A popular theory behind why cancer tumors recur post treatment is the existence of cancer stem cells (CSCs). These cells have stem cell-like qualities and are stubbornly resistant to common cancer cell killing techniques such as radiation and chemotherapy. CSCs are resilient and can reproduce themselves after all other cancer cells die off, creating new tumors and causing cancer relapse.
Cancer stem cells are resistant to typical cancer therapies and can cause tumor relapse.
The origin of CSCs and whether they exist in all types of cancers are questions that are still up for debate. However, it seems that the cancer field has come to a consensus that CSCs do exist in many forms of cancer, and that they are a prime target for the development of new cancer therapies. Researchers hope to develop combination therapies that target regular cancer cells and CSCs. Because what’s the use of treating tumors with drugs if they will just grow back because of pesky CSCs?
There are many proposed strategies for killing cancer stem cells. Some of them center around overcoming life-extending features that CSCs have evolved including the ability to avoid normal cell death processes. One promising technology for targeting CSCs is gene silencing. This technique uses tools that turn off the expression of specific genes (hence the silencing) that are causing cancer cells to survive or divide.
Two independent groups recently announced positive results from studies that use gene silencing technology to kill breast and colon cancer stem cells. These two stories are a great example of how pre-clinical biology from academia can translate into clinical research in industry.
On the Academic Side
A group from Lausanne University Hospital in Switzerland reported in PloS One that silencing the expression of a gene called BORIS prevented the growth of breast and colon CSCs.
BORIS inhibits the function of an important tumor suppressor gene called CTCF. A tumor suppressor gene acts as a stop sign and prevents normal cells from turning into cancer cells. When tumor suppressors can’t do their normal job due to rogue jay-walkers like BORIS, normal cells lose an important line of defense and can turn into cancer cells. Typically, BORIS is only expressed in germ cells during development and not in adult cells in the body. However, scientists have found that BORIS is reactivated in some cancer cells, typically in CSCs.
The PLoS study confirmed that BORIS was reactivated in both breast and colon CSCs. One hallmark of CSCs is their ability to survive in 3D culture systems by forming sphere-like structures. They then asked whether silencing BORIS expression in breast and colon CSCs would prevent the formation of spheres in culture. They found that without BORIS, CSCs could no longer form spheres and survive in suspension. They went on to show that when BORIS is silenced, expression of stem cell and CSC genes was reduced in both the breast and colon CSCs. The authors concluded that BORIS is an important gene for CSC survival and “could be a potential new CSC biomarker that could be used as a therapeutic target for cancer therapy.”
BORIS is expressed in breast cancer stem cells (red) but not in breast cancer cells (blue). (Alberti et al. 2015)
On the Industry Side
Regen BioPharma reported on Monday that it successfully used gene silencing technology to kill colon CSCs by silencing BORIS expression. Their positive results have prompted the company to improve and advance its gene-silencing techniques so that it can file an IND (investigational new drug) application for the BORIS gene silencing technology. An IND with the Food and Drug Administration is the final step to beginning a clinical trial in humans.
Regen has published previously in this area and acknowledged the recent findings published in PLoS. In a press release, Thomas Ichim, CSO of Regen said:
From 2006-2008, together with a team of scientists from the Institute of Molecular Medicine and the National Institutes of Health, we published that vaccinating against BORIS results in immune response against and tumor regression in breast cancer, melanoma, and glioma. Subsequently, we published that gene silencing of BORIS can be utilized to selectively kill breast cancer cells. As we saw in the recent publication, the role of BORIS as an “Achilles Heel” of cancer is becoming more and more apparent. We are currently in the process of advancing our gene-silencing based approaches, in part by leveraging lessons we are learning during dCellVax development, in order to file an IND for BORIS gene silencing technology.
Silencing BORIS gives cancer stem cells the boot. (Image source: Glassdoor.com)
The issue with chemotherapies and other cancer treatments is that tumors become resistant to them over time. Gene silencing offers an advantage over these strategies by directly targeting CSCs, which are resistant to first-line cancer treatments. By silencing genes in CSCs that are required for cancer cell survival and metastasis, scientists can target tumors at their source. For patients with aggressive or recurring cancers, BORIS gene silencing technology could be what the doctor will order to prevent future relapse or metastasis. Time will tell, but hopefully gene silencing technologies against CSCs will enter clinical trials sooner than later.