Targeted Therapies: Navigating the "Other" Web

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Julia Draznin Maltzman, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 25, 2004

Oncology is, without a doubt, one of the most exciting fields in Medicine. New developments in screening techniques, diagnostic options, and treatment possibilities, have been unsurpassed by any other medical discipline. New technology now enables better quality and faster imaging possibilities. An improved understanding of physics and computers enables patients to receive radiation therapy with fewer side effects and less healthy tissue exposure. There are even new options for less invasive and more precise biopsy techniques. Less invasive techniques decreases possible complications and potential side effects and render the procedure much safer for the patient. In the realm of therapeutics, the biggest change seen in the past few years is the discovery and use of targeted therapies. As scientists are better able to narrow the cellular changes that lead to cancer, they can concentrate on developing therapeutic options that target only this abnormality. Using therapies with specific and narrow targets ensures that only the cancer is destroyed and healthy tissues are spared toxic side effects. Usually this approach translates into a much more easily tolerable therapy.

The origins of targeted therapy lie in the continued discovery of molecular signals and their complex interactions. As researchers learn more about cell signaling and the aberrations within that result in the development of cancer, we are better able to piece together the “cause(s)” of cancer. In the life of a single cell, small and subtle molecular indiscretions can lead to the difference between the onset of cancer and maintenance of health. This week's news flash will help the reader understand the complex world of molecular biology and how it has revolutionized cancer therapy.

The origins of signaling

Cell to cell signaling was the focus of research in the late 1980s and early 1990's. Scientists looked for ways to stop cancer by inhibiting cellular interactions with its environment. There was a surge of investigation into cell adhesion molecules, cell surface molecules, and cell binding components. This research resulted in a more sophisticated understanding of how cells interact with one another and the matrices around them. Knowledge was gained about the mechanisms of cancer cell penetration through barriers such as membranes, blood vessels, and capsules. Science soon transitioned to focus their efforts more on the communication pathways that are transmitted within a cell. That is to say, once a cell receives a signal from the outside, how does that message get passed on from the cell surface to the nucleus? By analogy, when people get commands from others such as to eat, run, answer the phone, etc. the brain processes the information, and then sends signals to the part of the body performing the action – mouth, legs, speech center, respectively. How this process works within each microscopic cell, to this day remains unclear, and is the focus of much research today.

It is likely that each cell processes information slightly differently and one universal answer will never be available. What does seem to be a recurrent theme, however, is that cells transmit information into the nucleus by hundreds of molecular signals. These signals occur both in series and in parallel to one another. The multiple pathways can and do cross talk with one another and there are both positive and negative messages being transmitted. The result is a true web of signals.

What does that mean?

For example, a blood borne protein or carbohydrate stimulates a cancer cell surface receptor. The activated receptor activates one or more molecules that reside on the intracellular side (inside the cell) of the cell membrane. These molecules in turn, need to activate others that are either in the cytoplasm of the cell, can travel within the cytoplasm, or can build a scaffold on which other molecules can move and carry the information to the nucleus. In this process, there can be hundreds of signals transmitted between the cell surface and the coiled cellular DNA within a fraction of a second. To make things more intricate, these signals tend to overlap within this complex web of signal transduction. One molecule can be involved in two or three different signal transduction cascades at once. Scientists believe that this is nature's way of conserving resources and ensuring survival. A single molecule can be stimulated by two different receptors thereby ensuring that if one such receptor is mutated (gene mutation) or is missing (gene deletion), then the action can still occur.

Another possibility is the following scenario: a command to initiate cell division may begin with stimulation of a single cell surface receptor. This receptor stimulates two separate molecules, one that potentiates the cell division message, and the other molecule that may signal it to stop. At first the paradoxical result seems odd. However, this is simply nature's way of building in systems of checks and balances so that no one renegade signaling cascade overpowers the others. If two contradictory signals are simultaneously activated, one usually predominates over the other. Cells have sensory mechanisms in place such that when the balance of the two opposite signals grows significantly out of proportion to the other, the weaker signal will prevail. A deficiency of such checks and balances may result in uncontrolled growth, and thus, cancer.

Another clever trick of nature is the redundancy and support that one signaling cascade may offer another. The same pathway that signals for cell division, may activate multiple molecules that stimulate for cell growth, cell spread, and even cell differentiation. When we were cavemen and women, this seemingly duplicative role probably served as conservation of resources in the event of scarce food and nutrients -- ensuring that a single stimulation could lead to multiple related events that promote growth and survival.

Exploiting the signals

In the past decade, investigators noted that targeting specific cellular signals, especially those prevalent in cancer cells, can serve as effective and well tolerated anticancer therapy. Traditional chemotherapy targets rapidly dividing cells and preferentially kills them. The rationale being that cancer grows faster than normal, healthy cells, therefore drugs that target rapidly dividing cells would preferentially kill cancer cells. Although, this is true in principle, almost all cells divide, therefore all cells can and do eventually fall victim to chemotherapy. This makes sense, if one considers the most common side effects of chemotherapy – hair loss, diarrhea, and a decrease in blood counts. Cells in the root of the hair, lining the intestine, and the bone marrow, are by far the most rapidly dividing cells in an adult body. Side effects of chemotherapy would be most evident in these cells. In an effort to minimize side effects and to create more elegant and clean chemotherapeutics, researches realized that using specific molecules active in cancer as targets of therapy can be a safe and effective means of treating this disease.

The first

One of the first targeted therapeutics developed to fight cancer is rituximab, ( Rituxan , Genentech). Rituximab is an antibody that specifically targets a protein found on a subset of white blood cells called lymphocytes. It is used in the treatment of many different types of lymphoma. Rituximab revolutionized lymphoma therapy. It made available a non-chemotherapeutic option, with few side effects, which could be given to patients with mild organ dysfunction, while at the same time, producing an impressive response rate.

Almost simultaneously, breast cancer researchers were developing an antibody targeting the gene that seems to be overexpressed in aggressive forms of breast cancer. Traztuzumab (Herceptin,Genentech) was thus born. The leukemia world gained gemtuzumab ozogamicin (Mylotarg, Wyeth Ayerst) in its armamentarium of antileukemia drugs. This, too, is a monoclonal antibody targeting a specific protein seen only on leukemic cells. This particular antibody, however, is linked to a powerful antibiotic. As the antibody finds and binds to its target, the antibiotic is released and helps to kill the target cell. More recently, some patients with certain slow growing lymphomas have a new monoclonal antibody called alemtuzumab (Campath, Berlex Laboratories) that may help them. Alemtuzumab works in the same way as rituximab, but targets a different cell surface protein.

Certainly the two monoclonal antibodies that have attracted the most attention recently are bevacizumab (Avastin, Genentech) and cetuximab (Erbitux, Imclone systems). Both of these new agents approved in the setting of metastatic colorectal cancer and have totally altered the topography in its treatment. Just five short years ago, physicians had but one drug to offer patients with this disease. Today, two new chemotherapeutics and two monoclonal antibodies have been approved. Various combinations of these new agents are currently under investigation and, perhaps, one day, physicians would be able to tailor therapy to each individual patient, avoiding toxic side effects, and ensuring efficacy.

The next scientific step was the addition of a radioactive isotope to an antibody like rituximab. This ensures that the antibody would not only bind and kill the cell to which it is bound, but it would also release radioactivity, and kill surrounding cancerous cells that a plain antibody could not reach. Using such a radioisotope actually makes sense when we consider how a mass of malignant cells grows. When a tumor cells grow, they can form into a dense “ball” of cancer cells. The cells located at the center of this “ball” are not as accessible to therapy as the cells that are found on the outside. Upon binding to the tumor a radio-antibody can locally release radiation to kill other cancer cells in the vicinity to which the antibody could not specifically bind. This is the rationale behind ibritumomab tiuxetan (Zevalin, Biogen) and tositumomab (Bexxar, Corixa and GlaxoSmithKline).

No other drug revolutionized therapeutics quite as much as imatinib (Gleevec, Novartis). In some cancers such as acute myeloid leukemia and some gastrointestinal stromal tumors (GIST) an abnormal protein is produced. Gleevec, targets and inhibits this abnormal protein. Inhibition of this abnormal protein induces programmed cell death in the affected cell. This unique mechanism of action, results in the death of all cancerous cells harboring the protein without affecting normal/healthy cells. Gleevec is not an antibody, however, it is rather a small molecule that can inhibit proteins known as tyrosine kinases. Thus, it is also called a ‘tyrosine kinase inhibitor'. Tyrosine kinase is one of the most common molecules through which cell signaling occurs and is the largest family of dominant oncogenes. It is involved in cell growth, division, and differentiation. Another tyrosine kinase inhibitor was approved just last year to help fight lung cancer. Gefitinib, ( Iressa , AstraZeneca), offers lung cancer patients who failed primary therapy, some hope for symptomatic and quality of life improvement.

The new drug to keep an eye out for is Bay 43-9006 (Onyx Pharmaceuticals and Bayer). The uniqueness of this drug lies in the fact that it can inhibit two powerful signaling pathways that signal growth. One pathway inhibits tumor cell proliferation by targeting what is known as the ras-raf-mek-erk signaling pathway, and the other is the anti-angiogenesis pathway by targeting the tyrosine kinase receptor VEGFR-2 and PDGFR. Pre-clinical studies found this drug to have great activity in many cancers. Phase II and III trials are currently ongoing in kidney cancer, melanoma, lung cancer, pancreatic cancer, and liver cancer. This drug was just granted fast track designation by the FDA. This designation is a promise from the FDA that it will take all appropriate actions to expedite the development and review of the application for approval of each of these products. To date, the greatest activity has been seen in renal cell carcinoma and melanoma. There will be much more about this agent in the next few years.

For more Information on targeted therapies, please see our Targeted Therapy Section