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Disabling cancer by disabling cellular mechanisms

Molecular oncology research targets DNA recombination, repair

Microbiologist Wolf-Dietrich Heyer and postdoctoral candidate Jessica Sneeden are researching cancer's damage to DNA to find ways to repair it.
Microbiologist Wolf-Dietrich Heyer and postdoctoral candidate Jessica Sneeden are researching cancer's damage to DNA to find ways to repair it.

One of humankind's greatest medical challenges, cancer is so confounding and counterintuitive that trying to stop it may mean interfering with the body's natural defenses that fight it.

You read that right. To win the war against cancer, we might have to halt our own army.

No stranger to this concept, UC Davis microbiology professor Wolf-Dietrich Heyer has been working on a way to disable the cellular mechanisms that try to stop cancer before it starts. One of the UC Davis Cancer Center molecular oncology program's two new co-directors — associate professor of medical biochemistry Hongwu Chen is his partner — Heyer says the idea is simple.

The same mechanisms that protect normal cells, such as BRCA2 — a "recombinational DNA repair" gene that suppresses breast and ovarian cancer — can also protect tumor cells. Tumor cells divide very rapidly and experience DNA damage associated with their fast pace of duplicating their DNA. As a result, "tumor cells may become addicted to recombination to support their lifestyle," Heyer says.

Taking advantage of this paradox means disabling recombinational DNA repair in cancer cells to make them more susceptible to chemotherapy, radiation therapy and other anti-cancer treatments. It's an "out-of-the-box" approach that Heyer developed to move his basic science-oriented program to potential clinical application.

Upon his return from a recent radiation oncology conference where he was invited to present his work, Heyer marveled at the amazing progress in cancer biology.

"The next frontier is to integrate the basic DNA repair biology into cancer treatment, and this is happening right now," Heyer says.

Radical repair

The double helix structure of DNA - two coiled, intertwined strands that separate and recombine - lends  itself to both easy fixing and frequent damage from sunlight, cigarette smoke and metabolic malfunctions.

To correct problems quickly and efficiently, cellular maintenance teams are constantly repairing bits of damage that, left unattended, could fester, mutate and, eventually, metastasize.

Heyer has become one of the world's leading experts on two genetic repairmen, called Rad51 and Rad54, by studying yeast. These proteins work in concert to fix a radical form of DNA damage called  a "double-strand break," where each DNA strand is fractured. Yeast cells with both Rad proteins functioning normally can survive some 50 double-strand DNA breaks. But damage to either protein causes the yeast to be unable to recover from even one fracture.

Chemotherapy and radiation inflict double-strand DNA breaks on tumor cells. But as nature would have it, hard-charging Rad proteins rush in to repair the damage, a counterproductive process Heyer wants to halt to make cancer easier to kill.

Progressing from yeast to human cells, Heyer says his team has now purified human Rad51 and Rad54 proteins.

"We are designing quantitative assays to identify inhibitors that target their function and interaction," he says.

Inhibiting Rad51 or Rad54 will be difficult because their function is intrinsic to life.

"Like many other cellular proteins, Rad51 and Rad54 extract chemical energy for their function, so it will be difficult to obtain a specific inhibitor," Heyer says.

Interfering with the way Rad51 and Rad54 work together, however, may be more doable, he says.

Not satisfied to seek solutions in only one metabolic pathway, Heyer's research team is also studying a specific "DNA endonuclease," an enzyme that works like a molecular DNA scissor to resolve specific DNA junctions in replicating cancer cells, but not in quiescent normal cells. If successful, the research could lead the way in developing a highly targeted drug that could put the brakes on this process to stop tumors from growing while leaving healthy tissue alone.

Bridge building

Turning down several competing offers from other research institutions, Heyer came to UC Davis a decade ago from the University of Bern in Switzerland.

The next frontier is to integrate the basic DNA repair biology into cancer treatment, and this is happening right now.
—Wolf-Dietrich Heyer
co-director, UC Davis Cancer Center Molecular Oncology Research Program

"I was recruited by then-microbiology department chairman Dr. Stephen Kowalczykowski, whom I and many others consider to be the leading biochemist in our field," Heyer explains.

Subsequent milestones - including the UC Davis Cancer Center's receipt of National Cancer Institute designation — helped persuade Heyer to accept the co-directorship of the molecular oncology program.

"I was very impressed by the leadership of cancer center director Dr. Ralph deVere White, and deputy director Dr. Hsing-Jien Kung," Heyer says. "When Dr. Kung asked me to join him in leadership of the molecular oncology program, I saw the opportunity to bridge basic biomedical research on the Davis and Sacramento campuses."

Heyer welcomes this opportunity to further develop the Molecular Oncology Program.

"Dr. Kung built a great basic science program, and he challenged our generation, Hongwu and myself, to contribute our ideas and extend his vision," Heyer says.

To help build that bridge, Heyer organized the Recombination Repair Club, a group that meets every two weeks "to bring together the various laboratories working on DNA repair and recombination," he says. "Not only the faculty, but all lab members get to know each other and their projects." Club members also reach out with a seminar program that hosts speakers from around the U.S. and the world.

"An invitation to speak at a UC Davis recombination seminar is highly coveted, because speakers find a well-informed and interested audience," Heyer says.

Lab notes

Exploring the Heyer Lab starts with checking out a high-energy Web site that incorporates science, art, people - and a touch of whimsy.

"It's a reflection of the entire research group," Heyer says, as he describes each contribution.

"Excellent protein biochemist" Xiao-Ping Zhang created the "great photographs," while credit for the  "whimsical drawings" goes to former student and postdoctoral researcher Jachen Solinger.

"Many of the word plays and stories are from Vladimir Bashkirov, a long-time research associate and collaborator of mine," Heyer says. "The reference to [renowned Swiss impressionist painter] Paul Klee is an expression of my own admiration of his art."

In bringing together such diverse elements, Heyer says he strives to create "an environment that allows creativity, fosters intellectual exchange and challenges presuppositions."

Dedication to discovery

You've got to love the journey of science, because you're never going to arrive at a point where you can say, "We've learned everything there is to know about human biology."
—Postdoctoral researcher Jessica Sneeden

Proof that Heyer's approach is on target, postdoctoral researcher Jessica Sneeden's "tremendous energy, creativity and dedication to discovery" are assets he fosters and admires in his promising protégé.

Partly supported by an NCI training grant awarded to the cancer center, Sneeden says she came to UC Davis because "the projects in Wolf's lab represent an exciting and fast-moving area of cancer research."

Studying a protein called "polymerase eta" that helps repair sunlight-damaged DNA that can cause skin cancers, Sneeden says the university's "intense research atmosphere" has engaged her totally.

"Not all institutions are blessed with this level of scientific intensity," Sneeden says. "There are many amazing scientists on campus who make themselves accessible to students. The framework here sets up an environment for successful research."

And successful living. Whether it's working with fellow lab members on the world's tastiest chocolate soufflé, learning how to make a chessboard in a university-sponsored woodworking class or growing very big tomatoes with her two young daughters in their garden, Sneeden feels professionally and personally fulfilled.

"You've got to love the journey of science, because you're never going to arrive at a point where you can say, 'We've learned everything there is to know about human biology,'" she says. "I can honestly say I have one of the coolest jobs on the planet."