New Cancer Therapies: More power to Darwin

4. June 2012
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What does Charles Darwin's theory have to do with modern cancer research? More than one might think, because malignant cells undergo an evolution in fast motion. Now researchers are trying to reverse the process: Instead of eliminating cancer, control of malignant cells will be regained by natural processes.

Oncologists have a new hero: Charles Robert Darwin (1809-1882). While many of us recall his work “On the Origin of Species” in particular from biology classes, Darwin’s ideas are in cancer research more modern than ever. Evolutionary theory contributes in understanding natural selection, which by way of mutations ultimately leads to the manifestation of tumors.

Meltdown in the nucleus

It all begins with changes in the genome of a single cell. UV light, radiation or chemicals come into the question as causes of the damage. Yet the body does its best: an adult body consists of about 100 trillion cells. Every second 50 million of them are broken down – and become by and large built anew. Accidents are on the list of possible events, but it is amazing how rarely cancer develops. This is the result of biological processes that repair damaged cells – or drive them to controlled cell death, known as apoptosis. When worse comes to worse, mutations occur in areas that are used in controlling growth, the affected cell begins to proliferate unchecked. The terms initiation, promotion and progression describe underlying processes only vaguely, from a genetic point of view, however, everything is much more complex.

Evolution in high-speed motion

The genetic makeup of cancer cells in particular changes, as measured by evolutionary processes, at the speed of light. “In tumors 10,000 to 100,000 genetic alterations are able to be detected in comparison to normal cells, about ten of which are critical to growth and survival”, says Alan Ashworth, Chief Executive of the Institute of Cancer Research in London. An analysis of the genome of advanced kidney cancer illustrates the problem: Ashworth’s colleague Charles Swanton has now revealed 118 different mutations, only 40 of which are present in all, and 53 in most, biopsies. If the respective sections are relevant to the development of cancer, scientists speak of oncogenes, which originate by mutation of proto-oncogenes – so far around 230 representatives of this group have been uncovered.

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Back to the past

Via “chromosome maps”, Swanton was able to turn back time and identify the origins of certain subtypes of cancer cells. “We found a branched evolution pattern, which is not dissimilar to the tree of life”. Charles Darwin in 1837 supported his postulation with this model of how new biological species arise. Oncologists use his procedure today in order to identify key mutations. Although most of these alterations lead to the downfall of the cells in question, some individuals can be successful. They succeed, for example, with the help of Vascular Endothelial Growth Factor (VEGF) to generate blood vessels so as to feed the hungry colony of reproductively-active cells. Meanwhile, researchers discovered VEGF as a target structure and developed angiogenesis inhibitors: a rather rare stroke of luck.

New data – old therapies?

Although genome research does provide ever deeper insights into molecular massacre, these innovations are however only making themselves slowly noticeable in therapy. “Today we are for most types of cancer, despite all the efforts of pharmaceutical companies, attached to medieval methods: cutting (surgery), burning (radiation therapy) and poison (unspecific chemotherapy)”, says Alan Ashworth. “Once we better understand Darwinian processes by which cancer cells develop in the body, we should be able to control even advanced disease by specific combinations of drugs”. This means that instead of killing malignant cells, they will be brought back to their natural process of growth control. The immune system must also be strengthened, in order to fight, by itself and using its own resources, any remaining tumor residues. With use of such specific treatment, healthy tissue will be spared.

Stopped, but not removed

Things have not yet come so far: today, oncologists try to interrupt signal transduction using, for instance, antibodies. Bevacizumab belongs to this category; its target is the vascular growth factor VEGF. Cetuximab or Panitumumab aim for the epidermal growth factor receptor EGFR, and Trastuzumab has the human epidermal growth factor receptor HER2/neu as a target. As a further strategy, various low molecular mass tyrosine kinase-inhibitors have been developed in order to block important docking sites of growth factors. The respective inhibitors (Dasatinib, Imatinib, Nilotinib) direct themselves against products of the leukemia-related BCR gene; others (Erlotinib, Gefitinib, Lapatinib) against anti-epidermal growth factor receptor EGFR, often having other target structures. Biochemically speaking, this strategy only stops the growth of tumor cells, without removing them or driving them back into a normal cell cycle. For patients this mostly means a gain of a few months of life, for they are not healed.

Declared fair game

Use is made of the immune system for it’s own ends: If tumor cells have highly specific antigens on their surface, antibodies can be produced against them and natural killer cells drawn to them. In practice Alemtuzumab, Rituximab or Ofatumumab are suitable for use in binding to CD antigen target structure. EGF receptors correspond to Cetuximab and Panitumumab, and Trastuzumab is a match for HER2/neu. In the end, the cancer cell is destroyed while healthy tissue is not damaged. Parallel to that, treating physicians strengthen the immune system in general with doses of alfa interferon or interleukin-2.

Synthetic lethality makes its way

Ashworth is nevertheless not content with this. His concept of “synthetic lethality” aims to help beat cancers at their own game and make evolution run in reverse gear. Here’s how: As an example, with breast cancers, BRCA1 and BRCA2 are of critical sigificance: these are two tumor suppressor genes, whose products when in good working order repair damage in the genome. Mutations though may trigger unchecked growth. This selective advantage – if we keep going with Darwin – from a cellular perspective is simultaneously the cancer cells’ undoing: as Ashworth indicates, these react very sensitively to inhibition of the repair enzyme poly(ADP) ribose polymerase (PARP), since alternative mechanisms fail. PARP inhibitors make cells therefore not only more sensitive to radiation or chemotherapeutic agents. Rather, tumor cells can no longer self-repair damage to genetic material, including that produced by frequently-occurring mutations, and this leads to apoptosis: a new strategy for fighting cancer. Currently, various Phase I– and Phase II trials are running in order to study the properties of Olaparib (the name of this innovative inhibitor).

No big leaps, but outlook good

Is a major breakthrough imminent then? So says James Watson, the pioneer who working with colleagues in 1953 demonstrated the double helix structure of DNA: “We have recorded huge advances in progress, but no cancer researcher is jumping for joy in view of this, since in the past we were simply too optimistic”. He is nonetheless confident: “The research results of recent times allows us to hope to win the battle against the most incurable cancers over the next five to ten years”.

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Medicine, Oncology

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3 comments:

Prof. Humberto E.C.S.Ferreira
Prof. Humberto E.C.S.Ferreira

This is like JUDO strategy: use your oponent’s body to defeat it!!! Great work in the right direction!!!

#3 |
  1
Raja Moorty
Raja Moorty

A right approach to turn cancer to remission avoiding radiation and surgery.

#2 |
  4

Excellent article.

#1 |
  0


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