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Monoclonal Antibodies for the Treatment of Cancer

Introduction Monoclonal antibodies have emerged as mainstays of cancer therapy and have had a significant impact on the morbidity and mortality of several cancers. This chapter will discuss the attributes that make antibodies powerful cancer therapeutics, how some antibodies are used clinically, and the development of new antibodies with clinical promise. Antibody Structure and Function Antibodies are heterodimeric proteins composed of two heavy chains and two…

Pharmacogenomics

Introduction The term pharmacogenetics is believed to have first been used in 1959 by Vogel who defined it as “the study of genetically determined variations revealed by the effect of drugs.” Motulsky described the field similarly, but perhaps from the viewpoint of the clinical observer, calling the interaction “drug responses and their modification by hereditary influences.” With the advent of the ability to sequence the entire…

Phase I Trials Today

Introduction All commercially available anticancer agents must have undergone Phase I investigation as part of their clinical development. As novel anticancer drugs evolved from primarily cytotoxic agents to targeted therapies, clinical investigators have developed novel Phase I trial designs and endpoints. It is estimated that approximately 500 anticancer agents will present to the clinical arena within the next decade. It is a well-known fact that one…

Natural and Acquired Resistance to Cancer Therapies

Chemotherapy of cancers has resulted in some notable successes, such as the cure of the majority of patients with childhood leukemias, testicular carcinomas, and Hodgkin’s and non-Hodgkin lymphomas. In other cancer types, such as breast, colorectal, and lung, chemotherapy also cures some patients when used in the adjuvant setting, that is, after debulking of the cancers with surgery and/or radiotherapy. However, for these common epithelial cancers,…

Cancer Therapeutics

Cancer is characterized by the transformation of normal cells to ones characterized by abnormal cellular differentiation, proliferation, invasion, and metastases. The molecular and biochemical bases underlying the transformation process are becoming increasingly clear and provide critically important information for identifying new drug targets. Normal cell division results from the interaction of growth factors with specific receptors (plasma membrane, cytoplasmic, nuclear). This initiates a signal transduction cascade…

From Bench to Bedside with Targeted Therapies

Targeted therapy of human disease celebrated its 100th birthday in 2011. A century ago Paul Ehrlich, a German pathologist, produced the first “rationally designed” drug, which selectively targeted the microorganism Treponema pallidum , the cause of syphilis. The project was the outcome of a thoughtful hypothesis based on the observation that certain organic dyes were selectively taken up by some cells and infectious agents, and not…

Soft Tissue Sarcomas

Introduction Soft tissue sarcomas are a heterogeneous group of neoplasms arising in mesenchymal tissue. There are more than 35 histologic subtypes, often associated with distinctive clinicopathologic features. Based on advances in our knowledge of the molecular pathogenesis of these tumors over the past decade, sarcomas can be subdivided into those with recurrent, usually quite simple genetic alterations (approximately one third of sarcomas; Table 44-1 ) ,…

Thyroid Cancer

Cancer of the thyroid is the ninth most common malignancy diagnosed worldwide in women and 18th in both genders. In the United States, the incidence has been rising faster than that of any other malignancy; in 2012, overall incidence is projected to be 56,460 persons, ranked fifth among all newly diagnosed malignancies in women. Although only 1780 deaths from thyroid cancer are expected in the United…

Molecular Basis for Treating Cutaneous Melanoma

Introduction The mapping of the human genome, and more recently the unraveling of human cancer–specific genomes, has led to more detailed understanding of carcinogenesis, cancer growth, progression, and metastasis. With this understanding, new treatment paradigms for cancer have been developed, generating novel agents that have been successfully introduced into the clinic. Like normal tissues, tumor tissue exploits growth-receptor signal pathways for its maintenance and progression. Disruption…

Epithelial Skin Cancer

Acknowledgments Because of the breadth of this review, we apologize for the unavoidable exclusion of references to work done by many outstanding investigators working in these areas. We acknowledge Professor Andrzej Dlugosz for advice on BCC pathogenesis. Skin Cancer Research Has Helped Define the Biology of Cancer Pathogenesis Epithelial nonmelanoma skin cancer (NMSC, primarily basal cell and squamous cell carcinoma) is the most frequent cancer among…

The Biology of Primary Brain Tumors

Malignant primary tumors of the central nervous system (CNS) occur in about 25,500 individuals and account for an estimated 13,700 deaths in the United States annually, a mortality rate of 6.5 per 100,000. Based on most recent reports, benign tumors of the CNS are about twice as common as malignant brain tumors, but with a much lower mortality rate. Overall, CNS cancer is estimated to represent…

Molecular Abnormalities in Kidney Cancer

Kidney cancer is one of the 10 most common cancers in the United States in both men and women. A number of subtypes of kidney cancer exist. Historically these subtypes have been recognized based on their histological appearance, but it is also now known that each subtype has characteristic molecular abnormalities as well. Germline and somatic genetic studies have helped identify tumor suppressor genes and proto-oncogenes…

Molecular Basis of Prostate Cancer

Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in men in the United States. Prostate-specific antigen (PSA) screening began in the late 1980s and dramatically increased the diagnosis of this disease. An almost-simultaneous decrease in disease-specific mortality has been noted. Whether this is a result of early and enhanced screening, early treatment of localized disease, early and aggressive…

Molecular Pathogenesis of Ovarian Cancer

Acknowledgments These studies were supported in part by a grant from the National Cancer Institute R01 CA135354 , by the M.D. Anderson SPORE in Ovarian Cancer NCI P50 CA83639, the Shared Resources of the M.D. Anderson CCSG NCI P30 CA16672, the Ovarian Cancer Research Fund, the National Foundation for Cancer Research, philanthropic support from the Zarrow Foundation and Stuart and Gaye Lynn Zarrow, Golfers Against Cancer,…

The Molecular Biology of Breast Cancer

Acknowledgments This work was supported in part by research grants from the NIH/National Cancer Institute R01CA94118 (AVL), R01097213 (SO), the Breast Cancer Research Foundation (SO and NED), Susan G. Komen for the Cure (AVL), the Pennsylvania Department of Health (AVL and SO), and the Pennsylvania Breast Cancer Coalition (SO). Molecular Biology of Breast Cancer Initiation and Progression Normal Breast Development Studies of breast cancer from the…

Molecular Pathogenesis of Pancreatic Adenocarcinoma

The most common exocrine pancreatic neoplasm is pancreatic ductal adenocarcinoma, which accounts for more than 95% of all pancreatic malignancies. Other pancreatic malignant neoplasms include acinar cell carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, intraductal papillary-mucinous neoplasm, osteoclast-like giant cell tumor, solid pseudopapillary carcinoma, and pancreatoblastoma. It has been hypothesized that the development of pancreatic adenocarcinoma follows progressive stages of neoplastic growth through precursor lesions to adenocarcinoma, similar…

Colon and Rectal Cancer

Colorectal cancer (CRC) development is a complex process. Causal agents and mechanisms include environmental and dietary factors and inherited and somatic mutations. Great progress has been made over the past 30 years toward defining the constellation of molecular alterations contributing to colorectal tumor development. Specific oncogene and tumor suppressor gene defects have been identified in tumors of various stages, with oncogenes being broadly defined as those…

The Molecular Pathogenesis of Head and Neck Cancer

Epidemiology and Clinical Considerations Head and neck squamous cell carcinoma (HNSCC) arises in the oral cavity, oropharynx, hypopharynx, and larynx. It accounts for more than 90% of the cancers of the head and neck and is the sixth most common cancer by incidence worldwide. In the United States, approximately 40,250 new cases of HNSCC were expected in 2012, with the incidence in men being more than…

Molecular Basis of Lung Cancer

Acknowledgments We thank the many current and past members of the Minna lab for their contributions to lung cancer translational research and our especially our long-term collaborator, Dr. Adi Gazdar. Also we apologize to other investigators for the omission of any references. National Cancer Institute Lung Cancer Specialized Program of Research Excellence (SPORE) (P50CA70907), N R (NNJ05HD36G). JEL supported by NHMRC Biomedical Fellowship (494511). Lung cancer…

Molecular Mechanisms of Esophageal Cancer

Introduction The cancers arising from the esophageal mucosa, primarily esophageal adenocarcinoma (EAC) and esophageal squamous-cell carcinoma (ESCC), are clinically some of the most devastating and lethal cancers in the world. Collectively, they are the eighth most common cancer diagnosed worldwide, with approximately 482,300 new cases in 2008. International age-adjusted incidence rates vary drastically, with a nearly 16-fold difference between the high-incidence areas of southern and eastern…