Targeted Treatment Inhibits Growth of Aggressive Cancers

Pathway discovered that allows aggressive tumors to proliferate.

Researchers have identified a potential treatment for aggressive tumor growth by targeting a pathway that allows the cancer to grow and spread, according to a recent study.

Published in the January 16, 2015 issue of Science, the study examines a targeted treatment in which a small molecule blocks a key step in the pathway. Through the alternative lengthening of telomeres (ALT) pathway, the treatment was able to inhibit the growth and survival of ALT-positive tumor cells.

"Identification of genetic markers that predict cancer cell vulnerabilities and new drugs to exploit such vulnerabilities is a focal point of cancer research today," senior and co-corresponding author Lee Zou, PhD, said in a press release. "Cancer cells must rely on either the telomerase enzyme or the ALT pathway to bypass the normal processes of cell aging and death. Our findings may provide a new direction for the treatment of ALT-positive cancers -- which include osteosarcoma, glioblastoma and certain pancreatic tumors."

When telomeres deteriorate to a critically short length, a signal is sent to the cell to stop dividing in order to ensure genetic information remains intact while limiting the cell's lifespan. Cancer cells are able to overcome this process by continuously extending the eroded telomeres to maintain cell life.

Telomere elongation in cancer cells runs through 2 major pathways, with the more common path relying on enzyme telomerase to extend the telomeres, while the less common ALT pathway elongates telomeres through recombination with DNA sequences from other chromosomes.

For the current study, researchers evaluated how the action and expression of several key proteins changes in cancer cells that use the ALT pathway. By focusing on the ATR protein that serves as a master regulator of DNA repair and recombination, the study found that the protein also plays a vital role in ALT pathway regulation.

The researchers also found that ATR inhibitors VE-821 and AZ20 were able to eliminate ALT-positive osteosarcoma and glioblastoma cells from the panels of cancer cell lines, thereby suppressing their ability to extend telomeres, which led to cell death.

"This study suggests that inhibiting ATR may be a novel and important strategy in treating cancers that rely on the ALT pathway, including up to 60% of osteosarcomas and 40 to 60 percent of glioblastomas,” co-corresponding and lead author Rachel Flynn, PhD, said in a press release. “Such targeted treatments would only affect cancer cells and have little effect on the surrounding healthy tissue, potentially minimizing the harsh and debilitating side effects experienced with traditional cancer therapies."