Saturday, July 11, 2015

Reading the Genetic Tea Leaves

How a cancer drug diagnostic / prognostic panel works.

Molecular medicine is coming, slowly, but surely. Drug companies have been forced to lead the way, because drugs are molecules, affect other molecules in our bodies, and can't be understood without learning about the molecular workings of the body.

Cancer has been a leading focus for this approach, because of its thousands of molecular manifestations which can cross the traditional organ boundaries, and its protean mechanism of molecular progression, accumulating mutations in many genes before turning dangerous. And because of its maddening self-on-self method of attack. One of the most significant cancer-related genes is TP53, which is mutated in about half of all cancers, and which in most of the rest is mis-regulated by way of other mutations. It encodes a protein (p53) that plays a central role in activating DNA repair processes in response to damage and general stress, in halting the cell replication cycle, and even in activating cellular suicide when repair is impossible. Getting rid of this protein is naturally a key step to keeping a wayward cell alive and allowing it to accumulate even more mutations.

This is one reason why, in addition to sequencing our normal genomes as part of regular medicine in the near future, our tumors and other sampled tissues will also be sequenced and analyzed to find accidental mutations that may be causing disease. For instance, over 100 tumors are known to afflict the skin, causing all sorts of lesions, each with a different set of causal mutations.

A recent paper from the drug company Novartis concerns a drug it has developed for p53, and particularly its interaction with another protein, HDM2, which turns it off. This drug interferes physically with the binding of these two proteins, thereby leaving p53 more active, and allowing it to kill its host cell in case it is cancerous, via the suicidal processes of apoptosis. But all this can only work if p53 has not been mutationally deactivated in that cancer.

So the researchers looked for a reliable way to test patients for p53 activity, and came up with the work of this paper, which is a collection of other genes whose activity, when on, says that p53 is active and thus "druggable". The test is not to sample DNA, but RNA from the tissue, asking about the transcription and thus activity of these selected indicator genes. From the p53 gene itself, RNA may be quite abundant, but if it has some tiny mutation that kills the activity of the encoded protein, then it is functionally dead. It is thus more effective to test the activity of genes that are "downstream" from it, in circuit terms, to find out whether p53 is working or not. Since one big function of p53, which binds DNA, is to turn other genes on.

The panel consists of 13 genes, developed using cell lines that were carefully selected for their response (or lack of response) to this new drug which inhibits the p53-repressor interaction. These were filtered down from 10,000 or more genes that were tested at the outset, as being the most informative. Each of them are targets of p53 transcriptional activation, which makes them obviously downstream in a circuitry sense.

List of genes used in the diagnostic/prognostic test for p53 function, comprising other genes that p53 activates.

None of these genes are dramatically regulated in the drug treatment case, only about a couple fold change in RNA levels in most cases. But the technology is now sensitive enough to detect such small changes reliably. About a third of the genes in the panel are directly annotated to function in apoptosis, which, in addition to informing on the status of the cellular p53 protein, also informs on the status of the key pathway by which this drug works- the cell suicide pathway.

So there it is, a prognostic test that amounts to something like a thermometer to tell how the patient is doing, but in molecular terms, about a specific molecular pathway, that then indicates the use of specific molecular counter-therapies.

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