Monday, April 9, 2012

Personalized Medicine for Cancer

Cancer as genetic disease dominate approach to therapy
For many years, cancer therapy concentrated on attacking DNA replication, as cancer cells proliferate and replicate their DNA rapidly. But these generally cytotoxic drugs also harmed cells that divide rapidly under normal circumstances such as bone marrow cells, cells in the digestive tract and hair follicles, with inevitable side-effects: decrease in blood cells and immune suppression, inflammation of the gut, and hair loss [1].

More recently, newer therapies target the abnormal biology of cancer cells based on the belief that cancer is a genetic disease involving mutations in key ‘gate-keeper’ cancer genes (oncogenes). These include signal transduction and protein turnover pathways, apoptosis (programmed cell suicide) and signalling receptors. Some of these agents exhibited antitumor activity and have been approved for cancer therapy [2], and new candidates are popping up all the time [3].

Still, there have been no cures in advanced cancers, though it is hoped that some combinations of agents may do the job.

Nevertheless, the field of cancer therapy has been gripped by an “overoptimism” that soon, patients with a tumor will undergo a needle biopsy, and a personalized treatment will be devised on the basis of the distinctive genetic characteristics of the tumor. Already, several companies are marketing tests for the genetic signature of a tumor, with the expectation that the genetic signature will determine the treatment and predict treatment outcome.

But a serious flaw in that imagined future of cancer therapy based on personalized medicine is the underestimation of tumor genetic heterogeneity; not just between tumors, but heterogeneity within an individual tumor. This was highlighted in an Editorial in the 8 March 2012 issue of the New England Journal of Medicine [4].

Profuse genetic heterogeneity between tumors and within tumors
In the same issue of the journal, a team of 30 researchers led by Marco Gerlinger from the Cancer Research UK London Research Institute mapped out in detail how heterogeneous a single tumor can be [5]. Tumor samples were obtained from four patients with renal-cell cancer before and after treatment, with multiple samples taken from each patient’s primary and metastatic tumor sites. The team carried out exome sequencing (sequencing of all regions that code for proteins, roughly 1 % of the entire human genome), chromosome aberration analysis and ploidy profiling (to determine how many sets of chromosomes are present instead of the usual two). They also characterized the consequences of genetic heterogeneity within a single tumor using immunohistochemical analysis, mutation functional analysis and profile of messenger RNA expression.

Over a hundred mutations are typically found in each patient (just in the coding regions of the genome; over the entire genome it would typically be thousands), and a branching phylogenetic (evolutionary) tree can be drawn based on shared mutations in different regions. About two thirds of the mutations found in single biopsies were not uniformly detectable throughout all the sampled regions of the same patient’s tumor. Different regions of the same tumor gave a “favorable prognosis” and an “unfavorable prognosis” gene profile. There is no way a single tumor biopsy – the standard of tumor diagnosis and the cornerstone of personalized-medicine – can be considered to represent the genetic profile of the tumor, much less so, the cancer patient.

To make things worse, there are widespread alterations in the total number of chromosomes in the tumor cells (aneuploidy), and many allelic imbalances are found in which one allele of a gene pair is lost, either due to chromosome loss, or difference in gene imprinting that alter gene expression.

Another finding is that different regions of the tumor have different mutations in the very same genes (convergent evolution), suggesting that parallel alterations in epigenetic mechanisms (not immediately involving gene mutations) and signal transduction have taken place to ensure the tumor’s survival.

Cancer is not a genetic disease
There is, of course, the possibility that the genetic approach is misplaced. The gene mutations, even those in common ‘gate-keeper’ genes could be effects of a more fundamental cause. This is entirely likely given the fluidity of the genome, the ease with which genes can be silenced or activated, and both RNA and DNA sequence changes can occur in response to the environment as described in detail in my book [6]. It would also be consistent with the evidence that the causes of cancers are overwhelmingly environmental. An increase in somatic mutation rate provoked as the result of a stress response, for example, could explain why numerous different mutational changes are typically found from one individual cancer patient to the next, and even within a single tumor. Personalized medicine in cancer therapy may well be extremely time-consuming and costly, if not downright misdirected. Cancer cells under attack in one pathway can switch to another pathway, or else develop drug resistance that enable them to survive and multiply, as bitter experience in cancer therapy has revealed [7].

More information:
Cancer as an Epigenetic Disease

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