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Because normal endothelial cells are genetically stable, antiangiogenic therapy was initially theorized to be “a treatment resistant to resistance.” However, resistance to antiangiogenic therapy is a very real problem. Mechanisms of resistance to the antiangiogenic effects of cytotoxic agents likely also apply to novel antiangiogenic agents. The use of antiangiogenic agents as adjuvant therapy has potential barriers. The toxicity of chronic antiangiogenic therapy remains largely unexplored, as is the toxicity of combinations of chemotherapy with antiangiogenic therapy. Population-specific feasibility studies can identify toxicities that might not be acceptable in an otherwise healthy patient population.

Discovery of the estrogen receptors (ERs) has been critical for the development of endocrine therapy in breast cancer. Expression of ER-?, the predominant isoform, in breast tumors of both pre- and postmenopausal women is a highly predictive marker for response to antiestrogen treatment. Tamoxifen, an antiestrogen, that competitively blocks the actions of 17β-estradiol (E_2), binds and activates ER-? in breast tumors and is used for treating all stages of breast cancer. Although tamoxifen is effective in reducing recurrence fromER-positive early stage breast cancer, approximately 50% of patients do not benefit from its use, because their breast cancers have intrinsic or de novo tamoxifen-resistance. Additionally, most patients that do initially benefit from tamoxifen, will develop acquired resistance to the drug during the treatment regimen. Despite increasing use of the aromatase inhibitors as breast cancer therapies, tamoxifen remains the hormonal therapy of choice in premenopausal women, and is the only hormonal therapy approved for breast cancer prevention. Therefore, a current goal in breast cancer research is to elucidate the mechanisms of both intrinsic and acquired resistance to tamoxifen and other antiestrogens in order to develop new therapeutic strategies to prevent and/or treat resistant breast cancer.

Glucocorticoids are lipophilic compounds derived from cholesterol and are used in the treatment of some hematological malignancies such as multiple myeloma. Alternative splicing gives rise to numerous glucocorticoid receptor isoforms. The molecular basis of glucocorticoid resistance is poorly understood. Resistance can involve alterations in the glucocorticoid receptors or receptor-associated proteins, such as chaper-ones, that affect cellular response. Alternatively, glucocorticiods may be effluxed from cells, or there may be enhanced expression of proteins involved in cell survival, defective apoptosis machinery, or altered expression of adhesion molecules that can result in drug resistance.

Finding the appropriate patients and ensuring that molecular therapeutics are delivered to the tumor in biologically relevant doses are the backbone of targeted therapies. This chapter reviews mechanisms of resistance to trastuzumab (Herceptin(r)), an important targeted therapy in breast cancer management. Monoclonal antibodies that target the HER-2/neu ectodomain sensitize HER-2/neu activation and HER-2/neu-dependent gene expression, resulting in cell cycle progression and cellular differentiation. Trastuzumab activation of Akt is downregulated even in trastuzumab-resistant clones of breast cancer cells. The main mechanisms of resistance to trasuzumab known to date seem to evolve around complex interactions involving mainly the insulin growth factor receptor, phosphatidylinositol 3 kinase/Akt, and cell cycle regulatory pathways.

The development of cancer has been shown to occur through a process of malignant transformation that involves a series of genetic changes that provide a selective advantage over normal cells, and research over the past few decades has identified numerous genes and pathways involved in all stages of tumor progression. These genetic changes invariably disrupt fundamental cellular processes controlling proliferation, apoptosis, differentiation, and genome stability, and it is the combinatorial effect of these genetic changes that result in malignant transformation. Proliferating hematopoietic and epithelial cell populations are particularly susceptible to accumulation of a series of genetic changes required for full-blown malignancy, and nearly 90% of all human solid tumors arise from epithelial cells. The majority of patients who succumb to cancer die as a result of metastatic disease progression rather than from the primary tumor. The process of metastasis is extremely complex, and involves many steps including dissemination of tumor cells from the primary tumor through the vascular and lymphatic system coupled with the ability to colonize selectively distant tissues and organs. The pleiotropic cytokine transforming growth factor-β and its signaling effectors have been shown to be involved at numerous steps in the development of cancer. The role of transforming growth factor-β signaling in cancer is complex, with biphasic functions as a tumor suppressor in normal tissue and early-stage lesions and as a prometastatic agent in latestage disease.

In recent years, there has been an increasing awareness that the immune system, in particular the T-cell component, plays a significant role in tumor eradication. Advances in molecular immunology and identification of T-cell-defined human tumor antigens have accelerated the development of vaccines to promote T-cell-mediated antitumor immune responses. In general, many shared human tumor antigens are derived from proteins overexpressed or derepressed in tumors relative to normal cells. Alteration in the tumor suppressor gene product, p53 , is one of the most common events in human cancers, but mutant p53-based immunotherapy would require “custom-made” vaccines for use in relatively few patients. Because most mutations in p53 are associated with accumulation or “overexpression” of mutant p53 in the cytosol, the protein is more readily available for antigenic processing and presentation than are the low levels of p53 molecules expressed in normal cells. A vaccine targeting wild-type sequence (wt) or nonmutant sequence peptides derived from altered p53 molecules, therefore, is a more attractive approach for developing broadly applicable cancer vaccines. Extensive preclinical murine tumor model studies using peptide-based and DNA vaccines have demonstrated that wt p53-based vaccines can induce tumor eradication in the absence of deleterious antitumor autoimmune side effects. Like any T-cell-based immunotherapy, effective p53-based immunotherapy will be dependent on patients’ responsiveness to wt p53 peptides and the ability of their tumors to present these peptides for T-cell recognition. These and other issues and concerns related to p53-based vaccines are discussed together with a brief summary of the initial clinical trials of p53- based immunotherapy.

For many years, the impact of ionizing radiation on cell biology and survival was not fully understood, and thought to be solely dependent on the levels of DNA damage caused following radiation exposure. Similarly, the mechanisms by which growth factors and cytokines modulate cell behavior were largely unknown. In the mid-1980s, with the discovery of the first mitogen-activated protein kinase (MAPK) pathway and with subsequent discoveries of other MAPK family pathways in the early 1990s, our understanding of the hormonal control of cell biology was provided with a greater degree of molecular underpinning. In light of these findings, the ability of ionizing radiation to control the activity of MAPK family (and other) signaling pathways was first investigated in the mid-1990s. It was discovered that ionizing radiation in a cell type-dependent manner simultaneously activates multiple intracellular signal transduction pathways: the activation of some pathways has been reported to be DNAdamage dependent, that of others by generation of lipids such as ceramide, whereas others have been noted to be dependent on mitochondria-derived reactive oxygen/ nitrogen species and the activation of growth factor receptor tyrosine kinases. The precise roles of growth factor receptors and signal transduction pathways in cellular responses to radiation exposure are presently under intense investigation.

Resistance to chemotherapeutic agents represents a chief cause of mortality in cancer patients with advanced disease. Gene amplification has been shown to be one of the molecular mechanisms for tumors to escape the effect of chemotherapeutic drugs. The amplification and subsequent overexpression of the chemoresistant gene product are likely the results of tumor cell clonal expansion under the selective pressure of chemotherapeutic agents. In the past few decades, researchers have correlated the amplification of several target genes to drug resistance status in in vitro cell culture models. Although it is possible for gene amplification to be a widespread mechanismof chemore-sistance in cancer patients, only a few well-studied examples are presently available. Therefore, the future application of new advances in molecular genetic technology holds promise for the discovery of novel amplified chemoresistant genes, which may significantly affect our understanding of how tumors become chemoresistant as well as provide a molecular platform for customized treatment of cancer patients.

The most informative clinical trials are those in which correlative measurements are being done to determine if the intended target is, in fact, being affected as expected by the treatment being delivered. This chapter focuses on selected mechanisms of acquired drug resistance that have been the targets of novel therapies in the treatment of solid tumors.

Since the declaration of the &quote;war on cancer&quote; three decades ago, an improved understanding of molecular mechanisms behind malignant disease has led to the discovery of novel targets for cancer therapy. Despite such great efforts, many compounds that have performed well in the preclinical setting have failed in clinical trials. This may be because of the dynamic nature of cancer, where cells continuously acquire a series of genetic alterations that allow them to escape the constraints of normal cell proliferation and to develop resistance to various drug therapies. Therefore, it is crucial to understand how these genetic changes are involved in the etiology of cancer development and progression, and to identify the molecular mechanisms responsible for resistance to chemotherapeutic drugs. In recent years, the emergence of new genomic technologies has allowed us to address these fundamental issues. Because cellular and molecular heterogeneity of breast tumors involve many genes in pathways that control cell growth, death, and differentiation, the utility of microarray technology for genomic profiling of human breast cancer has provided remarkable insights into the multiple genetic alterations that are involved in the disease that may dictate clinical outcome. Examination of gene expression patterns are being correlated with tumor sensitivities or resistance to particular pharmacological agents. Taken together, microarray technology has led to more definitive classification of breast cancer, identification of signature markers for diagnosis and prognosis, and potential predictive response to clinical treatments that should greatly improve and individualize patient therapies.