Angiogenesis as a target for cancer therapy

Antiangiogenic drugs are unique for having highly specific targets while carrying the potential to be effective against a wide variety of tumors. Moreover, some of the major limitations of cytotoxic therapies likely will be avoided by this entirely new class of anticancer weapons. After the realization of the potential advantages of antiangiogenic therapy, the field of angiogenesis research is growing exponentially. Still, there is much to learn about the machinery that tumors use to recruit new blood vessels, and the results of the clinical trials will show the best way to apply that knowledge for cancer therapy.     

CD22 as a target for cancer therapy

Targeted therapies with monoclonal antibodies have been increasingly incorporated into the treatment for both lymphoid and myeloid hematological malignancies. Rituximab, the first approved monoclonal antibody for the treatment of cancer, has revolutionized our approach to the management of chronic lymphocytic leukemia and non-Hodgkin's lymphoma. However, there is still an unmet medical need for novel therapeutic approaches, especially for patients in the relapsed/refractory setting. Therapeutic agents with specificity against different surface antigens on malignant B cells hold promise for improving clinical outcome in these patients. Throughout the last decade, CD22, a B-cell-restricted phosphoglycoprotein of the immunoglobulin superfamily, has gained considerable interest as a therapeutic target for B-cell-directed therapies. Several novel therapeutic agents that selectively target CD22 are being developed as an alternative approach for cancer treatment. This review summarizes the current knowledge of CD22 and discusses the rationale for targeting CD22 in B-cell malignancies with immunotherapeutic agents. This review also describes some of the most promising investigational anti-CD22 agents for the treatment of B-cell malignancies.     

AXL kinase as a novel target for cancer therapy

The AXL receptor tyrosine kinase and its major ligand, GAS6 have been demonstrated to be overexpressed and activated in many human cancers (such as lung, breast, and pancreatic cancer) and have been correlated with poor prognosis, promotion of increased invasiveness/metastasis, the EMT phenotype and drug resistance. Targeting AXL in different model systems with specific small molecule kinase inhibitors or antibodies alone or in combination with other drugs can lead to inactivation of AXL-mediated signaling pathways and can lead to regained drug sensitivity and improved therapeutic efficacy, defining AXL as a promising novel target for cancer therapeutics. This review highlights the data supporting AXL as a novel treatment candidate in a variety of cancers as well as the current status of drug development targeting the AXL/GAS6 axis and future perspectives in this emerging field.     

The proteasome as a target for cancer therapy.

The proteasome is a multicatalytic proteinase complex responsible for the degradation of most intracellular proteins, including proteins crucial to cell cycle regulation and programmed cell death, or apoptosis. In preclinical cancer models, proteasome inhibitors induce apoptosis, have in vivo antitumor efficacy, and sensitize malignant cells and tumors to the proapoptotic effects of conventional chemotherapeutics and radiation therapy. Interestingly, transformed cells display greater susceptibility to proteasome inhibition than nonmalignant cells. Therefore, proteasome inhibition holds promise as a novel approach to the treatment of cancer. Inhibitors of the proteasome impact on cells in part through down-regulation of nuclear factor kappaB, but also through modulation of cell cycle proteins and other pro- and antiapoptotic pathways. Bortezomib (VELCADE; formerly PS-341), the first such inhibitor to undergo clinical testing, has demonstrated impressive antitumor activity and manageable toxicities in Phase I and II trials both as a single agent, and in combination with other drugs. It has been approved recently by the Food and Drug Administration for therapy of patients with multiple myeloma who have received at least two prior regimens and progressed on the last of these. Ongoing preclinical evaluations of the mechanisms that underlie the antitumor effects of proteasome inhibitors, and clinical trials in a variety of tumor types, will allow additional refinement of the role these agents will play in cancer therapy. Below we discuss the rationale behind targeting the proteasome for cancer therapy, and review the preclinical and clinical data on proteasome inhibitors alone, and in combination with conventional chemotherapeutics.     

Angiogenesis as a strategic target for ovarian cancer therapy

Angiogenesis is a complex and highly regulated process that is crucial for tumor growth and metastasis. Insights into the molecular mechanisms of tumor angiogenesis have led to the identification of potential angiogenic targets and the development of novel antivascular agents. Many of these agents are being evaluated in clinical trials and have shown promising antitumor activity. This Review highlights the results of the latest clinical studies of antivascular agents in ovarian cancer and discusses the challenges and opportunities for future clinical trials.     

以多胺代谢为靶点的抗肿瘤研究进展

肿瘤细胞的恶性增殖依赖细胞内的高多胺水平,抑制多胺合成或促进多胺分解均能够降低肿瘤细胞内的多胺水平,因此通过耗竭肿瘤细胞中的多胺含量抑制肿瘤细胞增殖成为新的抗肿瘤研究策略。本文简要综述了近年来以多胺代谢为靶点,通过多种方式耗竭肿瘤细胞内多胺的抗肿瘤研究进展。      

FOXO在肿瘤靶向治疗中的研究进展

 FOXO转录因子参与多种信号传导通路,并在各种病理生理过程中发挥重要的作用包,括增殖、凋亡,因此FOXO转录因子可作为癌症治疗药物的靶点。就FOXO蛋白在癌症靶向治疗的研究进展作一综述。     

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

In contrast to prior belief, cancer cells require oxidative phosphorylation (OXPHOS) to strive, and exacerbated OXPHOS dependency frequently characterizes cancer stem cells, as well as primary or acquired resistance against chemotherapy or tyrosine kinase inhibitors. A growing arsenal of therapeutic agents is being designed to suppress the transfer of mitochondria from stromal to malignant cells, to interfere with mitochondrial biogenesis, to directly inhibit respiratory chain complexes, or to disrupt mitochondrial function in other ways. For the experimental treatment of cancers, OXPHOS inhibitors can be advantageously combined with tyrosine kinase inhibitors, as well as with other strategies to inhibit glycolysis, thereby causing a lethal energy crisis. Unfortunately, most of the preclinical data arguing in favor of OXPHOS inhibition have been obtained in xenograft models, in which human cancer cells are implanted in immunodeficient mice. Future studies on OXPHOS inhibitors should elaborate optimal treatment schedules and combination regimens that stimulate—or at least are compatible with—anticancer immune responses for long-term tumor control.     

Thioredoxin reductase as a novel molecular target for cancer therapy

Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. The understanding of these complex mechanisms should lead to the identification of potential targets for therapeutic intervention. Redox-sensitive signaling factors also regulate multiple cellular processes including proliferation, cell cycle, and pro-survival signaling cascades, suggesting their potential as molecular targets for anticancer agents. These observations suggest that redox-sensitive signaling factors may be potential novel molecular markers. We hypothesized that thioredoxin reductase-1 (TR), a component of several redox-regulated pathways, may represent a potential molecular target candidate in response to agents that induce oxidative stress. There have been numerous biological studies over the last decade investigating the cell biological, biochemical, and genetic properties of TR both in culture and in in vivo models. In addition, using a series of permanent cell lines that express either a wild-type TR or a dominant mutant TR gene or a chemical agent that inhibits TR we demonstrated that TR meets most criteria that would identify a molecular target. Based on these results we believe TR is a potential molecular target and discuss potential clinical possibilities.     

结直肠癌中表皮生长因子受体靶向治疗的意义

表皮生长因子受体抑制剂在结直肠癌治疗中的应用效果显著,近年来一系列的基础、临床研究表明,抗表皮长因子受体的单克隆抗体(C-225)联合化学治疗其疗效和生存均优于单纯化学治疗。表皮生长因子酪氨酸激酶受体抑制剂的临床研究结果到目前为止还不理想,但就目前的研究结果对其疗效进行评价还为时过早。目前有一些正在进行Ⅰ期临床研究的新型表皮生长因子受体的单克隆抗体和酪氨酸激酶受体抑制剂,有可能给结直肠癌的治疗带来新的希望。     

Research News Sphingosin-1-phosphate as a target for cancer therapy

Phospholipids and their derivatives were considered ＂neutral＂ in that they were thought either to serve a simple structural role in cell membrane organization or to provide energy for beta oxidation, glycolysis and other metabolic processes. It has only recently been appreciated that many lipids play significant roles as bioactive signaling mediators. Sabbadini in a minireview in Brit J Cancer （2006, 95：1131-1135） summarized the role of sphingolipid, a signaling molecules with pleiotropic effects, in carcinogenesis.     

The development of PARP as a successful target for cancer therapy

Introduction: PARP1 and BRCA genes are essential genome caretakers and their interaction has been the first example of synthetic lethality, a genetic concept proposed in the early 20th century, but deeply explored in cancer patients only in the last decade.

Areas covered: This review describes PARP1 and BRCA main functions and different roles in genome protection. Furthermore, an overview of the principle mechanisms of action and resistance to PARP inhibitors (PARPi) is presented. This review illustrates the concept of BRCAness, and how this discovery has broadened the routes of PARPi to several different malignancies such as ovarian, breast and prostate cancer. Finally, an insight is provided into the key data of PARPi in these distinctive clinical settings.

Expert commentary: PARP inhibition could be a new therapeutic option for a number of tumors in the near future. However, several aspects will be of paramount interest for future investigations, including the molecular bases for PARPi synthetic lethality, the DNA repair independent functions of PARP and BRCA genes, the resistance and biomarkers of response to PARP inhibition, and the mechanisms of interaction between PARPi and antiangiogenic or immunotherapeutic agents.     

A link between lipid metabolism and epithelial-mesenchymal transition provides a target for colon cancer therapy

The alterations in carbohydrate metabolism that fuel tumor growth have been extensively studied. However, other metabolic pathways involved in malignant progression, demand further understanding. Here we describe a metabolic acyl-CoA synthetase/stearoyl-CoA desaturase ACSL/SCD network causing an epithelial-mesenchymal transition (EMT) program that promotes migration and invasion of colon cancer cells. The mesenchymal phenotype produced upon overexpression of these enzymes is reverted through reactivation of AMPK signaling. Furthermore, this network expression correlates with poorer clinical outcome of stage-II colon cancer patients. Finally, combined treatment with chemical inhibitors of ACSL/SCD selectively decreases cancer cell viability without reducing normal cells viability. Thus, ACSL/SCD network stimulates colon cancer progression through conferring increased energetic capacity and invasive and migratory properties to cancer cells, and might represent a new therapeutic opportunity for colon cancer treatment.     

The rapamycin-sensitive signal transduction pathway as a target for cancer therapy.

The high frequency of mutations in cancer cells which result in altered cell cycle regulation and growth signal transduction, conferring a proliferative advantage, indicates that many of these aberrant mechanisms may be strategic targets for cancer therapy. The macrolide fungicide rapamycin, a natural product with potent antimicrobial, immunosuppressant, and anti-tumor properties, inhibits the translation of key mRNAs of proteins required for cell cycle progression from G1 to S phase. Rapamycin binds intracellularly to the immunophilin FK506 binding protein 12 (FKBP12), and the resultant complex inhibits the protein kinase activity of a protein kinase termed mammalian target of rapamycin (mTOR). The inhibition of mTOR, in turn, blocks signals to two separate downstream pathways which control the translation of specific mRNAs required for cell cycle traverse from G1 to S phase. Blocking mTOR affects the activity of the 40S ribosomal protein S6 kinase (p70s6k) and the function of the eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), leading to growth arrest in the the G1 phase of the cell cycle. In addition to its actions on p70s6k and 4E-BP1, rapamycin prevents cyclin-dependent kinase activation, inhibits retinoblastoma protein (pRb) phosphorylation, and accelerates the turnover of cyclin D1 that leads to a deficiency of active cdk4/cyclin D1 complexes, all of which can inhibit cell cycle traverse at the G1/S phase transition. Both rapamycin and CCI-779, an ester analog of rapamycin with improved pharmaceutical properties and aqueous solubility, have demonstrated impressive activity against a broad range of human cancers growing in tissue culture and in human tumor xenograft models, which has supported the development of compounds targeting rapamycin-sensitive signal-transduction pathways. CCI-779 has completed several phase I clinical evaluations and is currently undergoing broad disease-directed efficacy studies. The agent appears to be well tolerated at doses that have resulted in impressive anti-tumor activity in several types of refractory neoplasms. Important challenges during clinical development include the definition of a recommended dose range associated with optimal biological activity and maximal therapeutic indices, as well as the ability to predict which tumors will be sensitive or resistant to CCI-779.     

The epidermal growth factor receptor as a target for colorectal cancer therapy

The epidermal growth factor receptor (EGFR) is the prototypical member of the erbB receptor family. The EGFR axis is activated by a variety of ligands that are crucial in the formation and propagation of many tumors, including colorectal cancer, through their effects on cell signaling pathways, cellular proliferation, control of apoptosis, and angiogenesis. The importance of the EGFR axis in tumorigenesis and tumor progression makes it an attractive target for the development of anticancer therapies. A variety of targeting strategies to exploit the role of EGFR in tumors have been employed. The most highly developed of these anti-EGFR approaches are the monoclonal antibodies and the tyrosine kinase inhibitors (TKIs). Clinical evaluations of these compounds have yielded some promising results. The role of the EGFR axis in colorectal cancer formation and progression is reviewed and the clinical development of these anticancer EGFR-targeted drugs is reviewed and updated.     

The epidermal growth factor receptor as a target for gastrointestinal cancer therapy

Opinion statement The epidermal growth factor receptor (EGFR) is a member of the family of transmem-brane protein kinase receptors known as the erbB or HER receptor family. When activated, EGFR phosphorylates and activates other intracellular proteins that affect cell signaling pathways, cellular proliferation, control of apoptosis and angiogenesis. EGFR signaling is best thought of as a network of activating and inactivating proteins with EGFR as the entry point into the network. EGFR overexpression occurs in most GI malignancies and while data are not entirely consistent, EGFR overexpression often confers a poor prognosis in those GI malignancies that have been studied. It often correlates with poorly differentiated histology, more advanced stage and other known poor prognostic markers. The EGFR is a tempting target because of its presence and overexpression on so many tumor types. However, downstream of the EGFR are several proteins that may be activated without EGFR thus allowing blockade to be overcome. Therefore, while blocking the activity of the EGFR protein appears to be a promising anticancer strategy, a simplistic strategy of blocking only EGFR is likely to only impact a minority of patients. It is time for the laboratory and clinical researchers to work closely together to develop this treatment strategy, moving back and forth from clini-cal to laboratory to best understand how to block this network effectively enough to produce a broader antitumor effect. While multiple methods of targeting the EGFR pathway are under development, including the inhibition of downstream proteins, only two modalities have entered clinical trials in GI malignancies: small molecule inhibitors of the intracellular kinase domain of EGFR and antibodies designed to block the extracellular ligand-binding domain of EGFR. EGFR inhibitors are still experimental in every GI malignancy with the notable exception of cetuximab that is approved for second or third-line therapy of metastatic colorectal cancer, used either alone or in combination with irinotecan (Camptosar, Kalamazoo, Mich). Data on clinical applications of these agents in GI malignancies will be the focus of this paper.