In nature, species evolve thanks to those lucky organisms who cheat death. An environmental pressure may come in and kill of a high percentage of critters, but those critters who survive the bloodbath live on to spread their genes. When this bottle-necking occurs in disease-causing bacteria, we call it drug resistance: an antibiotic may knock off 99 percent of a species, but the 1 percent immune to the treatment will live on to reproduce and create an entire population immune to the drug.
As the drugs developed to fight cancers become more and more sophisticated, a similar principle is in play for tumor cells. New “targeted” chemotherapy drugs, such as sorafenib or imatinib, which attack tumor cells by one specific mechanism, have typically shown initial success followed by recurrence and resistance. The reason, suggests Wei Du, associate professor in the Ben May Department for Cancer Research at the University of Chicago, is evolutionary.
“If you really think about it, it’s sort of like evolution on the scale of your body,” Du said. “Cancers are heterogeneous and often display genomic instability. When the selective pressure of a drug is applied, a small number of cancer cells will likely be able to survive and grow. This will eventually lead to the development of resistance, just like antibiotics for the bacteria.”
In bacterial infections, doctors get around the resistance threat by ganging up on the bacteria, hitting a patient with multiple antibiotics that each employ unique killing strategies. That “Magnificent Seven” approach would be ideal for treating cancers, but physicians are limited by the limited number of mechanistically unique chemotherapy drugs available.
In a recent paper published in Cancer Cell, Du’s laboratory set out to remedy that problem by laying the groundwork for a new cancer-killing strategy. When a cell becomes cancerous, its genetic factory goes haywire, with some gene products being over-produced and others under-produced. Many drugs are developed to try to rein in the former, known as oncogenes, but few attempt to target the inactivated “tumor-suppressor” genes normally tasked with policing excessive cell growth.
One of those lost policeman is a gene called retinoblastoma protein, or Rb. The Rb gene is mutated in roughly 10 percent of tumors and functionally inactivated in many more, making the protein a factor in a majority of cancers. Rb-inactivated cells lose the brakes for proliferation, producing the uncontrolled cell growth characteristic of tumors. Du’s group launched a hunt for a “synthetic lethal” gene, a second, coincident mutation that would cause Rb-negative cells to self-destruct while sparing the innocent, non-cancerous cells standing by.
“The idea will be that the mutation by itself does not cause cell death, but in conjunction with loss of tumor suppressors you actually have a synergistic effect for cell death induction,” Du said. “That type of drug would be really nice in that it will have very low toxicity, but have specificity for the cancer cells.”
To find such a gene, Du and his colleagues used the heroic Drosophila fruit fly. The laboratory created flies with two mutations in the genes of their eye cells – an inactivated Rb gene and a randomly induced second mutation – looking for signs of cell death. They found it in double-mutations of Rb and a gene called gigas in flies (TSC2 in humans), which resulted in smaller double mutant tissues in the eye.
Researchers then tested whether artificially lowering the amount of TSC2 (through a method called RNAi) would cause Rb-negative cells to self-destruct. In Rb-negative osteosarcoma, prostate and breast cancer cells, the TSC2 knockdown worked, inhibiting cell growth while increasing cell death.
“The mutation of TSC2 by itself leads to overgrowth of the mutant tissues. But in conjunction with loss of Rb it actually leads to loss of cells with this double mutation, which actually fits with our idea of a synthetic lethal mutation,” Du said. “What we see supports that TSC2 can potentially be used as a target for specific cancers with Rb mutations.”
But discovering the target is not the same as finding the pharmaceutical arrow to hit it. The RNAi method used in Du’s cell experiments has proved frustrating as a therapy in humans – “it’s not clear whether this delivery method will work,” Du said. His next step instead will be to conduct high-throughput screens for a small molecule inhibitor of TSC2 that could serve as a new chemotherapy drug.
That drug would not be a magic bullet cure for cancer, of course. And experiments in Du’s paper suggest that tumors will evolve resistance to TSC2 inhibition, just as they have done for other drug strategies. But a wrecking crew combination of a TSC2 inhibitor with drugs that block protein kinases, blood vessel formation and other tumor promoters may just be the combination punch needed to knock out a tumor before evolution can take hold.
“I think any of the single agent treatments are likely to create resistance,” Du said. “But by targeting multiple aspects of the requirements of cancer at once, it hopefully will cause a synergistic kind of killing.”