With V Foundation funding, Agata Smogorzewska M.D., Ph.D., from the Rockefeller University, is studying tumors from Fanconi anemia and comparing them with the same types of tumors found in people without this disease.
“When I started this work, nothing was known about cancers in Fanconi anemia patients except that they were extremely aggressive and developed at a young age,” said Smogorzewska. “Sometimes even teenagers would develop cancer, although, on average, patients were in their 20s and early 30s. There were no therapies available for these patients except for surgical resection.”
This research is already revealing insights that could lead to better ways to screen for and treat cancer in Fanconi anemia patients, who cannot use standard cancer therapies due to severe side effects that occur in people with this disease. It could also reveal new therapy targets for people in the general population who develop these cancers.
‘It’s like a bomb went off inside the cell’
People with Fanconi anemia lack a particular DNA repair process. Smogorzewska wondered whether this may explain why they are so prone to cancer. With V Foundation funding, she and her team tapped into a unique registry of Fanconi anemia patients that began at Rockefeller University in the 1980s. They gathered healthy tissue samples from people with Fanconi anemia and followed up with patients who later developed cancer.
The researchers recently published their findings in the journal Nature. The study showed that tumors from Fanconi anemia patients contain a large number of genome variants in which whole pieces of DNA appear in places they shouldn’t be or parts of the chromosomes are copied too many times. The changes were on a whole different level than the single-point mutations researchers are used to seeing.
“It’s like a bomb went off inside the cell and caused genomic havoc,” Smogorzewska explained. “The extent of the genomic instability was certainly surprising.”
Without the capability to properly repair DNA when it becomes damaged, it seems the genomes of these patients amassed more and more changes — including changes in the number of copies of particular genes that are important for growth or suppression of tumors.
Rare cases provide broader clues
The researchers then compared the genomic changes seen in Fanconi patient tumors to those found in the same types of cancers in patients without Fanconi anemia. To separate out the effects of human papillomavirus (HPV) in cancers known to be caused by HPV infection, they focused on head and neck cancers in the general population, which are thought to be associated with alcohol and tobacco exposure. The researchers found that tumors from people without Fanconi anemia had genomic copy number variants similar to those in Fanconi patients, but there were just fewer of these changes.
“This led us to hypothesize that some of the changes that occur in the general population tumors may come from the same DNA repair pathway problems found in the Fanconi anemia patients not being able to repair the changes that occurred due to tobacco and alcohol,” Smogorzewska said. “We know that chemicals present in tobacco and alcohol metabolites can make very similar DNA lesions to the ones not being repaired in the Fanconi patients.” This implies that in those without Fanconi anemia, exposures to tobacco and alcohol can overwhelm the normal DNA repair process, leading to their cancer.
Better treatments and screening
With this new knowledge, the researchers set to work figuring how it might translate into new strategies for preventing, detecting or treating cancer. They created cells that model the specific changes found in Fanconi patients in an effort to understand whether those changes cause vulnerabilities that could be targeted with treatments. In addition, they developed patient-derived xenografts by implanting pieces of tumors into mice, an important tool for screening new treatments that can be shared with other researchers for use in a variety of studies.
Based on the data gathered so far, the researchers are developing new protocols for early detection of cancer in Fanconi patients. Their studies are also providing powerful clues on how to combine different therapies to better treat patients with Fanconi anemia. These combined treatments might also be useful for patients in the general population whose tumors have similar genomic patterns.
Of course, prevention would be the ultimate goal. If scientists can pinpoint which naturally produced chemicals contribute to the DNA problems that lead to cancer, it might be possible to intervene and prevent cancer in people at high risk.
Smogorzewska points out that rare diseases are inherently difficult to study and get funding for because it is typically unclear how a particular rare disease could inform treatments for a larger number of people. “The V Foundation is unique in that they supported our study of a rare disease,” she said. “They also supported our work to first understand the fundamental biology of these cancers and then to study the vulnerabilities of this cancer while also developing new tools to do this.”