Personal Cancer Treatment

Reference: Muller et al. “Passenger deletions generate therapeutic vulnerabilities in cancer.” Nature (2012) 488, pgs 337 – 341

Reference: Lehner and Park. “Exploiting collateral damage.” Nature (2012) 488, pgs 284 – 285 

Reference: Johnston, Iain. “The chaos within: Exploring noise in cellular biology.” Significance (2012) August, pgs 17 – 21 

                Innovative ways to specifically kill cancer cells within the context of a living human body are necessary.  The scientific community has plenty of ideas: Trojan horse proteins bearing chemotherapeutics, exploiting the nature of cancer cell surface receptors, intense high throughput studies to identify cancer-sensitive compounds and targeted therapies towards known oncoproteins.  Unfortunately, just as each human is unique, cancer is an all-encompassing term for hundreds of different diseases that each has their own set of complications to be overcome.  Forward thinking and ingenuity are keys to successful progression.  To this end, Muller et al. report in this week’s Nature magazine about an experimental design that identifies key vulnerabilities in cancer cells by highlighting what proteins are not present.

                Enolase is an essential enzyme necessary for the second to last step of glycolysis.  Three homologues of this enzyme exist with three different gene expression profiles: ENO1 is ubiquitous, ENO2 is restricted to neurons, and ENO3 is only in muscle.  It has been shown that invertebrates and mice carry several homologous genes that encode for proteins capable of doing each other’s jobs.  The beauty of this redundancy occurs when one of the genes is knocked out: the other proteins are able to pick up the slack and death isn’t an inevitable result.  In the case of enolase, both ENO1 and ENO2 are expressed in neural cells and both are capable of performing the same function.  But, imagine that one gene becomes mutated.  The cell would then have an unhealthy reliance on the other ENO gene.  Since the enzyme is essential, a blow to the other enolase homologue should result in death to that cell.

                Cancer cells have an unhealthy habit of collecting mutations.  The Cancer Genome Atlas Research Network has sought to study the genomes of cancer to establish what mutations have turned a once healthy cell into a feast of illness.  Gliobastomas are a type of brain tumor that affects glial cells, which expresses both ENO1 and ENO2, but is far more reliant on ENO1.  Interestingly, the lp36 locus, home of the ENO1 gene (among others) is often deleted in glioblastoma.  In theory, this should create an Achilles Heel out of ENO2. 

                Muller et al. began with two different cells lines: one expressed both ENO1 and ENO2 (ENO1 wild type) while the other only expressed ENO2 (ENO1-null).  Upon two independent shRNA-mediated knockdowns, only the cells only expressing ENO2 displayed marked inhibition of proliferation.  Wanting to further prove their concept, the authors then treated the cells with the enolase inhibitor phosphonoacetohydroamate (PHAH).  The compound displayed potent toxicity towards the ENO1-null cells and little impact on the ENO1 wild type cells.  Finally, PHAH was titrated into cells with varying degrees of both ENO1 and ENO2 expression.  Intriguingly, the data showed a direct relationship between the sensitivity of the cells to PHAH and their enolase activity profiles.  

                The lp36 locus contains other essential housekeeping proteins.  In addition to these cells being reliant on ENO2, they might also be unnaturally resting on other individual proteins whose homologues have been knocked out.  Determining what they are and inhibiting them as well could lead to even greater effectiveness at cancer cell-specific death.  The paper ends up with this thought: “By one estimate, 11% of all protein-coding genes in the human genome are deleted in human cancers.  Thus, given the large number of homozygous deletions across many different cancer types spanning many hundreds of genes, the model described here for [glioblastoma] should be applicable to the development of personalized treatments for many other cancer types.”

                While reading this paper, I kept thinking back to another article I read in the journal Significance concerning the random events and complete chaos that is the inside of a cell.  Take two cells with exactly the same genome.  Variability exists in the expression profiles of all genes between those two cells due to random chance.  In the Muller et al. example, one single cancer cell in a gliobastoma may express ENO2 at a much higher level than its neighboring cell, which means that Cell A will need more drug to kill it than Cell B even though both have the exact same genome.  But scientists don’t consider Cell A and Cell B, we consider whole cell populations and assume they are all acting identically.  One IC₅₀ value represents the cells in that particular plate at that particular time and is averaged with other cell populations at different times.  Eventually, scientists are looking at averages of averages.  We make broad assumptions on broad pieces of data that are based on what is happening right then.  But cancer isn’t static; tumors within a human body are an ever evolving entity that picks up more mutations and creates more roadblocks as time goes on.  Cancer is a many-headed hydra.