FRESH SCIENCE for Clinicians

News about basic science of interest and relevance for cancer clinicians

Wednesday, August 15, 2012

Don’t Ignore the Passengers: A new strategy exploits passenger mutations to knock out tumors

Cancer researchers often divide genetic mutations in a tumor into two classes: drivers, which are critical for cancer formation and growth; and passengers, which appear to have little impact on tumor biology. Logic goes that therapeutic strategies need to target the drivers to kill cancer cells.


But that might not be the case, researchers report in today’s issue of Nature.


The novel approach takes advantage of some basic biochemistry and chromosome biology, according to lead author Florian Muller, PhD, an instructor in the Department of Genomic Medicine at the University of Texas MD Anderson Cancer Center.


Chromosomal deletions of tumor suppressor genes are frequent drivers in cancer. Many of those deletions eliminate neighboring genes as well as the tumor suppressor itself.


Dr. Muller and colleagues reasoned that the loss of those neighboring genes might make tumor cells weaker than their genetically intact healthy neighbors –– and therefore susceptible to the right type of inhibitor.


For example, homozygous deletions of the 1p36 tumour-suppressor locus are common in glioblastoma. That deletion also eliminates the enolase 1 (ENO1) gene, which is involved in glucose metabolism. About 5% of glioblastoma tumors lack both copies of ENO1 and 15-20% lack one copy, according to Dr. Muller.


If ENO1 were the only enolase working in a cell, deleting it would kill the cell. But like many housekeeping genes, ENO1 is functionally redundant, sharing responsibility with two other enolases, ENO2 and 3. Therefore, glioblastoma cells lacking ENO1 survive but are vulnerable to further loss of enolase, particularly ENO2, which is the most abundant enolase in neural tissues.


In fact, Dr. Muller and his colleagues found that knocking out ENO2 function with a short-hairpin RNA or with an enzyme inhibitor killed glioblastoma cells that lacked both copies of ENO1.


By contrast, healthy cells that carry all three ENO genes were relatively insensitive to the blockade. That differential sensitivity might mean the strategy could be tweaked to kill tumors that still carry one copy of the targeted housekeeping gene.


Neither inhibitor strategy used in the current experiments is suitable for testing in patients at the moment, Dr. Muller says. But the work is proof of principle that passenger deletions can be exploited for anti-tumor therapy.


In the paper, the researchers list nine other housekeeping genes that reside near tumor suppressor genes and are sometimes deleted in glioblastoma. Each of those genes may provide a new opportunity for therapy, according to the team. “And there are many more,” Dr. Muller says.


If the strategy works in patients –– a possibility that makes good logical sense but still needs to be tested –– researchers may just find they need to pay attention to those passengers after all.