Supportive Care

Advancements toward earlier detection and improved outcomes with new targeted therapies promise to transform cancer into a chronic and manageable condition rather than a uniformly fatal disease. In this context, ameliorating symptoms caused by the underlying cancer or side effects of toxic therapies with supportive care are increasingly important in the management and treatment of cancer. The advent of molecular biological and bioinformatic techniques makes it possible to begin to understand the pathological basis of cancer-associated cachexia, pain, and depression, for example. In addition to acting as tumor therapeutics, antibodies may be especially well suited to supportive care in treatment of cancer, given their targeted nature.

TNFa is a good example of a potential antibody target for supportive care in treatment of cancer, as TNFa is believed to play a crucial role in mediating cancer-related morbidity. The utility of blocking TNFa with the chimeric antibody Remi-cade is under preclinical and clinical investigation. Remicade is currently FDA-approved for the treatment of immune-mediated inflammatory disorders, including Crohn's disease and rheumatoid arthritis. The range of potential indications for supportive care is broad and diverse due to the pleiotropism of TNFa action and includes cancer-associated depression, fatigue, cachexia, treatment of toxicities due to chemotherapy and radiotherapy, treatment of metastatic bone pain, and graft versus host disease (GVHD) [15-19].

A wealth of evidence implicates TNFa as a mediator of cachexia [20]. In fact, TNFa was initially called "cachectin" because it caused severe wasting in rodent models of disease. TNFa has also been shown to be important for cachexia at the cellular and molecular levels, both by increasing destructive proteolysis in mature skeletal muscle and by inhibiting the differentiation of myoblasts necessary for the repair of damaged or stressed muscle tissue [21].The molecular details of TNFa action on skeletal muscle are starting to be elucidated. Acharyya et al. [22] provide evidence that TNFa, acting in concert with interferon y (IFNy), specifically down-regulates the expression of myosin heavy chain. These observations help to explain the molecular pathology of cancer-related cachexia and may point the way to measurable pharmacodynamic markers of anti-TNFa activity. Clinical trials are now testing the ability of anti-TNFa agents such as Remicade to inhibit wasting in cancer patients [20, 23]. Additional targets that have been associated with cancer cachexia and may be attractive antibody targets include interleukin (IL)-1, IL-6, proteolysis inducing factor (PIF), and IFNy [23].

Several other cancer-associated conditions could be potentially attributed to TNFa activity. Cancer-related pain remains a significant unmet medical need. TNFa appears to be important both for the pain signal itself as well as metastatic bone erosion [24, 25]. TNFa also appears to mediate many of the unwanted side effects of radiation therapy. Radiation-induced production of TNFa by tumor cells enhances the intended local proinflammatory effects of ionizing radiation, but also damages normal tissue and can cause unwanted fibrosis. Preclinical and clinical data suggest that TNFa plays a role in mediating radiation-induced normal tissue damage and fibrosis and that anti-TNFa therapy may be effective treatment for the prevention of these deleterious side effects [26, 27].

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