New treatment strategy for aggressive cancers identified

A Group of researchers has identified a new potential treatment method that could prevent several kinds of aggressive tumor from growing.

Telomeres are located at the end of chromosomes and protect the genetic information found within.

The study, published in Science, details how disrupting a pathway used by cancerous cells to proliferate could be the key to inhibiting the growth and survival of tumors.

Identification of genetic markers that predict cancer cell vulnerabilities and new drugs to exploit such vulnerabilities is a focal point of cancer research today.

Cancer cells survive by avoiding the natural processes of aging and death that normal cells undergo.

In normal cells, repetitive DNA sequences called telomeres regulate these processes. Telomeres are found at the end of chromosomes, protecting them and ensuring that cells do not lose genetic information when dividing.

Over time, telomeres erode and shorten. Once telomeres have been eroded down to a critically short length, a signal is sent which tells the cell to stop dividing, protecting the genetic information while simultaneously cutting short the cell's lifespan.

Cancer cells attempt to promote cellular mortality by lengthening telomeres. There are two major pathways of telomere elongation and in most cases, an enzyme called telomerase extends telomeres.

The other pathway is referred to as the alternative lengthening of telomeres (ALT) pathway. In this pathway, telomeres are lengthened via recombination with DNA sequences from other chromosomes.

This new study represents the first time that a therapy has been identified specifically for treating the ALT pathway.

Cancer cells must rely on either the telomerase enzyme or the ALT pathway to bypass the normal processes of cell aging and death. These latest findings may provide a new direction for the treatment of ALT-positive cancers - which include osteosarcoma, glioblastoma and certain pancreatic tumors.

Findings could represent a 'novel and important' treatment strategy

The research team at, Boston University School of Medicine (BUSM), set out to examine how certain key proteins act and are expressed in cancer cells using the ALT pathway. They identified a protein called ATR specializing in the regulation of DNA repair and recombination as being crucial to regulating the ALT pathway.

Known ATR inhibitors, VE-821 and AZ20, were then found by the team to selectively destroy certain tumor cells from the panels of cancer cell lines. Eliminating these tumor cells suppressed their ability to elongate their telomeres via recombination and ultimately led to the death of the cancer cells.

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 40-60% percent of glioblastomas.

Being able to specifically target a single protein with modes of therapy can be extremely beneficial.

"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."

Clinical trials of telomerase inhibitors are underway, but up to 10% of tumors would not respond to this type of drug on account of using the ALT pathway. However, that testing tumors to identify which pathway they use is not routine practice.

If VE-821 or other ATR inhibitors are clinically successful, it would support such testing and may lead to more personalized and targeted therapeutic regimens for several cancers refractory to traditional chemotherapeutics.

The authors conclude by writing that their findings offer an unexplored direction for future preclinical and clinical studies.

References:

Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors, Rachel Flynn, et al., Science, published online 15 January 2015.
BUSM news release, accessed 15 January 2015.