Use of Transcription Factors as Agents and Targets for Drug Development
Use of Transcription Factors as Agents and Targets for Drug Development
Cancer is a genetic disease wherein mutations of growth regulatory genes result in abnormal proliferative capacity, recognized clinically as the occurrence of a malignant tumor. Transcription factors govern the expression of genes, be they "housekeeping" or regulatory. These factors organize the first crucial step in establishing the function of the gene, namely, the transcription of information in DNA into messenger RNA (mRNA). Translation of mRNA results in the synthesis of the oncogenic protein. Hence, the design of therapeutic agents targeted at transcription factors regulating the initial flow of "bad" information from "damaged" genes should be the ultimate goal of efforts to develop new weapons in the therapeutic armamentarium of the oncologist and, indeed, the general internist.
Ideally, recognition of abnormal transcription factor activity leading to the expression of "proneoplastic" genes could allow introduction of specific therapy targeted at the abnormal transcription factor. The action of such a therapy would quiet down the unruly gene, and therefore, avert the neoplastic catastrophe lying in wait for the patient. Alternatively, a critical transcription factor related to sustaining the actual growth of the tumor could be counteracted, with the resultant death of the established tumor.
Are these goals "pie in the sky"? On one level, no. Every oncologist who prescribes tamoxifen (Nolvadex) for metastatic breast cancer, uses leuprolide (Lupron) to treat metastatic prostate cancer, or considers retinoid therapy for patients who have survived an initial upper aerodigestive tract cancer is manipulating transcription factors as the initial step in the efficacy of those respective therapies. Indeed, measurement of the estrogen-receptor content in a particular patient's tumor is a recognized predictor of the efficacy of tamoxifen treatment, and the estrogen receptor is a member of but one of the families of therapeutically relevant transcription factors reviewed by Smith and Birrer. The critical questions are, how to generalize from these examples to the variety of transcription factors affecting other neoplasms, and how to increase the efficacy of that approach? And these questions lead to a consideration of a number of problems surrounding the development of such agents.
Issues in Developing Anti-Transcription Factor Agents
One major unknown is how "neoplastic cell" transcription factors differ from "normal cell" transcription factors. As Smith and Birrer point out, the sharing of a tumor's growth-regulatory pathways with those of normal cells from the tissue of origin raises the concern that the ultimate therapeutic index for such an approach may be narrow. However, this issue has not been clearly or accurately investigated in the vast majority of human tumors. In fact, there is hope from recent studies in hematopoietic neoplasms that there may, indeed, be very tumor-specific rearrangements of transcription factors.
For example, as reviewed by Gauwerky and Croce, the t(1:19)(q23;p13) chromosomal translocation present in 30% of pediatric B-cell acute lymphocytic leukemia (B-ALL) apparently encodes a chimeric transcription factor that joins the effector domains of a transcription factor regulating immunoglobulin gene expression with the DNA-binding motif of a homeotic gene. The product resulting from this "monster gene" is clearly like nothing else found in the organism and would be a potentially useful point of departure for considering agents to interdict its function. This circumstance therefore highlights the need to better understand how transcription factors and their complexes in epithelial neoplastic cells actually differ from "normal." Workers investigating the common epithelial neoplasms have not paid attention to this issue with as much clarity as might be useful.
A second general problem is the utility of current models in supporting the development of anti-transcription-factor-related therapies. In general, the pharmaceutical industry is not very interested in antineoplastic agents that do not cause overt shrinkage of the usual repertoire of established human tumor xenograft models. Given our understanding of the biology of how transcription factors would be expected to promote neoplastic growth, these models probably are not at all relevant to the development of anti-transcription factor-directed therapeutics.
At best, anti-transcription factor therapies may be cytostatic or differentiating, rather than overtly cytotoxic. At worst, if any useful effect is to emerge, such agents may need to be used early in a tumor's ontogeny. This circumstance would call for a means to detect the presence of a "protoneoplastic" population of cells to identify patients in whom the efficacy of such therapies could be demonstrated. This state of affairs would entail challenges to the normal developmental process for such drugs, both preclinically and in clinical trials. Therefore, efforts to develop anti-transcription factor-directed therapies for the common adult neoplasms must go hand in glove with efforts to define the role of transcription factors in tumor pathogenesis. Only then will models be defined that will clearly delineate the potential of such agents.
How to Discover Anti-Transcription Factor Drugs
Smith and Birrer describe several potential modes of screening for anti-transcription factor drugs, including: (1) examination of the interdictors of "marker gene" activity, such as chloramphenical acetyl transferase (CAT) assays in engineered cell lines; (2) modulation of the kinases and phosphatases that would be expected to regulate the activity of the transcription factor complex; and (3) efforts to design molecules related to the structure of the transcription factor. In my opinion, it is the last generic type of effort that should be focused on with intensity. We must define agents that can interact with high affinity with the structural domains of transcription factors important in promoting complexing with either other transcription factors or specific DNA sequences.
The authors gloss over the realities of delivering large molecules, such as transcription factors or even fragments of transcription factors, into cells. Rather, the true value of the "dominant-negative" technology described in the article and practiced so elegantly by Dr. Birrer's laboratory is to define the important molecules and thus help find small molecules that may act like the dominant-negative mutants. In this way, the dominant-negative approach described by Drs. Smith and Birrer will not only prove to be the Rosetta stone for understanding the basis of the action of transcription factors but also will lead to the building of Trojan horses to abrogate their tumor-promoting action.
1. Allegra J, Lippman M, Thompson E, et al: Estrogen receptor status: An important variable in predicting response to endocrine therapy in metastatic breast cancer. Eur J Cancer 16:323-331, 1980.
2. Gauwerky CE, Croce CM: Molecular genetics and cytogenetics of hematopoietic malignancies, in Mendelsohn J, Howley P, Israel M, et al (eds): The Molecular Basis of Cancer, pp 18-37. Philadelphia, WB Saunders, 1995.