In cancer therapy, the most persistent and alarming problem is the development of resistance to therapy. Relapse into disease often leads to metastasis, the primary mortality event in cancer. When the tumor dissociates and finds a new home at an essential organ such as the brain, lung or liver, it can often be very difficult to detect and eradicate. Therefore, finding a treatment that circumvents relapse can be the silver bullet for cancer.
That silver bullet, it would seem, is the targeting of so-called cancer stem cells. These cells live within the tumor and are thought to help it regrow after an insult. Cancer stem cells are also able to survive detachment from the tumor and the journey to a new site, where it can touch down and form a metastasis. Most alarmingly, traditional chemotherapy drugs are unable to destroy cancer stem cells because they do not divide rapidly. In fact, insults like surgery or chemotherapy can actually stimulate the cancer stem cells to metastasize.
Targeting cancer stem cells is a viable therapeutic strategy, and many researchers and drug companies are enthusiastically embracing it in cancer therapy. What are some of the findings that support this avenue for treatment?
Evidence for Myc inhibition in lung cancer
In a recent Genes and Development article from the lab of Dr. Laura Soucek titled "Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice," the researchers were able to show that gene therapy eradicates lung cancer in mice.
In short, mice harboring a mutation in the gene KRas that causes lung cancer were treated with an inhibitory form of the protein Myc, which is well-known for its critical role in the formation of most cancers. Myc is required for KRas-driven tumor formation and progression in humans. It is a potent oncogene that acts as one of the four "Yamanaka factors" for generating stem cells from skin cells. It should come as no surprise, then, that Myc helps to make cells more like stem cells, which means it may help cancer cells become cancer stem cells.
Prior to this study, it was unknown whether targeting Myc would help to eradicate tumors. The researchers sought to answer this question in tumor-bearing mice. To do so, they created mice with a "dominant negative" form of Myc that could be induced on demand. Dominant negative refers to a form of the protein that will compete against the normal form and create inhibition of its activity.
When the dominant negative Myc was induced in mice that had tumors due to KRas mutation, tumor burden was found to decrease significantly. The dominant negative Myc protein extended the average lifetime of these mice.
Next, the researchers asked whether Myc inhibition could affect the relapse of tumors. As expected, when dominant negative Myc induction was stopped, the tumor did come back. Incredibly, re-introduction of the inhibitory Myc forced the tumor back into regression. This cycle was repeated five more times, and eight out of eight mice survived. In contrast, most mice died within 15 weeks of losing the inhibitory Myc if it was not put back in place.
Other evidence from embryonic development
The biological pathways known as Hedgehog and Wnt are key players in embryonic development. They help to control stem cell growth and differentiation into other tissues. Recently, clinical trials have begun to test the role of these pathways in cancer. Drugs that block Wnt signaling have started phase I safety trials in humans with solid tumors. It will not be known until at least next year whether these drugs have any efficacy and are safe, so there is not much known about them. Overall, however, there is much promise in the field of targeting cancer stem cells.
Further discussion of this project will take place at the IATI-BioMed Israel 2013 conference, sponsored by Teva Pharmaceuticals, a firm involved in stem cell research, June 10-12 in Tel Aviv, Israel.
Zack Fisher is a writer and a research fellow in biomedical sciences at the West Virginia University School of Medicine. His writing focuses on helping people understand and leverage biotechnology and its impact on society.