Three Fred Hutch investigators have won awards from the National Cancer Institute's Provocative Questions Project. Together the awards total nearly $3.6 million.
The Human Biology Division's Drs. Denise Galloway and Patrick Paddison and Basic Science Division's Dr. Robert Eisenman are among 57 investigators in the U.S. to receive the NCI's first set of Provocative Questions awards.
In 2010, NCI director Dr. Harold Varmus led a series of workshops to define new directions for cancer research in this country, with the goal of ultimately funding more challenging and creative research projects. The group came up with 24 questions to guide such research and put out a call for applications. This year's awards go to projects attempting to answer 20 of those questions.
Galloway aims to answer the question: "Given the recent discovery of the link between a polyomavirus and Merkel cell cancer, what other cancers are caused by novel infectious agents and what are the mechanisms of tumor induction?"
In collaboration with the Vaccine and Infectious Disease Division's Dr. Corey Casper, Public Health Science's Dr. Margaret Madeleine, and Dr. David Wang from Washington University in St. Louis, Galloway will look for new links between infection and cancer. Up to 25 percent of the world's cancer cases are caused by infections. These cancers are even more prevalent in immunosuppressed people, such as HIV infected individuals and organ transplant recipients, because dampened immune systems are less able to defend against the cancer-causing viruses.
Well-known examples of infection-associated cancers include cervical cancer, which is caused by human papillomaviruses (HPV), and liver cancer, which is caused by hepatitis B virus (HBV). Galloway's group was instrumental in drawing a definitive link between HPV and cervical and other anogenital cancers.
Her group will screen human DNA and RNA from tumor samples for the genetic signatures left by viruses and bacteria. The samples come from HIV positive patients at the Uganda Cancer Institute with lung cancer, non-HPV associated genital cancers, or certain types of lymphomas. Uganda has one of the world's highest rates of infection-associated cancers, in part because of the high levels of HIV infection in that country. The cancer types Galloway's group is studying occur at much higher rates in HIV positive and other immunosuppressed people, so she suspects that some or all of these cancers may have infectious roots that are yet to be uncovered.
"This is a risky project, but with a very high reward potential," Galloway said. "If we find even one virus that's associated with one type of cancer, it will make a huge difference."
Paddison's project addresses the question: "Why do certain mutational events promote cancer phenotypes in some tissues and not in others?"
Despite certain similarities among all cancer cells, cancers in different tissues tend to behave very differently. For example, spontaneous mutations in certain genes can frequently lead to cancers in one tissue type but not another. The growing tumor's local environment is clearly very important to its specific development, but researchers currently understand very little about these tissue-specific effects. This means we lack targeted therapies for most cancer types.
Paddison's group is studying gliobastoma multiforme, the most aggressive and common form of brain cancer in adults. They have developed a technique to isolate the tumor-forming stem cells from patients' tumors and grow them in the lab, meaning they have patient-specific experimental models of tumor cells. Unlike traditional cancer cells used for lab experiments, the cells Paddison studies retain their patient- and tissue-specific genetic and epigenetic characteristics.
In collaboration with Dr. Jun Zhu from Sage Bionetworks, Paddison's group is now using a gene knockdown technology, called RNA interference, to disable genes one at a time in these brain tumor cells to determine which genes are necessary for the tumor's survival. This project will help the researchers understand which cellular processes are important for brain tumor development and survival, and could ultimately lead to targeted therapies for glioblastomas.
Eisenman will attempt to answer the question: "Are there new technologies to inhibit traditionally 'undruggable' target molecules, such as transcription factors, that are required for the oncogenic phenotype?"
Transcription factors, proteins that activate or de-activate genes, play important roles in cancer development but have traditionally proved to be difficult drug targets. Eisenman studies the transcription factor known as Myc, which is involved in activating many different genes in many different cell types. His group has characterized how Myc goes haywire in cancerous cells, and has found many other proteins that interact with Myc to regulate its function. In healthy cells, Myc's gene-activating activity is balanced by another protein, Mxd, which represses many of the genes that Myc turns on.
"When Myc is deregulated in cancers, this balance is lost," Eisenman said, and many genes that would normally remain silent are aberrantly activated.
Inhibiting Myc's abundant activity in cancer cells could vastly improve cancer treatments, but finding drugs to bind and disrupt Myc has been difficult due to its large binding surfaces. Eisenman's group plans to use a type of experimental evolution to find a protein piece able to disrupt Myc but not Mxd, by rapidly changing the peptide's sequence in the lab and selecting for those that best bind to Myc. The researchers will then test whether these potential anti-Myc drugs can kill off cancer cells in the lab.