Oncology, Molecular

Abstract

Molecular Oncology can be defined as that branch of medical science that looks at the cancer problem from a molecular point of view. For several reasons, “molecular oncology” represents “the heart of the matter” of cancer.

As it would be quite an ambitious, and virtually impossible, task to pretend to cover the whole subject of “Molecular Oncology” in a single unipersonal review, what follows is a short personal view of what the author regards as the basic molecular understanding of cancer in the year 2004, and the more likely therapeutic implications of this new molecular knowledge.

We should not forget the huge prevalence of malignant diseases in the developed world. Cancers are probably responsible for one-third of deaths in men in industrialized countries and for almost one-fourth in women. At the beginning of the twenty-first century, these diseases still cause a lot of human suffering, despite very significant progress in their early detection, improvements in radical treatments (local or systemic), and better medical control of iatrogenic side effects of chemotherapies.

In the same way as the invention and later refinement of the microscope eventually led to the discovery and classification of pathological microorganisms, the discovery of DNA, RNA, proteins, proteoglycans and other regulatory molecules (including lipids, arachidonic acid derivatives, steroids, and sex hormones) is rapidly leading to a better and deeper understanding of cancer, and remains the best promise to lead to better and more effective methods for cancer prevention, early detection, prognostic classifications, and cure.

This is because it is currently believed that cancer can be truly understood in terms of those molecular changes, genetic and epigenetic, that gradually lead a given cell clone, within a given tissue field, to develop a certain “competitive advantage” over neighboring cell clones, enabling the transformed cell clone to gradually displace its neighbors and grow into a neoplastic tissue. Finally, this “new tissue” can go on to transform itself into a malignant neoplasia, leading to invasion of local organs, or distant spread (generally through the bloodstream, the lymphatic system, or both). The growth of cancer cells at distant sites is called metastasis.

“Cancer” is a state, whereas “carcinogenesis” is a process. Key to the multistep genetic nature of cancer is that carcinogenesis is “progressive.” In most epithelial tissues, progression means the sequential accumulation of somatic mutations, or even epigenetic changes (like abnormal DNA methylation patterns). In some cases of familial predisposition to cancer, some of these mutations are inherited.

Gradually, a given target tissue experiences a transition from normal histology, to proliferative and/or dysplastic changes, to so-called intraepithelial neoplasia (IEN), which can be early or severe, to superficial cancers (in situ), and finally to invasive disease. In some instances, this process of malignant transformation may be aggressive and relatively rapid (e.g. in the presence of a DNA repair-deficient genotype, or an aggressive oncogenic virus, or a lethal combination of “oncogenic hits”), but in general these changes occur over a long period of time, like 3 to 30 years.

The problem is that in the past two and a half decades there has been an “explosion” of information, rather than true knowledge, about the molecular aspects of cancer. More than 300 different genes and their respective protein products have been described as being directly or indirectly linked to cancer. The number of such ‘cancer-related genes’ is constantly increasing and the final figure could well be more than 1000. Although it seems reasonable to believe that some, or many, of these ‘cancer-related’ genes may represent the consequence rather than the cause of the cellular development of the cancer cell phenotype, the ‘trees’ are so many that there is a real risk of missing the “wood.”

Indeed, some believe that, in the not too distant future, relevant information will pass from the Molecular Pathology Laboratory to the busy Cancer Clinical Units only with the help of clever computer programs. Before clinicians can make up their minds about the curability or incurability of any given cancer, and in order to decide which sequence and combination of drugs to use to treat a particular patient, they will have to consult a computer program and the Molecular Pathology Laboratory. Although there is still no treatment for any of the major lethal cancers that is as effective as, say, antibiotics are against infections, there is vast accumulated knowledge of the fine regulatory mechanisms that are deranged in cancer cells, and this undoubtedly promises new therapeutic insights. For example, selective oral tyrosine-kinase inhibitors (Gleevec), for chronic myeloid leukemia, and specific monoclonal antibodies (Herceptin) for breast cancer or some lymphomas (Mabthera), have been introduced into routine clinical use.

In contrast to the situation twenty years ago, not only do we now know of many molecular targets to design new drugs for the chemoprevention or treatment of cancer but, paradoxically, we have an apparent excess of targets for our current resources of drug development worldwide. The Human Genome Project has completed its first basic human genome map well ahead of schedule, and it is likely to give us further insights and more potential targets. It is now estimated that the human genome contains some 35 000 genes, which is less than had originally been estimated by most researchers. Many of these genes are well characterized and their functions in various pathways are known. But the real function of the majority of these human genes remains inconclusive. In other words, the rate-limiting step in true progress against cancer is the amount of resources we can spend, and the optimization and coordination of this huge research process, rather than a shortage or lack of therapeutic targets.

Selecting the right targets for cancer therapy can make a big difference. If, for example, we were clever or lucky enough to correctly guess the right targets for the main human cancers, and if large multinational pharmaceutical companies agreed to focus their efforts and enormous resources on these right targets, then revolutionary new cancer treatments might become available for clinical testing within 5 to 10 years. But, if we got it wrong, or not enough importance was given to this war against cancer by politicians or business people, then it might take another 20 or 30 years, or even more.