Beyond the Magic Bullet: The Anti-Cancer Cocktail

BEYOND THE MAGIC BULLET

SQUARE ONE PUBLISHERS

Chapter One

With the wide range of treatments at hand today, we should be able to revolutionize our treatment of cancer. The limitations of current cancer therapy may not be due to a lack of understanding of how the disease works or a lack of effective treatments, but rather a failure to implement an optimal treatment strategy despite what we know and have. The limitations of the conventional cancer treatments—surgery, chemotherapy, radiation, and newer targeted therapies—may largely result from the one-dimensional and simplistic strategy that is usually followed to the exclusion of other approaches. But to appreciate the possibility of a new cancer treatment strategy, we must first understand the complex and diverse nature of the disease, which is often overlooked, as well as the limitations of the standard treatments used in conventional medicine. This understanding will provide a rational basis for using a new approach that could potentially revolutionize cancer therapy.

THE COMPLEXITY OF CANCER

To devise a better treatment strategy for cancer, it is essential to understand the complexity of cancer biology. The first question we must ask is, "What is cancer?" According to the National Cancer Institute (NCI), cancer can be defined simply as "diseases in which abnormal cells divide without control and are able to invade other tissues." But if uncontrolled growth is all there is to cancer, effective treatments would need only stop or reduce the growth in the same way that antibiotics kill bacteria. Obviously, cancer has proven itself to be not so simple a condition, as we have not yet invented or found an antibiotic capable of killing the cancer "germ."

Cancer is like the multi-headed hydra. It involves not only complex genetic and molecular pathways that control cell growth, but also dynamic interactions between cells and their surrounding tissue environment. Cancer's deadliness is due to its inability to stop multiplying, its tendency to spread and recur, and its capacity to build resistance to treatment. An insightful description of the disease was recently put forth by a group of scientists: "Cancer cannot be simply understood as individual mutations. The effect of a mutation often depends on the context of other mutations within the same cell, the context of other mutant cells within the same tumor, and the context of ... the environment of the tumor and the patient." Therefore, in order to better understand the nature of this deadly disease, let's begin by looking at its initiation and its progression—two aspects of cancer that reveal its complexity and diversity.

The Initiation of Cancer

The word cancer is a general descriptive term that encompasses more than 100 distinct abnormal conditions in the human body. Cancer is complex in its forms and its formation, or initiation—the term used to describe the complexities that bring about cancer and how the disease manifests in the body. Cancer can arise in any organ and affect various types of cells, such as blood cells, germ cells, epithelial or lining cells, glandular cells, and nerve cells. Sometimes, cancer may affect more than one type of cell within the same organ. Some forms of cancer have a hormonal component (breast and prostate cancer) or a hereditary component (breast cancer, ovarian cancer, and melanoma). The initiation of cancer can also be related to gender or age; there are cancers that occur more frequently in women than men and vice versa, and cancers that affect children more than adults. For example, children are more frequently diagnosed with certain forms of leukemia as well as cancers of the central nervous system, such as medulloblastoma and neuroblastoma.

In addition, cancer's initiation may be linked to ethnicity, geography, or lifestyle, as well as exposure to sunlight, chemicals, parasites, viruses, and certain bacteria. For instance, nasopharyngeal cancer is more common among the Chinese population, while Burkitt's lymphoma occurs most frequently among people from equatorial Africa. Lifestyle factors can also play a role in cancer development, as smoking is a known risk factor for lung cancer, and shift work has been associated with breast cancer risk. Moreover, excessive exposure to sunlight is correlated with skin cancer, and contact with chemicals such as aflatoxin, benzene, and asbestos may cause liver cancer, leukemia, and mesothelioma, respectively. There are also microbes that can initiate the disease, like the parasite Clonorchis sinensis (gallbladder cancer), the bacterium Helicobacter pylori (stomach cancer), and a number of viruses, including hepatitis B and C (liver cancer), the Epstein-Barr virus (nasopharyngeal cancer and some lymphomas), and the human papillomavirus (cervical cancer). Still, most cancers have unspecified causes or are caused by a multiplicity of factors and further affected by genetics, diet, environment, and even emotions.

The Progression of Cancer

The progression of cancer, which refers to its growth and proliferation, as well as the various ways in which it evades medical intervention, is at least as complicated and diverse as its initiation. Some cancers are fairly slow-growing, taking their toll over the course of a decade or more, while other types are aggressive, tearing through a life in a matter of months. Inexplicably, some cancers even shrink on their own. (Unfortunately, most do not.)

Cancer generally grows in a series of steps. These steps range from hyperplasia, a condition in which a normal-looking cell cannot stop multiplying; to dysplasia, when cells appear to have abnormalities, mutations, or atypical structural changes within them; to anaplasia, in which cells completely lose properly functioning structures. All of these steps reflect the cells' increasing loss of self-control, or what is called uncontrolled cell division. The final phase involves wild and unbridled cell growth.

The uncontrolled cell growth that characterizes cancer is a result of disturbances within the cell's growth cycle, which may be caused by genetic changes or mutations. For example, when proto-oncogenes, which normally control cell signals, mutate to become oncogenes, cell growth switches into overdrive. Additionally, defects can occur in tumor suppressor genes (or anti-oncogenes), which act as brakes to cell growth, as well as genes that normally have a repair function, in turn leading to cellular disrepair. As if this wasn't complex enough, disruptions in the cellular growth cycle can also be connected to an imbalance of proteins, such as cyclin-dependent kinases (CDKs), which were discovered and characterized in the 1990s. The synchronization of a cell's growth cycle depends on a balanced amount of these proteins, which is disturbed in most cancers. (See Figure 1.1 on page 11.) In sum, cancer can be viewed as a genetic malfunction at the most basic DNA level, or as a dysfunction at a higher level of cellular activity—cell signaling, programming, and other regulatory processes.

A recent study published in Science provides a glimpse of the complexity with which we are dealing. An international research team sequenced more than 20,000 genes in cells from twenty-four patients with advanced cancer and found that a typical case of cancer involves an average of sixty-three genetic mutations involving twelve abnormal cellular pathways. Delving further into this complexity, a new field of biology called epigenetics has highlighted the importance of not only mutations and defects at the DNA level, but also the "switching on and off" of otherwise normal genes, an abnormal process that is affected by a web of other processes. This phenomenon can be likened to identical twins: Their genes may be completely identical, but there are differences between the two in part because some genes that are active in one twin may not be active in the other. The "turning on" of cancer-promoting genes and the "turning off" of cancer-suppressing genes plays a key role in the development of cancer, from its initiation to its progression.

There are other important aspects of cancer progression beyond simple cell growth, including the ability of cancer cells to invade tissue, spread to distant sites in the body, build up resistance to treatment agents, and escape the body's immunological detection. Cancer cells even have the uncanny ability to circumvent therapies directed at them. Indeed, multidrug resistance (MDR) is a major hindrance to effective cancer treatment. MDR occurs in cancer cells in which the MDR-1 gene is overexpressed, as this gene is responsible for coding P-glycoprotein (P-gp). This substance, which is overproduced in such cancer cells, acts as a "pump" to remove anti-cancer drugs directed at the cell.

All of this information is not intended to leave your head spinning, but rather illustrate the complexity of cancer. This disease involves the interaction of cancer cells and their genetic and subcellular functions, the surrounding tissue environment, and the immune system. In recent years, scientists have also learned that the cancer's immediate environment—its blood and nutrient supply, acidity and oxygen levels, and balance of cellular signals called cytokines—also intimately affects the progression of the disease. In other words, cancer is not a stand-alone phenomenon.

THE NATURE OF THE BEAST

Hardly half a century ago, scientists understood cancer simply as unrestrained cell growth. Yet as Fabio Grizzi, a researcher at the Instituto Clinico Humanitas in Milan, has observed, medical scientists have been looking for simplicity only to find more complexity. As such, the scientific community may be finally awakening to the enormous difficulty of the challenge we are facing.

In January 2004, a fierce snowstorm crippled much of the Washington, DC area, but it did not stop more than seventy doctors and researchers from traveling to the National Cancer Institute for a landmark meeting about its newly formed Integrative Cancer Biology Program (ICBP). Recognizing the inadequacy with which cancer biology had been researched and understood in the past, the program was intended to launch initiatives focusing on the complexity of cancer, with the overall goal of promoting the disease as a complicated biological system.

Dr. Dinah Singer, Director of the NCI Division of Cancer Biology, put it like this: "We now appreciate that cancer is a disease of genes and we understand the regulation and function of a huge number of these genes.... We have [a] detailed understanding of how proteins interact, both structurally and functionally, in regulatory, signaling, and metabolic pathways. What we are lacking is a systematic approach to integrate various kinds of data and processes ... where we can analyze the complex biological systems that are cancer." In other words, although we may understand the individual parts and underlying mechanisms of cancer, we have not been able to completely grasp the whole. We can see the trees, but not the forest.

A comprehensive basis for understanding the intricate biological interplay that constitutes cancer is the prelude to a radical rethinking of a better treatment strategy for the disease. Where does this understanding leave us with the direction of treatment? It is obvious that a simple condition can be treated simply, as a strep throat can be healed with penicillin. But a disease like cancer should not—and cannot—be treated using the same simplistic strategy of applying one drug at a time, one punch after another. Now that we know how many heads this "hydra" called cancer has, it is clear that we need not only new and improved medicine, but also a new and improved strategy that reflects and addresses the complexity of the disease.

CANCER BIOLOGY'S IMPLICATIONS FOR A NEW STRATEGY

Over a decade ago, scientists thought that exhaustively identifying, studying, and describing the parts, processes, signals, and pathways of cell growth would lead to innovations in cancer treatment. Robert Weinberg, a professor of biology at the Massachusetts Institute of Technology who identified the first oncogene and suppressor gene, predicted that "a new set of talents will be brought to bear on the cancer problem. Mathematicians with expertise in analyzing complex multicomponent systems will explain how the minicomputers inside cells actually function.... With increasingly detailed information on the metabolism of normal and cancerous cells, it will become possible to design highly selective drugs that strike cancer cell targets." In reality, however, effective cancer treatment will likely involve more than understanding the details of cell growth. As scientists have uncovered the underlying genetics of both normal and cancerous cells, the mechanisms and deficiencies of the immune system, and the pathways by which cancer cells spread and invade other tissues, they are increasingly appreciative of how complicated a disease cancer truly is. Figure 1.2 (see page 14), which illustrates a typical cancer cell pathway, provides a glimpse of the degree of complexity involved. As Dr. Bert Vogelstein of Johns Hopkins University succinctly put it in a recent interview, "Cancer is very complex—more complex than we had believed."

CONCLUSION

In order to set the stage and provide a rationale for a better treatment strategy, we must start by emphasizing—and, more importantly, understanding—the complexity of cancer. It would be naive to imagine a complex problem to be solvable in simplistic terms. Current treatment methods such as surgery, chemotherapy, radiation, and simple drug regimens applied one after another reflect such naivety. Before presenting a new strategy for cancer based on a deeper biological understanding of the disease, we will first go over these conventional medical treatments and their shortcomings. The next two chapters provide a picture of where we stand today in terms of cancer treatment.

Chapter Two

As demonstrated by recent advances in cancer research, the modern era is seemingly one of limitless information and technological advances. We know more about the complexity of cancer than ever before, including how it starts, behaves, and spreads throughout the body. However, our current ability to treat the disease pales in comparison to the knowledge we have about it. The classical treatments that form the backbone of current cancer therapy—surgery, chemotherapy, radiation, and hormone therapy—have been employed for a long time but, in many instances, remain quite limited in their ability to cure or even curb the disease. And although recent years have seen many medical breakthroughs and more cutting-edge treatments, novel therapies are generally used only when the standard treatments fail.

Simply put, the current strategy and standards for treating cancer are inadequate. As a result, survival rates for many cancers—such as brain, colorectal, lung, and pancreatic cancer—have not significantly improved over the last thirty years. This chapter reviews the conventional treatment methods, both classical and modern, that comprise cancer therapy today and explains why they are insufficient.

CLASSICAL CANCER TREATMENTS

Up until the turn of the twenty-first century, there were few treatment options for a person diagnosed with cancer. With the exception of hormone therapy, cancer treatment was focused largely on the annihilation of cancer cells. The cancer was removed surgically (in the form of a tumor), eliminated with drugs and chemicals via chemotherapy, or destroyed with radiation. These four methods—surgery, radiation, chemotherapy, and hormone therapy—continue to serve as the mainstay of cancer treatment. Despite the success of these treatments for some localized and early-stage cancers, as well as less common cancers such as testicular cancer and some forms of leukemia and lymphoma, such treatments cannot effect a cure for the majority of adult cancers. Worse is the fact that some of them, particularly radiation and chemotherapy, are toxic and cause undesirable side effects, in turn placing limits on how long and intensely they can be used. This section takes a closer look at each of these treatments and their limitations.

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Excerpted from BEYOND THE MAGIC BULLET by RAYMOND CHANG Copyright © 2012 by Raymond Chang. Excerpted by permission of SQUARE ONE PUBLISHERS. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
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