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The mammalian target of rapamycin (mTOR) plays a central role in the regulation of cell growth and proliferation by controlling translation in response to nutrients, energy levels, and growth factors. A number of proteins both upstream and downstream in the mTOR signaling pathway have been found to be modified in multiple cancers. As a result, significant interest has been generated in developing small-molecule inhibitors directed against mTOR. Over 30 yr ago a naturally occurring macrolide antibiotic, rapamycin, was isolated that subsequently was identified as a specific inhibitor of mTOR. Rapamycin has played a critical role as a chemical probe for defining the role of mTOR and served as a template for developing compounds with improved therapeutic properties. This chapter will describe our current understanding of the cellular functions of mTOR, modifications of the mTOR pathway currently identified in various types of cancer, the status of clinical trials using rapamycin analogs targeting mTOR, and future possibilities for novel small-molecule inhibitors of mTOR. [ABSTRACT FROM AUTHOR]

Cyclo-oxygenase-2 (COX-2) is an enzyme induced in pathologic states such as inflammatory disorders and cancer, where it mediates production of prostanoids. The enzyme is commonly expressed in both premalignant lesions and overt cancer of different types. A growing body of evidence links COX-2 with tumor development, aggressive biological tumor behavior, resistance to standard cancer treatment, and adverse patient outcome. Preclinical investigations have demonstrated that inhibition of this enzyme with selective COX-2 inhibitors enhances tumor response to radiation and chemotherapeutic agents. These preclinical findings have been rapidly advanced to clinical oncology. Clinical trials of the combination of selective COX-2 inhibitors with radiotherapy, chemotherapy, or both in patients with a number of cancers have been initiated, and preliminary results are encouraging. This chapter discusses the role of COX-2, its products (prostaglandins), and inhibitors of the enzyme in tumor growth and treatment. [ABSTRACT FROM AUTHOR]

ATP site-directed competitive and irreversible inhibitors of receptor tyrosine kinases have been extensively investigated in the search for new targeted antitumor agents. This chapter provides a comprehensive overview of key results and achievements for three receptor tyrosine kinases, EGFR, c-Kit, and FLT3, in which drug discovery and development activities have advanced with some success. Three additional receptor tyrosine kinases (IGF-IR, c-Met, and RET) have been selected to illustrate new opportunities and challenges in the identification of drugs for tailored cancer treatment. [ABSTRACT FROM AUTHOR]

The proteasome is a multicatalytic protein complex whose principal function is the degradation of vital proteins many of which are involved in cell cycle regulation, tumor suppression, apoptosis, transcription, and angiogenesis. The inhibition of the proteasome is a promising novel therapeutic approach to cancer treatment. Bortezomib (Velcade) is the first proteasome inhibitor to have shown anticancer activity and reach clinical trials. Preclinical and early clinical trials in both solid tumors and hematological malignancies demonstrate that bortezomib is a relatively well-tolerated and active agent, either alone or in combination with traditional chemotherapeutic drugs. Most recently, its efficacy has been shown in multiple myeloma. Currently, clinical trials are ongoing in order to determine the efficacy as well as safety of bortezomib in the management of solid tumors, especially in combination with traditional cytotoxic agents. [ABSTRACT FROM AUTHOR]

The use of genomics technologies for cancer research has resulted in a vast amount of data that need to be handled and organized using informatics approaches. Through the use of controlled vocabularies and ontologies, biological data can be annotated in a consistent manner so that scientists can more easily integrate datasets and collaborate. Datasets are being coded using Extensible Markup Language (XML) to aid in the communication and transfer of data. Numerous software applications have been built to facilitate the analysis and visualization of research data and some of these have incorporated features that facilitate data uniformity and sharing. To aid with postgenomics analysis, grid-computing initiatives are providing the computational horsepower so that complex patterns and analyses can be performed on the large datasets. In this chapter, we give a brief overview of the methodologies used and resources available for bioinformaticists wishing to explore cancer biology datasets. [ABSTRACT FROM AUTHOR]

The introduction of the monoclonal antibody rituximab has expanded the treatment options for patients with B-cell non-Hodgkin's lymphoma (NHL). In patients with indolent B-cell lymphomas, rituximab is highly effective both as a single agent and in combination with chemotherapy regimens. Ongoing studies evaluating maintenance rituximab therapy and new combinations suggest clinical outcomes defined primarily by improvements in progression-free survival. In chronic leukemia, the use of rituximab in combination with chemotherapy has led to improved response rates and durable remissions. Studies in aggressive NHL indicate that the addition of rituximab to first-line chemotherapy is associated with improved clinical benefit, and ongoing studies are better defining the optimal use of rituximab in this setting. Radioimmunotherapy with Y-90 ibritumomab tiuxetan has been shown to be safe and effective for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL. Of importance, radioimmunotherapy does not preclude the use of other NHL therapies in these patients. This chapter will provide an extensive review of clinical trials with rituximab and Y-90 ibritumomab tiuxetan for the treatment of patients with B-cell NHL. [ABSTRACT FROM AUTHOR]

Novel biological agents are being developed as cancer therapeutics to target the signaling pathway that mediates programmed cell death. The ability to directly signal apoptosis and the relatively restricted tumor cell expression of the tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL) cell surface receptors reflect their potential as specific, therapeutic cancer targets. Therapeutic agents being developed to activate this pathway include agonist human and chimeric TRAIL receptor monoclonal antibodies and the ligand TRAIL. This chapter will summarize the current knowledge of the targets in the TRAIL cell death pathway and the status of the agents being developed to activate this pathway. [ABSTRACT FROM AUTHOR]

Recent success of antibody therapeutics in oncology has revived a keen interest in the development of monoclonal antibodies (mAbs) for the treatment of cancer. To date, eight mAbs have been approved in the United States for the treatment of hematological malignancies or solid tumors. The increased success has been largely attributed to advances in antibody technology such as chimerization and humanization of mAbs and the development of fully human antibodies allowing for reduction in immunogenicity and creation of antibodies of desired affinity and isotype. XenoMouse® technology is a technology that allows for the generation of fully human mAbs in transgenic mice. Using this technology, the anti-epidermal growth factor receptor (EGFR) antibody, panitumumab, has been created. Panitumumab (ABX-EGF) is a fully human IgG2 anti-EGFR mAb. Panitumumab binds EGFR with high affinity, inhibits ligand-dependent receptor activation, and effectively inhibits the growth of multiple human tumor xenografts in mouse models. To date, in phase 1 and phase 2 clinical studies, panitumumab has been generally well tolerated, exhibited no immunogenicity, and demonstrated low interpatient and intrapatient pharmacokinetic variability. Objective responses have been observed in patients with metastatic colorectal cancer and advanced renal cell carcinoma. [ABSTRACT FROM AUTHOR]

The HER family is composed of four receptors, HER1 to HER4, is dysregulated, and/or shows abnormal signaling activity in a broad range of human tumors. The essential role of HER2 in the HER signaling network led to the development of anti-HER2 monoclonal antibodies (mAb) for cancer therapy. In particular, the humanized antibody trastuzumab (Herceptin™) has antitumor activity against HER2-overexpressing breast tumors and is widely used for the treatment of women with HER2-overexpressing breast cancers. However, trastuzumab activity relies on the presence of HER2 overexpression and it is not active against tumors that express moderate or normal levels of HER2. Importantly, there is a large population of breast cancers and many other tumors that have normal (nonoverexpressed) HER2 expression yet show abnormal HER signaling activity. In such tumors, HER2 functions as a preferred coreceptor to form heterodimers with HER1 (EGFR), HER3, or HER4. For this reason, a humanized mAb, called pertuzumab (2C4; Omnitarg™), that targets HER2—the preferred pairing partner—was developed and is now in clinical development. Importantly, pertuzumab is directed at an extracellular region of HER2—the dimerization domain—and blocks HER2 from dimerizing with other receptors and prevents the activation of HER signaling cascades. Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerization inhibitors (HDIs). Given the good preclinical activity of pertuzumab and its potential to target a broad range of human tumors, including those with low HER2 expression, the antibody was recently moved to the clinic. Phase I trials with pertuzumab have shown promising results and phase Ib and II trials are ongoing against a variety of tumor types. Current results and ongoing strategies with these anti-HER2 antibodies are discussed. [ABSTRACT FROM AUTHOR]