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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 by others. Ehrlich postulated the presence of specific receptors on cells and bacteria to which the dyes bound and were internalized. He then proposed to attach a toxic molecule (in this case, arsenic) to a dye molecule that was selective for a receptor on the bacterium, with the goal of producing selective cytotoxicity against the bacterium ( Figure 45-1 ).
Paul Ehrlich: birth of targeted therapy, 1911.
To carry out this work in an efficient and systematic way, he invented an array-like approach to his research. A series of large organic molecules were attached to arsenic by his colleague, Sahachiro Hata, a synthetic chemist, and then were tested by Ehrlich for selective toxicity. Number 606—actually, a modification of the original number 606—was effective and became arsphenamine (Salvarsan). To demonstrate efficacy and lack of toxicity, Ehrlich first performed experiments with rabbit models of syphilis (mice resist the infection), followed by what we would call Phase I and II clinical trials with patients—keeping careful records. Finally, after obtaining positive results, he scaled up production and marketed the first synthetic “blockbuster” chemotherapeutic agent in 1911, a mere decade after initiating the project. It remained the standard of care until antibiotics were discovered.
The subsequent production of numerous chemical agents that can cure disease or prolong life is a magnificent story of moving discoveries from the research bench to the patient’s bedside, and from the patient back to the research bench. In the history of chemotherapy for cancer, progress developed in two phases. During the first phase, from 1946 to the mid-1980s, the drugs produced were screened for efficacy primarily by assaying cytotoxicity against cancer cells in culture and in animal models, and then in patients. Most of the drugs acted by interfering with DNA replication or cell division. It is remarkable that until the1970s, medical students were taught that the biochemical and molecular abnormalities in cancer cells were quantitative (altered amounts) rather than qualitative (altered chemical composition and structure). During the second phase, which began in the mid-1980s, the targets for drug development became products of the aberrantly functioning genes that produce cancer. This progression was made possible by new knowledge about oncogenes and suppressor genes, and by new technologies for accurately detecting abnormalities in DNA and proteins.
Drug Development
The First Phase
Chemotherapy for cancer began in the 1940s, with the development of agents that target and eliminate malignant cells. The observed toxicity of mustard gas against blood leukocytes led Louis Goodman and Alfred Gillman to produce a form of this DNA alkylating agent, which could be delivered intravenously. This chemotherapy, named nitrogen mustard, produced objective clinical responses in patients with lymphoma. Another novel therapy that targeted DNA synthesis was developed by Sidney Farber. Knowing that folic acid was required for DNA synthesis, he worked with a synthetic chemist to produce folate antagonists. Amethopterin and later Aminopterin (methotrexate) produced dramatic but short-lived responses in children with acute lymphoblastic leukemia. With these two reports, the pharmacological therapy of cancer was born.
Although the title of this chapter is “From Bench to Bedside,” it is important to emphasize that the movement of ideas is invariably in both directions, back and forth between clinical researchers and the laboratory researchers. Nitrogen mustard was developed because physicians observed destruction of leukocytes and lymphocytes in soldiers gassed during World War I. The antifolate, Aminopterin, was developed because Sidney Farber tried treating leukemic children with folic acid (reasoning that their malignant cells appeared similar to cells observed with folate deficiency), and the acuteness of their disease became worse, not better. These observations, in turn, stimulated and informed laboratory research.
For the next 40 years, great progress was made in developing additional chemotherapeutic anticancer agents. Two approaches were used. The first approach involved synthesis of specific targeted agents—as with methotrexate. The next success was 6-mercaptopurine, another inhibitor of DNA synthesis, produced by George Hitchings and Gertrude Elion and shown by Joseph Burchenal to be effective in acute leukemia. The synthesis of new therapeutic molecules has been greatly enhanced by the development of three-dimensional models of target molecules, enabling chemists to design small lead molecules and test them using in silico computer-based screening.
The second approach involved screening of large numbers of natural products and led to the discovery of taxanes and camptothecin. These successes were followed by discovery of the anticancer properties of vinca alkaloids, platinum-based agents, nitrosoureas, and anthracyclines, all of which remain in use today.
The pharmaceutical industry has used these two general approaches—synthesis of new compounds and broad screening of natural products—to develop many therapies against cancer and bring them to the clinic for investigation in therapeutic clinical trials ( Figure 45-2 ). The successful chemotherapeutic agents that have been developed are summarized in Chapter 46. Today new methods of targeting and screening are being used to find therapies that counteract the function, or loss of function, of the products of aberrant genes that cause cancer (see later discussion).
Two other major breakthroughs in the development of cancer therapies during this first phase deserve emphasis. The first is the development of combinations of therapies administered simultaneously. This was applied to leukemia by Emil Freireich, Emil Frei, and James Holland in 1956, soon after combinations of antibiotics were found to produce enhanced efficacy against bacterial infections such as tuberculosis. The principle is to use two or more agents that provide additive killing capacities against a target, but with different toxic side effects that are not additive. In the late 1950s and early 1960s, this principle was first applied successfully in a series of clinical trials by these investigators and others for the treatment of childhood leukemia, and it was first used for the successful treatment of a solid tumor, testicular cancer, by M. C. Li and colleagues.
Leukemia researchers also pioneered the idea that treatment must continue beyond the time that the cancer is clinically detectable, in order to prevent recurrence due to the persistence of subclinical disease. Today this is standard practice for the care of many types of cancer. As with the combination therapy studies, the results of leukemia research in murine models provided the rationale for these studies.
A second major breakthrough in cancer therapy and the treatment of many diseases took advantage of a new technology invented by Kohler and Milstein, which enabled production of large quantities of a monoclonal antibody raised against a specific antigen. This technique was rapidly applied to the production of antibodies targeting molecules on the surface of cancer cells. Major clinical responses in lymphoma patients were reported by Ronald Levy and colleagues in 1982, with an anti-idiotype antibody against the specific immunoglobulin molecule expressed on the surface of the patients’ malignant B cells. Today, nearly half of the agents that are approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer are monoclonal antibodies, a revolution in targeted cancer therapy that has occurred in the past three decades.
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