New Wave Cancer Therapy: Disease-Specific Strategies

A tacit assumption underlying the search for anticancer drugs over the last 30 years has been that all cancer cells, irrespective of tissue origin, share certain common features that account for their unregulated growth and malignant properties. Accordingly, drugs effective against one type of tumor should be active against other classes of cancer. Unfortunately, this has not been the case. While many of the 40 FDA-approved cancer drugs are effective against certain leukemias and lymphomas (the so-called liquid tumors), their impact on the so-called solid malignancies (principally lung, breast, and colon) has been minimal. There are exceptions, however Cisplatin, introduced in 1978, has increased con- siderably the survival of patients with testicular cancer—a solid malignancy—but not with other classes of cancer. These differential responses to chemotherapy of the liquid and solid malignancies, and among the different types of tumors within these classifications, demonstrate clearly that malignant tumors do not display a uniform sensitivity to any particular cancer drug. In fact, the opposite is true; sensitivity (or refractoriness) is critically dependent upon the tissue origin of the cancerous cell. The experience with interferon-alpha illustrates this principle. Interferon-alpha, once heralded as a breakthrough cancer drug, has failed to meet expectations and has significant therapeutic utility only against a rare (440 cases per year) form of cancer known as hairy cell leukemia. It is not approved for the therapy of other neoplasms. Biologically, these observations are unsurprising. When a cell within a specific tissue acquires malignant properties, not only does it display unregulated growth but it also retains many of the differentiated functions characteristic of the original tissue. We must expect, therefore, that the biological behavior of individual tumor types will be influenced to a large extent by the functional characteristics of the tissue from which the malignant cell was derived. Some examples may help clarify this concept. Circulating white cells, upon becoming malignant, retain their capacity to maneuver throughout the vascular and lymphatic systems, and indeed it is the peripatetic nature of these cells that accounts for the multifocal pathology of leukemias and lymphomas, including multiple skin eruptions (T-cell lymphomas) and involvement of several lymph nodes (B-cell lymphoma). Similarly, glandular epithelial cells in lung and colon produce large amounts of mucus to protect these organs from chemical (for example, smoke) and biological (for example, bacterial and viral) insult. This feature is also expressed by their malignant counterparts (adenocarcinomas). This argument is especially applicable to colorectal cancer. In the normal colon, glandular epithelial cells (and secreted mucus) serve as a defensive barrier against the luminal contents of the large bowel which includes toxins, carcinogens, viruses, parasites, and bacteria. These cells, to be maximally effective, must have acquired over the course of evolution specialized biochemical mechanisms to deal with such a range of injurious agents. We might expect this cell population, following malignant conversion, to be particularly well-armed to handle assaults by chemotherapeutic agents and other cytotoxic modalities. Clinically, this is what is observed; colorectal cancer is essentially untreatable by available chemotherapeutic drugs. These arguments have important implications for cancer drug discovery. It is clear, based on historical precedent alone, that efforts aimed at seeking breakthrough agents effective against a broad range of liquid and solid malignancies are unlikely to be rewarding. A more attractive approach is to target specific types of cancer (such as lung, breast, and colon) and incorporate into the drug discovery strategy an appreciation not only of the malignant cell but also its normal counterpart. In other words, the chances of finding a therapeutic chink in the armor of a cancerous colon cell are significantly greater if we have some insight into the biochemical processes that regulate the growth and differentiation of a normal colon cell. While understanding these same processes in white blood cells may prove useful in discovering drugs for leukemiss and lymphomas, it is unrealistic to expect these agents to have any impact on such a biologically distant cell lineage as malignant colon epithelial cells. Interferon-alpha has already been mentioned as a disease-specific cancer drug, but there are other examples that demonstrate more emphatically how an appreciation of normal cell function can lead to therapeutic opportunities in treating malignant disease. The first is prostate cancer. DHT (5-dihydrotestosterone) is the major trophic hormone for the developing prostate and was early on suspected of playing a significant role in promoting the growth of prostate cancer. Protocols were devel- oped to ablate DHT activity in afflicted patients, with considerable success. Several forms of intervention have been developed including castration (which removes the principle source of testosterone, the precursor for DHT), estrogens and LHRH analogs (which disrupt testosterone synthesis), DHT receptor antagonists like flutamide and, more recently, inhibitors of the enzyme 5-dihydroreductase, which converts testosterone to DHT. Although these treatments are not curative, they do provide symptomatic relief to many prostate cancer patients and, in some cases, increase survival. Endocrine therapy of prostate cancer is a good example of how a biological understanding of a normal tissue can be instrumental in developing new protocols for malignant disease. Tamoxifen, an antiestrogen, falls within the same category. This agent has found wide acceptance in the treatment of breast cancer. Its effectiveness probably reflects the estrogen-dependency of breast cancer cells, a characteristic they derive from the normal glandular breast epithelium. New Opportunities We believe these types of agents are the wave of the future in cancer therapy. They will be distinguished by their disease specificity, relatively nontoxic profiles and, as analogs of trophic hormones, their actions through cytostatic, rather than cytotoxic, mechanisms. As basic biological research unearths the hormonal dependency of other tissue systems (in particular, lung and colon epithelium) they will provide new opportunities for discovering drugs effective against the corresponding malignancies Progress in identifying local mediators of cell growth and differentiation will also have important implications for development of new disease-specific strategies. The major function of these molecules (inchiding TGF-beta. PDGF, and FGF) is to mediate wound repair with full restoration of differentiated function. There is now increasing speculation that agents of this type play a pivotal role in promoting the growth of metastatic tumor cells in distant organs. Since several of the major solid tumors display organ-specific metastatic spread (colon carcinoma/liver and lung breast carcinoma/stomach and bone; and lung carcinoma/brain), it is possible that availability of local growth factors within the afflicted organ and the tumor cells’ ability to respond to them may underlie these patterns of metastatic dissemination. If correct, then blocking these mediators may provide a novel way of disrupting tumor cell growth. Again, this will involve a diseasespecific strategy because, as indicated above, different tumors display different patterns of metastasis. An agent that blocks the growth of colon metastases in the liver would not be expected to halt proliferation of breast metastases in bone. Once more, the emphasis is on understanding the biological behavior of individual types of tumors and on developing appropriate strategies for intervention. Eventually these may involve combinations of both trophic and local growth factor antagonists. By focusing on the biological uniqueness and thelife history of different classes of neoplasm and by using stealth instead of (or in combination with) brute force, incre- mental but significant improvements in the therapy of the major neoplasms may be achievable within the next 15 to 20 years.

New Wave Cancer Therapy: Disease-Specific Strategies

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