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Seeking a cancer cure amid DNA chaos

  Saturday, 07 l 05 l 2011  Source: The Straits Times   
By: Andy Ho

seeking-cancer-cureWHY IS there still no cure for cancer? Actually, quite a few can be cured. Some blood cancers -leukaemia and lymphoma -and some solid tumours - breast and colon cancers, say do respond very well to treatment. This is especially if the cancer is in its early stages. However, if the cancer is widely disseminated already, prospects remain bleak.

Cancer is actually not a single disease. Instead, it is hundreds of diseases, differing fundamentally at the DNA level. But cancers do share certain common themes. A main one is that their cells grow unchecked because they have stopped responding normally to growth signals. In cancers that grow aggressively, their cells have become very good at evading the body’s defences to overcome the signals that control cell growth. Many cancers also stimulate surrounding tissues to grow new blood vessels to provide them with nutrients and oxygen so they continue to grow and proliferate.

In different cancers, cells also share the capacity to evade their programmed time of death (apoptosis). Also, many cancer cells can invade the circulatory system and then migrate to other organs where they deposit themselves and start proliferating there as well. But different cancers acquire these abilities through different mutations, the focus of much cancer research.

In 1971, the very first cancer-causing gene, or oncogene, was discovered. It was only in 1986 that the first tumour-suppressor gene was found. This was specifically the gene that prevents a childhood eye cancer called retinoblastoma from developing. In the new millennium, scientists had hoped to quickly identify crucial mutations that drive the processes which tip cells over into malignancy. But now we know there is no mutation that is common to all cancers. There are also few common mutations to be found in several cancers. Moreover, cancers can change biologically with exposure to therapeutic agents. A recent Harvard study of different lung cancer types showed how DNA in cancer cells changed with exposure to different agents. The study confirmed that some lung cancers acquired mutations that conferred drug resistance over time.

It also found that when chemotherapy was stopped for a time in some cases of “non-small cell” lung cancer that had become resistant to drugs, the cells later transformed themselves into “small cell” lung cancers that were sensitive to drugs. It took a series of biopsies to reveal the genetic changes that conferred drug resistance and those that brought drug responsiveness back. However, oncologists may not be paying enough attention to such changes. This is because, in practice, many a cancer patient is treated based upon the results of a single biopsy, usually performed at the initial diagnosis. Even when the genome in such cancer cells is sequenced, what doctors get may well be only like a snapshot of what was transpiring at the time of biopsy. A one-off biopsy is not like a video that can show up profound DNA changes in cancer cells occurring over time.

But cancer cells have very messed-up DNA. A recent Yale-Harvard-Cornell study published in Nature examining the genomes of prostate cancer cells found absolute DNA chaos: Not only were there misspelled words in the Book of Life but huge paragraphs were also misplaced. That is, not only did the genes (which are functional or “non-junk” DNA) have individual changes in their letters (A, T, G, C) but the genes themselves had been wildly reshuffled as well. In addition, even “junk DNA” around the genes had been rearranged. (Junk DNA - the letters around genes, previously thought to have no functions - are now known to have regulatory roles.)  

Such rearrangements previously thought to matter in blood cancers only are now known to be important in solid tumours as well. The chaos is so great that a biopsy provides merely a snapshot likened to that of the inside of a china shop after a bomb has gone off. There may be few, if any, traces of the bomb that went off, that is, the mutation(s) that triggered the malignancy’s development in the first place. Instead, much of the visible chaos may well be crockery shattered by flying shards of china rather than bomb shrapnel. Once the absolute DNA chaos in cancer cells became better appreciated in recent years, research efforts began moving away from identifying mutations per se.

Instead, the idea was to lump mutations together based upon what signalling pathways they might involve, which would logically be fewer in number. The idea was that therapy would then focus on blocking these far fewer pathways rather than the innumerable mutations. But the DNA chaos is so thoroughgoing that the newer approach does not seem likely to translate into significantly fewer pathways to block anyway. Sadly, then, despite all the hype in the last decade about personalised medicine, prospects for cures in advanced cancers have not improved significantly.

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