with the promise of further refinement in treatment selection based on molecular tumor characteristics.     

Antiemetic therapy in cancer: an update

Although nausea and vomiting are widely recognised as two of the most distressing symptoms of cytotoxic therapy, there is still concern over the adequate control of these symptoms in the cancer population. Recently updated Antiemetic Consensus Guidelines recommend the prophylactic treatment of all patients at moderate-to-high risk of experiencing nausea and vomiting following chemotherapy and radiotherapy. It is important that these guidelines are fully adhered to; however, when considering which antiemetic regimen is most appropriate in an individual patient, it is also important to consider individual patient-related factors. In addition, certain patient groups, such as the young or the elderly, may be in need of specific consideration due to age-related factors that may influence treatment decisions.     

Angiogenesis: a target for cancer therapy

The induction of neoangiogenesis is a critical step already present at the early stages of tumor development and dissemination. The progressive identification of molecules playing a relevant role in neoangiogenesis has fostered the development of a wide variety of new selective agents. Antiangiogenic drugs should be integrated with conventional therapies; however, the design of the best sequence and timing for such combined treatments are still under investigation. In this review will be discussed the signal transduction mechanisms of angiogenic molecules, the development of specific inhibitors and their translation into clinical studies and, finally, the new perspectives in antiangiogenic therapy.     

乙酰肝素酶——癌症转移治疗的靶点

近年来研究表明,乙酰肝素酶与癌症组织的转移有极为密切的相关性,通过抑制乙酰肝素酶可以阻止癌细胞的转移,提示乙酰肝素酶可成为癌症转移治疗的靶点。1乙酰肝素酶及其作用机制侵染性细胞尤其是转移性肿瘤细胞和白细胞可通过调节一系列降解酶从而通过胞外基质和基底膜两层屏障。起初,科学家认为这两层屏障的主要成分———结构蛋白的破坏是肿瘤细胞转移的决定性步骤,因此,过去的研究大多集中在底物为结构蛋白的丝氨酸蛋白酶、半胱氨酸蛋白酶类和基质金属蛋白酶(matrix metalloproteinases,MMPs)类上。事实上,作为胞外基质和基底膜的另一主…     

New horizons: gene therapy for cancer

p53 gene mutations appear in numerous human cancers and are associated with anumber of cellular mechanism changes including a lack of apoptosis. Repeated intratumoral injection of the adenoviral p53 vector (Ad5CMV-p53) in patients with non-small cell lung cancer and head and neck cancer is feasible and well tolerated. Treatment results in expression of the p53 transgene and evidence of increased apoptosis. Dose-related antitumor activity has been seen in phase I trials in both lung and head and neck cancer. Transgene expression appears to occur even in patients who mount an immune response to the adenoviral vector. The evidence to date indicates that gene transfer can occur without contamination of health care workers by the vector. There is preliminary clinical evidence suggesting that the in vivo synergy seen between Ad5CMV-p53 and cisplatin may also occur in patients. Phase II trials are justified and have been started.     

Liposomal cancer therapy: exploiting tumor characteristics

Importance of the field: More than 10 million people worldwide are diagnosed with cancer each year, and the development of effective cancer treatments is consequently of great significance. Cancer therapy is unfortunately hampered by severe dose-limiting side effects that reduce the efficacy of cancer treatments. In the search for more effective cancer treatments, nanoparticle-based drug delivery systems, such as liposomes, that are capable of delivering their drug payload selectively to cancer cells are among the most promising approaches.

Areas covered in this review: This review provides an overview of current strategies for improving the different stages of liposomal cancer therapy, which involve transporting drug-loaded liposomes through the bloodstream, increasing tumor accumulation, and improving drug release and cancer cell uptake after accumulation at the tumor target site.

What the reader will gain: The review focuses on strategies that exploit characteristic features of solid tumors, such as abnormal vasculature, overexpression of receptors and enzymes, as well as acidic and thiolytic characteristics of the tumor microenvironment.

Take home message: It is concluded that the design of new liposomal drug delivery systems that better exploit tumor characteristic features is likely to result in more efficacious cancer treatments.