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
industrialised countries, and almost one fourth in women. At the beginning of the XXIst c. of the Christian era, 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 micro-organisms, 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 neighbouring cell clones, enabling the transformed cell clone to gradually displace their neighbours, 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 throug the bloodstream, the lymphatic system or both). The growth of cancer cells at distant sites is called
“Cancer” is a state, but “carcinogenesis” is a process. Key to the multi-step genetic ature 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 4
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 : 5 to 30 years.
The problem is that in the past two and a half decades there has been a true “explosion” of information, rather than true knowledge, in the molecular aspects of cancer: over three hundred different genes and their respective protein products have been described as directly or indirectly linked to cancer, but the number of “cancer related genes” is constantly increasing and the final figure could well be over one thousand . 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 programmes . Before clinicians can make their mind on the curability or incurability of any given cancer, and in order to decide which sequence and combination of drugs to use to treat any patient, they will have to consult a computer programme and the Molecular Pahology Laboratory.Although there is still no treatment for any of the major lethal cancers that is as effective as the antibiotics are for infections, the knowledge that has accumulated on the fine regulatory mechanisms that are deranged in cancer cells
is vast and undoubtedly promises new therapeutic insights. The introduction into routine clinical use of selective oral tyrosine kinase inhibitors (Gleevec), for example for chronic myeloid leukemia, and specific monoclonal antibodies (Herceptin) for breast cancer or some lymphomas (Mabthera), are good examples.
In contrast to the situation twenty years ago, not only do we know 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, less than originally thought 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 speculative. In other words, the rate-limiting step in true progress against cancer is the amount of resources we can spend , and the optimisation 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 five to ten 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.