Cancer Therapy: Molecular Targets in Tumor-Host Interactions Chapter Abstracts
Chapter 1
Identification of Target Genes by Differential Display
Emily K. Thomas, Susanne Stein, Roger S. Jackson II and Peng Liang
Abstract
The complete sequencing of the human genome was a dramatic accomplishment aimed at stimulating the understanding of DNA structure, organization, and function. Although the human genome is comprised of more than 30,000 genes, it is still unclear how all of these genes are selectively expressed and controlled in such a manner as to develop the different tissues and organs of the body. Regulation of this process is very important, as uncontrolled gene expression can lead to a variety of disease states, including cancer. Identifying those genes that are deregulated is essential toward understanding cancer progression. To this end, Differential Display (DD) was developed recently as a way to detect differentially expressed genes in a given biological system. Due to the ability of this technology to directly compare most mRNAs between or among related cells and tissues, DD has wide-ranging applications in developmental biology, cancer research, pathology, endocrinology, and in many other fields of study. The simplicity, sensitivity, reproducibility, and versatility of this method have made it one of the most widely used approaches for studying differential gene expression.
Chapter 2
Oncogenomics: Progress Towards Personalized Molecular Diagnoses and Therapies for Cancer
Sergio Kaiser, Franklin O. Smith and Bruce J. Aronow
Abstract
Oncogenic transformations result from genetic alterations of genes involved in pathways as diverse as those that control cell signaling, proliferation, differentiation, cell death, and immune suppression. Through the use of continuously improving molecular tools and technologies, it is now possible to characterize many cancers with respect to both their specific
genetic alterations and their gene expression profile signatures. Gene expression signatures are both the consequence of oncogenic mutations and are the major determinants of tumor cell behavior. Thus, molecular genetic and genomic expression pattern characterizations of tumors can enable improved tumor classification, a better understanding of the molecular
mechanisms that underlie their neoplastic transformation, and a high degree predictive value for tumor cell behavior. Dissecting the specific molecular anatomy of a tumor is likely to be critical for the development of more specific, efficacious and safer cancer treatments that can be based on an individual tumor's oncogenic mechanisms. The past century has seen the development of the four cornerstones of anti-cancer therapy: surgery, radiation therapy, chemotherapy and hematopoietic stem cell transplantation. Modern chemotherapy has evolved around three basic principles: multiagent combinations, dose intensity, and early use (e.g. adjuvant therapy) (Balis et al., 2002). Unfortunately, while increasingly effective, chemotherapy regimens are empirically derived, are non-selective (e.g. depend upon differential effects on cancer and normal cells and tissues) and target macromolecules (e.g. DNA) and metabolic pathways that are essential to both malignant and normal cells.
Chapter 3
Cell Differentiation and Cancer Prevention by Retinoids
Lucia Altucci and Hinrich Gronemeyer
Abstract
Retinoids and rexinoids are promising anti-cancer tools, generally believed to act mainly as differentiating agents. The introduction of retinoic acid therapy for acute promyelocytic leukemia (APL) has changed a cancer with a poor outcome into one of the most treatable forms of myeloid leukemia, resulting in the cure of more than 75% of the patients. This has stimulated major research efforts, which have provided a detailed molecular understanding of APL pathology and the action of RA in this prototypic differentiation therapy. Furthermore, multiple studies have confirmed the cancer therapeutic and cancer preventive capacity of retinoids and rexinoids in non-APL systems. Retinoids mediate their actions through multiple isoforms, and a plethora of distinct heterodimers, composed of the retinoid (RAR) and rexinoid (RXR) receptors. With the exception of APL, and despite these observations, the molecular basis of the anti-cancer activity of these compounds has remained largely elusive. However, retinoids and rexinoids are active beyond the borderlines of the well-defined chromosomal translocation that gives rise to curable APL. The recent elucidation of growth-regulatory pathways controlled by retinoids will help to exploit the beneficial aspects of this powerful class of compounds for cancer therapy and prevention.
Chapter 4
Apoptosis in Cancer Formation and Progression
Simone Fulda and Klaus-Michael Debatin
Abstract
Apoptosis, the cell's intrinsic death program, plays a key role in physiological growth control and regulation of tissue homeostasis. Therefore, tipping the balance between cell death and survival in favor of cell survival may result in tumor formation. Also, killing of cancer cells by cytotoxic therapies currently used for treatment of cancer, e.g. chemotherapy, γ-irradiation, immunotherapy or suicide gene therapy, largely depends on activation of apoptosis programs in cancer cells. Thus, defects in apoptosis programs that suppress cell death during tumor development can also confer resistance to cancer therapy. Understanding the molecular mechanisms that regulate apoptosis, and how tumor cells evade apoptotic events, may provide a paradigm to link carcinogenesis and cancer therapy. Also, novel strategies targeting resistance of tumor cells will be based on insights into apoptosis mechanisms as well as other forms of cell death.
Chapter 5
Redefining TGFβ as a Target in Cancer
Mary Helen Barcellos-Hoff
Abstract
Since its discovery more than 20 years ago, transforming growth factor β (TGFβ) has often been invoked as a target for therapeutic manipulation in a variety of diseases, but meeting this objective has been frustrated because of its diverse, and often paradoxical, roles in normal and disease processes. The initial thought in cancer therapy was to inhibit the 'transforming'activity of TGFβ, but it was quickly realized that apparent role was much more limited in scope than its capacity to profoundly inhibit proliferation of epithelial cells. Engineered overexpression and deletion mouse models, coupled with decreased growth inhibition observed in human cancer cells, strengthened the paradigm in which the major role of TGFβ is to actively suppresses epithelial cancer. Nonetheless many human tumors produce abundant TGFβ after losing growth control, suggesting that TGFβ somehow contributes to their maintenance. Several models of cancer progression now support that this switch from growth inhibited to malignancy stimulated is an important determinant of metastatic progression in certain tumors. A second area of active interest is the role of TGFβ in therapeutic response, both from the standpoint of normal tissue toxicity and from therapeutic response. TGFβ has recently been shown to have a profound impact on the ability of cells to respond to DNA damaging agents that are commonly the front line of therapy. The broad range and complex timing of events modulated by TGFβ are a challenge for pharmaceutical exploitation. Recent research provides further motivation that a better understanding of TGFβ biology will help refine strategies for its targeting for therapeutic benefit in cancer.
Chapter 6
Inhibition of Tumor Metastasis by Targeting Metastasis Genes: BRMS1 as a Prototype
Douglas R. Hurst and Danny R. Welch
Abstract
The leading cause of mortality in cancer patients is metastasis. Disruption of this complex process would therefore be a useful treatment strategy. Metastasis suppressor genes prevent metastatic growth without affecting tumorigenicity and may provide unique therapeutic targets. Breast Cancer Metastasis Suppressor 1 (BRMS1) was discovered in 2000 and the potential roles of BRMS1 in the suppression of metastases are only beginning to be sorted out. One pathway suggests regulation of transcriptional activity. Another pathway (that may or may not be mutually exclusive) involves gap junctional intercellular communication. This chapter reviews the short history of BRMS1 and the potential roles for BRMS1 suppression of metastasis.
Chapter 7
Integrins in Angiogenesis: Implications for Tumor Therapy
T. Arndt, U. Arndt, U. Reuning and H. Kessler
Abstract
Integrins are a family of cell surface glycoproteins that are considered pharmaceutical targets in a number of therapeutic areas. Vascular integrins are critical mediators and regulators vascular homeostasis, physiological, and pathological angiogenesis, including tumor angiogenesis. The physical interaction of integrins with extracellular matrix (ECM) proteins provides cell adhesion and migration, and furthermore affects signaling pathways, that regulate cell proliferation, survival, migration and differentiation. The modulation of integrin activity and strength of adhesion to a substrate involves global conformational rearrangements of integrin molecules and avidity changes through integrin clustering, thus profoundly affecting integrin function. Integrin-targeting antibodies, peptides or small molecules suppress angiogenesis and tumor progression in various animal models and are currently evaluated in clinical trials for efficacy in anti-angiogenic cancer therapies. This work will review structural aspects of integrins and integrin activation, and the role of integrins in signaling, tumor cell survival, tumor angiogenesis and apoptosis. We will discuss therapeutic consequences highlighting the investigations on anti-angiogenic integrin inhibitors in clinical and pre-clinical development and tumor associated integrins as valuable targets for targeted drug-delivery and diagnostic imaging techniques, respectively.
Chapter 8
Anti-angiogenesis in Search of Mechanisms: Angiostatin as a Prototype
Laura Paleari, Claudio Brigati, Luca Anfosso, Raffaella Del'Eva, Adriana Albini and Douglas Noonan
Abstract
The process of new capillary formation, angiogenesis, is regulated by a balance between pro-angiogenic and anti-angiogenic stimuli: a shift of this balance to the angiogenic phenotype is a key event in tumor progression. The use of anti-angiogenic agents to restore this balance represents a promising approach to cancer treatment, and it has been proposed that employment of physiological inhibitors will limit side effects, a key aspect given the need for long-term therapy in anti-angiogenesis as a strategy. Several physiological inhibitors of angiogenesis are known, including some cytokines and a series of proteolytically generated fragments that harbor activities quite diverse than that of the parental molecule, the prototype of these is angiostatin. Angiostatin is a large proteolytic fragment of plasminogen first identified as a circulating factor produced by primary tumors that inhibits the growth of metastases. The metastasis inhibition effects of angiostatin appeared to be due to repression of angiogenesis; this has now been demonstrated a variety of tumor types and models, and it can be considered a prototype for a whole class of proteolysis generated angiogenesis inhibitors. The action of angiostatin appears not to be specific for tumor inhibition, but can act as a regulator of angiogenesis in other scenarios as well, as it has been found to inhibit neutrophil recruitment and inflammation in animal models. This may also be a common aspect of many angiogenesis inhibitors. Anti-angiogenic cancer therapy with protein angiogenesis inhibitors requires prolonged administration of the peptide. However, the production of functional compound is expensive and technical problems related to physical properties and purity are frequently encountered, as are problems in administration due to their relatively short half lives. Gene transfer represents an alternative method to deliver these types of inhibitors, including angiostatin. Gene therapy has the potential to produce the therapeutic agent in sustained concentrations also locally if needed, thereby avoiding many problems arising with long-term administration of recombinant proteins, monoclonal antibodies, or anti-angiogenic drugs.
Chapter 9
Therapeutic Targeting of the Endothelin Receptor in Cancer
Anna Bagnato
Abstract
The endotelin (ET) system, that includes ET-1, ET-2, ET-3, and the ETA receptor (ETAR) and ETBR, represents a novel and promising target in tumor treatment. ET-1 may directly contribute to tumor growth and indirectly by modulating tumor-host interactions a variety of tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast carcinoma, Kaposi's sarcoma, brain tumors, and cutaneous melanoma. Upon being activated, ET-1 receptors mediate multiple steps of cancer progression including cell proliferation, inhibition of apoptosis, invasiveness, angiogenesis, development and progression of bone metastasis and pain responses. ET-1, acting directly on endothelial cells, regulates different stages of neovascularization and stimulates neovascularization in vivo. ET-1 also induces vascular endothelial growth factor (VEGF) production by increasing levels of hypoxia-inducible factor-1a, prostaglandins and cyclooxygenase-2. These findings indicate that ET-1 system is an important target for direct and indirect cancer therapy. The relevant role that ETAR plays in cancer has led to the development of small molecules that antagonize the binding of ET-1 to ETAR. The emerging preclinical data presented here provide a rational for the clinical evaluation of these molecules alone and in combination with cytotoxic drugs or molecular inhibitors leading to novel anticancer therapies by targeting endothelin receptors.
Chapter 10
Hemostatic Regulators as Drug Targets in Tumor Angiogenesis
Carolyn A. Staton and Claire E. Lewis
Abstract
Angiogenesis, the development of new blood vessels from the existing vasculature, and hemostasis, the coagulation cascade leading to formation of a clot, are among the most consistent host responses associated with cancer. These two pathways are not functionally distinct, however, but interrelate in a manner that has implications for the design of treatments for cancer. Blood coagulation and fibrinolysis influence tumor angiogenesis directly, thereby contributing to tumor growth. Moreover, platelets, which play a central role in the coagulation cascade, release numerous factors that stimulate (e.g. vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) & platelet-derived growth factor (PDGF)) or inhibit (e.g. Thrombospondin-1 (TSP-1) & platelet factor 4 (PF-4)) angiogenesis. Elements of the cascade itself act as controllers of angiogenesis including tissue factor, thrombin, and fibrin. Also proteolytic cleavage has been shown to release active domains, which also influence tumor angiogenesis, including angiostatin, fibrinogen E-fragment and anti-angiogenic anti-thrombin (aaAT). As so many components of the hemostatic pathway influence angiogenesis many are likely to be potential targets for future therapies. Here, we review the various hemostatic proteins known to influence angiogenesis and their potential importance in the design of new therapeutic agents.
Chapter 11
Anti-angiogenesis by Inhibition of Protein Kinase Signaling
Beverly A. Teicher
Abstract
Small molecule antitumor kinase inhibitors directed toward targets on malignant cells and/or vascular cells have antiangiogenic activity. Kinase inhibitors such as those directed toward EGFR, Her2/neu, BCR-ABL, c-KIT, PKC, Raf and PI3, are antiangiogenic by virtue of blocking secretion of angiogenic factors by affected malignant cells. Kinase inhibitors such as those directed toward VEGFR2, VEGFR1, PDGFR, PKC, Raf and PI3, are antiangiogenic by effects on vascular cells. Those molecules that are having success in the clinic are likely inhibiting a spectrum of kinases important to the function of cell involved in the malignant disease process. While mutations in some kinase genes are well-recognized in the field, recent data indicate that mutations in kinase genes may be more wide-spread and frequent than previously understood. These mutations may lead to amino acid substitutions in the kinase proteins that alter sensitivity to inhibitors and may enhance selection of patients for specific therapeutics. Small molecule kinase inhibitors are proving useful as antiangiogenic/antitumor agents in the clinic. It is likely that kinase inhibitors represent only the first 'targeted' enzyme inhibitors that be useful in the treatment of cancer.
Chapter 12
Targeting the Immune System to Tumor-associated Antigens
Michele Maio, Luca Sigalotti, Sandra Coral, Anna Maria Di Giacomo, Maresa Altomonte, Elda Lamaj and Ester Fonsatti
Abstract
The identification, molecular and functional characterization of novel immunogenic tumor-associated antigens, together with a better knowledge of cancer immunology is prompting the design of new and eventually more effective clinical approaches of cancer immunotherapy. In this chapter we will provide a general picture of ongoing immunotherapeutic strategies against distinct tumor-associated antigens, together with a brief mention to the major mechanisms of tumor escape from immune control possibly affecting the clinical efficacy of cancer immunotherapy. Major emphasis will be given to the functional role of HLA class I antigens in the presentation of tumor antigens, to the scientific background and recent clinical evidences on anti-idiotipic vaccination in solid tumors, and to the role of DNA methylation in the regulation of the expression by neoplastic cells of different components of the "tumor recognition complex". In particular, the foreseeable use of epigenetic drugs to set-up new combined chemo-immunotherapeutic strategies in cancer patients will be discussed.
Chapter 13
The Role of Chemokines in Tumor Development and Metastasis
Pantea Houshmand, Tracy M. Handel and Albert Zlotnik
Abstract
Chemokines and their receptors are known to play a pivotal role in many important human diseases, including inflammatory diseases, through their ability to control cell migration in vivo. Recently, however, chemokines have been implicated in cancer metastasis, again through their ability to control cell migration. Here, we review the information available on this subject. A key observation is that tumor cells express chemokine receptors in a non-random manner, suggesting that they play a role in determining the metastatic destination of various cancers. The original studies were done in breast cancer, but now there is information available on most cancers including leukemias, lymphomas, lung, ovarian, pancreatic, prostate, etc. The most widely expressed chemokine receptor in different cancers is CXCR4. Its ligand, CXCL12 is strongly expressed in common metastatic destinations like lung, liver, and bone marrow. A wide array of information in the literature points to the CXCR4:CXCL12 axis as being of particular importance in cancer metastasis, in fact, in various cancers it is the only chemokine receptor expressed. However, we still do not know much about the molecular mechanisms that are controlled by this receptor in tumor cells, but this field is very likely to grow because the control of metastasis has strong therapeutic implications.
Chapter 14
Tumor Killing by Natural Killer Cells
Erika Cretney, Shayna E. A. Street and Mark J. Smyth
Abstract
NK cells are a unique subset of innate lymphocytes that play an important role in tumor immunity. NK cells are able to reject tumors by a variety of effector functions and these functions are controlled by both a variety of cytokines in the environment and the balance between inhibitory and activating signals triggered by target cell recognition. NK cell inhibitory receptors bind to self-MHC class I molecules on tissue cells, whereas NK cell activating receptors bind to ligands expressed on activated, stressed, transformed, and virus-infected tissue cells. The cellular and molecular links between NK cells and adaptive immunity remain poorly understood and are the subject of much current debate. Nevertheless, to date NK cells have been usefully engaged in cytokine-based cancer immunotherapy and the protective graft versus leukemia effects stimulated following some forms of bone marrow transplantation. A more sophisticated picture of the development, differentiation, and cellular context of NK cell function should improve our ability to target NK cells to suppress tumor initiation, growth and metastasis.
Chapter 15
Drug Resistance: A Problem and Possible Solutions
Richard D. Baird and Stanley B. Kaye
Abstract
Clinical drug resistance is a major cause of death in a large proportion of patients presenting with metastatic cancer. Solid tumours can either be refractory to chemotherapy at the outset of treatment (intrinsic resistance), or despite being initially chemosensitive, can develop resistance with time (acquired resistance). In any event, drug resistance eventually emerges in most (but not all) cancer types. Despite significant progress in the chemotherapy of many tumours over the last few decades, further advances in combatting drug resistance will need to be based on an understanding of the mechanisms involved. These are likely to be complex and multifactorial, and may be due to inadequate drug exposure, changes in the cancer cell itself, or changes in the tumour microenvironment. This chapter focusses on the treatment of ovarian cancer and attempts to circumvent resistance to platinum and taxane-based chemotherapy. Future progress will require the development of novel cytotoxics, resistance modulators and above all, the rigorous study of resistance mechanisms in tumour samples taken from patients before and after chemotherapy.
Chapter 16
Virus-directed Suicide Gene Therapy
Jo Morrison and David Kerr
Abstract
Virus directed suicide gene therapy uses a viral vector to express a transgene inside cancer cells. The transgene product is an enzyme which converts an inactive prodrug into a chemotherapeutic agent within the cancer cell. Intracellular chemotherapy has the potential to reduce the toxic side effects normally encountered with chemotherapy and increase the therapeutic index by delivering effective doses specifically to cancer cells. There is an increasing selection of enzyme/prodrug combinations for use with a variety of viral vectors. As yet the perfect gene therapy vector does not exist and the choice of vector is tailored to the clinical scenario, taking account of the advantages and disadvantages of different approaches. Suicide gene therapy can be targeted to the selected tissue or tumor by transductional and transcriptional modifications to the viral vector, and can be combined with other virotherapy and immunotherapy approaches. Results in pre-clinical and phase I/II trials have been promising but successful treatment is currently limited to tumors suitable for direct intra-tumoral injection.
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