According to a new study, published in the October issue of Molecular Cancer Therapeutics, a peer-reviewed journal of the American Association of Cancer Research, stem cells responsible for creating deadly brain tumors can be identified and characterized by chemical compounds that can target the stem cells. For the study researchers at the UCLA’s Jonsson Comprehensive Cancer Center developed and utilized a high-throughput molecular screening approach to identify and characterize these chemical compounds.

Glioblastoma is one of the deadliest forms of brain cancers usually killing people within 12 to 18 months. It consists of two different cell types, a larger heterogeneous population of tumor cells and a smaller sub-population of stem cells that are resistant to treatment.

Senior author Dr. Harley Kornblum, a Jonsson Cancer Center scientist and a professor of psychiatry and biobehavioral sciences said that the screening system was specifically designed to identify drugs able to target this sub-population and prevent it from re-seeding the brain cancer.

Kornblum, who also is a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA commented:

“We’re pleased that we can present a different way to approach the discovery of potential new cancer drugs. And by finding these drugs, we may be able to reveal things about the biology of these cancer stem cells.”

Kornblum explained that the researchers tested over 31,000 compounds from seven chemical libraries in an initial screen and discovered 694 compounds that showed some activity against the brain cancer stem cells. Following a further reduction process down to 168 compounds, they decided to concentrate on four compounds in their future studies, which proved to be the most successful in inhibiting the brain cancer stem cells.

Kornblum and his team used an approach similar to the reverse of the usual screening processes. Normally high-throughput screenings involve seeking a drug to hit a specific target that researchers know is on a cancer cell, for example a protein that is causing the target to growth or a gene preventing the target from dying, however, Kornblum and his team basically conducted their search blindfolded as there is still little knowledge of the biology of these brain cancer stem cells.

Kornblum explained:

“When brain cancer stem cells were first discovered, we all realized rapidly that we would need to find drugs that attack these cells specifically, because they’re resistant to our conventional therapies. We needed a way to kill these stem cells.”

As many as 100,000 compounds can be screened in a single day by using UCLA’s high-throughput screening technology. Researchers normally develop cancer cells lines after which they create an assay, a molecular biology procedure for testing or measuring a drugs activity or biochemical compound in an organic sample, i.e. cancer in this case.

The high-throughput screening technology consists of a computerized, robotic screening system in which cells are loaded into plates, which are approximately the size of an adult’s palm of the hand. Each plate contains 384 wells to which the drugs are added. The system executes this process from start to finish, adding the compounds sitting in the tiny wells in the plates to the cancer cells, located in corresponding assay plates.

Kornblum and his colleagues had a few hints in this study, which assisted them in the reduction process for potential candidates that kill brain cancer stem cells. One of the approaches was focused on a prior discovery made by Jonsson Cancer Center researchers who identified genes that correlate with how aggressive a brain tumor is. Kornblum set out to identify potential drug candidates that might reduce the expression of these genes. His other approach was to identify which of the molecules killed brain cancer stem cells with a greater potency than they attacked other cells within glioblastoma.

Kornblum used human tissue obtained from UCLA glioblastoma patients to grow his cell lines, knowing that a certain method of culturing brain cancer cells resulted in a large number of brain cancer stem cells in the population. He then screened these cells with a molecular library of 31,624 compounds available through the cancer center’s Molecular Screening Shared Resource. These compounds encompass a wide range of structures and are therefore likely to influence virtually all cellular functions.

Kornblum explained:

“We decided on this type of approach because, although we have learned a great deal about brain cancer stem cells in the past several years, we still have not discovered enough of their biology to be sure that any single target will be the right one to hit.”

Kornblum and his colleagues will continue to conduct further studies into the four identified “lead” compounds to establish whether they can help to reveal the biology of the brain cancer stem cells and possibly result in a new, more effective therapy for these deadly brain cancers.

The authors comment:

“One of our goals was to determine whether some compounds selectively act on glioblastoma stem cells compared to the less tumorigenic cells from the same tumor. This selectivity may allow for the delineation of pathways and processes that are highly important to these cells. By making sure that a drug candidate has the potential to attack these stem cells, one might ensure the highest chance of therapeutic success.”

The Jonsson Comprehensive Cancer Center, the National Cancer Institute and the National Institute of Neurological Disorders and Stroke funded the study.

Written by Petra Rattue