Author: Charlotte Schubert, Ph.D.
Treatment for head and neck cancers is largely stuck in the past. Patients typically receive some combination of surgery, radiation and chemotherapy, treatment approaches that have not changed much over the decades. About 450,000 people die of head and neck cancer worldwide each year.
A new study delves into the molecular underpinnings of some of these tumors and posits a more targeted approach toward treatment. The study provides evidence that some head and neck cancers may respond to the drug olaparib or the combination of olaparib with decitabine. Both olaparib and decitabine are approved for use in other tumors but are not used routinely for head and neck cancers.
“There has not been a rationale to test them in these tumors,” said study co-leader Lluis Morey, Ph.D., a scientist at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine. The new study provides such a rationale.
The findings are in cells and preclinical models of disease. But Sylvester scientists are already conducting further research that could potentially lead to clinical trials in certain head and neck cancer patients.
The new study appeared in the journal Genes & Development.
Targeting the Histone Molecule
Dr. Morey became intrigued by an earlier study showing that about 20% of head and neck tumors had specific types of defects in a molecule called a histone. Histones associate tightly with DNA and help control everything from replication to cell division. Dr. Morey, an associate professor of human genetics, decided to take a closer look at these histone defects.
He and his colleagues found that the histone defects had knock-on effects in tumor cells. The same histone often gained a so-called “epigenetic mark,” the addition of a molecule called a methyl group at a certain location in the histone. The mark caused widespread DNA damage within the cell.
The researchers showed that they could kill human cells containing the mark with olaparib or similar drugs, which target enzymes involved in DNA repair. Olaparib also shrank tumors in early preclinical studies.
The researchers also looked at affected tumor cells that did not gain the epigenetic mark. They found they could coax the addition of the mark by treating cells with decitabine. They could then kill these cells with olaparib or similar drugs. The combination of decitabine and olaparib shrank tumors in early preclinical studies.
The findings suggest that tumors that contain the specific histone defects might respond either to olaparib or olaparib combined with decitabine.
Basic Research May Lead to Clinical Study
The study is a classic example of basic research illuminating the path toward human studies, said Lucas Caeiro, Ph.D., a Sylvester postdoctoral associate. Dr. Caeiro was first author on the study, along with former Sylvester postdoctoral associate Yuichiro Nakata, Ph.D.
“In the beginning, we were only interested in the mechanism behind these affected tumors, the basic stuff,” said Dr. Caeiro. “But when we saw the sensitivity to olaparib, we started to think that maybe we can use what we learn to benefit patients.”
Ultimately, the researchers want to initiate a clinical trial at Sylvester to test the drugs. But first, they are assessing tumor samples from head and neck cancer patients at Sylvester to see how many have the necessary histone defects. This will inform the feasibility and design of a potential clinical study.
The researchers are also collaborating with outside scientists who are developing new models of the disease to test the drugs’ effects further. Other types of cancers also have underlying defects in histones, including certain lung and brain cancers, noted Sylvester researcher Ramiro Verdun, Ph.D., an associate professor of medicine at the Miller School who co-led the study with Dr. Morey.
Dr. Verdun speculated that the histone defects may be some of the earliest molecular lesions in head and neck tumors. The resulting DNA damage may lead to additional mutations that drive tumor growth.
Drs. Verdun and Morey credit the research milieu and contact with physician colleagues at Sylvester for helping to guide the study. The Translational Research office at Sylvester is now providing funding and advice to advance the research.
Additionally, the National Institutes of Health awarded an R01 grant to Drs. Morey and Verdun to investigate how epigenetic mechanisms control head and neck cancers.
“Our journey depended so much on Sylvester funding, support and facilities,” said Dr. Verdun. “We are extremely lucky to have support from the cancer center for this.”