The American Cancer Society has awarded UC Davis researcher Lifeng Xu a four-year, $720,000 grant to conduct research aimed at better understanding how some cancer cells manage to remain immortal. The work promises to improve the efficacy of cancer therapies currently in clinical trials that focus on blocking the activity of an enzyme called telomerase.
"Telomerase is activated in about 90 percent of tumors," said Xu, a UC Davis assistant professor of microbiology.
Xu's research focuses on what happens in the other 10 percent of cancer cells that manage to remain immortal without the presence of telomerase.
Telomerase is an enzyme that prevents the constant loss of specific DNA sequences from the tips of chromosomes, called telomeres, during cell division. Telomerase is found in embryonic stem cells, which allows these cells to divide over and over during development in utero. Adult, or somatic cells, only express telomerase at low levels and only at certain times in their life cycles.
Nearly all forms of human cancer, however, express telomerase, and have acquired the ability to replenish their telomeres to sustain unlimited cell proliferation," said Xu.
Because telomerase is not essential for normal cell function, scientists have homed in on this enzyme as an ideal target for treating a host of cancers. Telomerase inhibitors are now being tested for the treatment of brain and breast cancers, for example.
"But there are still some cancers that use other mechanisms to replenish telomeres and keep cells dividing," said Xu. "Our goal is to understand these alternate mechanisms to design better drugs."
Every cell in the human body with a nucleus contains the identical DNA organized into 23 pairs of chromosomes. The telomeres found at the tips of these chromosomes become shortened every time cells in the body divide. Eventually, the tips become too short, and a reliable copy of the DNA cannot be made, and the cell dies.
Cancer occurs when genetic mutations cause a cell's normal brakes on cell division to fail. Once that happens, scientists believe telomerase activity kicks in. The enzyme works by adding DNA sequence repeats to the telomeres. Scientists believe it is telomerase that allows mutant cells to divide indefinitely.
And, while new drugs are in the works to block telomerase activity, the problem remains that the cells of some tumors do not express telomerase and can maintain their telomeres through a process that occurs during recombination, called homologous recombination-based alternative lengthening of telomeres (ALT) pathway.
Although only a small number of tumors initially rely on ALT, ALT may be activated in larger number of tumors upon telomerase inhibition, allowing cells to survive telomerase-inhibition cancer therapy. Xu is studying how recombination-based ALT pathway may become activated in human cells.
Her research promises to give scientists additional tools for fighting the growth and spread of cancer by better understanding the regulation of telomere recombination. Knowledge obtained from the study could lead to future development of ALT-blocking drugs to be used in combination with anti-telomerase drugs to boost their efficacy.
"Our research will provide clues on how cancer cells activate the recombination-based ALT mechanism from which we can design complimentary anticancer therapy accordingly," said Xu.