ABSTRACT

process that is out of date and not attuned to what is required at the clinical evaluation stage. Emphasis on unwieldy and time consuming clinical trials makes it very difficult to develop drug combination protocols in a timely manner. Finally, the biomedical community has been slow to consider the implications that many types of cancer may have as their necessary cause infectious agents, including both viruses and bacteria.

INTRODUCTION

Malignancies arising in epithelial tissues constitute by far the largest number of clinically occurring cancers. Although cancers arising in orbital structures are relatively uncommon compared to carcinomas of the aerodigestive tract and breast, collectively the epithelial cancers represent a formidable clinical and scientific challenge. While there has been some progress made in the management of certain of these tumors, the distressing fact remains that the great majority of these malignancies remain incurable once they have reached an advanced stage.

In the last few years there have been a number of conceptual advances made in our understanding of cancer at the molecular level and for the first time it has become possible to envisage rationally constructed treatment strategies. There remain many problems, however, not the least of which are (in this writer’s opinion) overly conservative thinking by the biomedical research community and the entrenchment of a drug development and approval process that is excessively bureaucratic and poorly set up to expedite novel treatment approaches.

STEPS TOWARD TUMOR SPECIFIC THERAPY

For more than 50 years the principal drugs used in the treatment of metastatic cancer have been a variety of cytotoxic chemicals that have been found in the process of empirically screening many hundreds of thousands of both synthetic and naturally produced organic compounds. From this huge

inventory, some 50–60 agents have been discovered, which have at least some clinical activity against some cancers and which have a satisfactory therapeutic index. In addition, a number of hormonal agents such as androgen and estrogen analogues and corticosteroids have been found to have a useful role in the management of certain types of malignancy.

Virtually all of the cytotoxic agents act by interfering in DNA function or synthesis or by damaging the mitotic spindle. This in turn triggers a cellular auto-destruct sequence (apoptosis) with resultant cell death (1). Hormonal agents likewise can initiate apoptosis in certain cell types. However, only a minority of cancer types are highly susceptible to cytotoxic drug inhibition and for the most part these do not include the common epithelial cancers of middle and older age. Hormonal agents are active in breast and prostate cancers but do not appear able to yield cures against advanced disease, even when used in combination with cytotoxic agents.

New cytotoxic agents are always being added to the inventory but all suffer from the same limitations as the older drugs and they have not significantly expanded the range of tumors that can be effectively treated. It appears self-evident that new strategies will be required to develop drugs that will have both different spectra of activities as well as superior therapeutic indices.

CANCER SPECIFIC MOLECULAR TARGETS

Recent studies have produced comprehensive molecular models of the transformation of a normal cell to the malignant state (2). Three broad categories of alterations are required to produce the full blown malignant phenotype. The first involves one or other of the signal pathways that provide growth signals to the cell nucleus. This usually is a consequence of overexpression or constitutive activity of one or more of the many growth factor receptors. Many of these growth factor receptors have regions that function as tyrosine kinases (3). That is, they are able to catalyze the transfer of a

phosphate group to a specific tyrosine residue in an adjacent protein. This changes the shape of the protein and permits interaction with other proteins in turn altering their shape, activity, etc. A common biochemical mediator of these signals consists of a series of phosphorylation–dephosphorylation reactions, which ultimately initiate DNA synthesis by activating DNA transcription factors.

Another critical change involves activating the genes that block the various programmed cell death pathways. As a result, processes that would normally act to put a brake on continuous cell division and to cull cells that are expressing abnormal growth signals are suppressed, allowing the neoplastic cell unimpeded growth.

It appears that human cells require a third fundamental change to permit continuous cell proliferation. This involves activation of the enzyme telomerase, which acts to prevent the shortening of the telomeres at the ends of chromosomes. Progressive shortening of the telomeres normally provides a signal for the cell to stop dividing after a set number of divisions. This occurs in all normal somatic cells with the exception of stem cells and germ cells. However, normal stem cells still respond to appropriate physiological stimuli to regulate their growth and total numbers. Malignant cells that have largely lost their capacity to respond to these signals are thus not constrained in their relentless expansion.

The identification of these molecular alterations also suggests that inhibition of one or more of these steps might represent the basis for potent and specific antitumor drug treatments. Preclinical data as well as preliminary clinical trials indicate that this is indeed the case and that whole new classes of antitumor agents can be produced, which can be rationally used against specific categories of clinical malignancy.

Some of the most promising of these newer agents are specific inhibitors of the tyrosine kinase growth factor receptors. A particularly interesting drug is STI 151, a 2-phenylaminopyrimide compound that is undergoing largescale clinical evaluation (4). This drug has been found to be particularly effective in inhibiting the abnormal fusion

protein, bcr-abl, which is a hallmark of chronic myelogenous leukemia (CML). The bcr-abl protein functions as a continuously active tyrosine kinase growth factor receptor in CML and plays a major role in the continuous proliferation of myeloid cells in this disease. Treatment with STI 151 results in greater than 95% remission rate in CML with very little toxic side effects. Turning off bcr-abl results in massive apoptosis of leukemic cells without concomitant damage to the normal myeloid elements as they lack the bcr-abl gene, which arises due to a chromosomal translocation. Shutting down the growth stimulus provided by the abnormal protein removes the block to apoptosis that would otherwise occur to regulate cell numbers (5–7).

STI 151 also is a powerful inhibitor of the c-kit oncogene, which is structurally similar to bcr-abl. c-kit is overexpressed in the rare gastrointestinal malignancy, gastrointestinal stromal tumor, or GIST, which is a slow growing mesenchymal tumor of the gastrointestinal tract. More than 50% of these otherwise refractory malignancies show an excellent clinical response to treatment by STI 151 (8).

The responses seen with this drug are not permanent in most cases, with relapse by drug resistant tumors being the rule. This clearly argues for combination therapy with agents that act on the new pathways that are activated in the drug resistant state. As will be mentioned below, scientific validation and demonstrated clinical need of a drug is no assurance that the drug approval process will actively encourage it.

Another drug that has entered clinical trial is the quinazoline compound ZD 1839 (Iressa), which inhibits the epidermal growth factor receptor (EGFR) that is commonly dysregulated in many epithelial malignancies (9). Iressa has shown responses in nonsmall cell lung carcinoma (NSCLC), a tumor which is typically unresponsive to standard cytotoxic drug protocols. However, the responses tend not to be complete or highly durable, indicating that this agent will have to be employed as part of a sophisticated drug combination.

A large number of other compounds are being evaluated, which act at various points in the growth factor signaling pathways. Immediately downstream from the EGFR kinase