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DNA mutations are a hallmark of cancer. As the genetic mistakes add up, mutations can alter normal cellular pathways. Some of these changes may actually make the cancer cells susceptible to certain targeted drugs, but not all changes can be directly traced to a change in genetic code. Now, a Fred Hutchinson Cancer Research Center team led by Dr. Christopher Kemp and the late Dr. Eduardo "Eddie" Méndez shows that they can tease out tumor vulnerabilities even when they aren’t clearly linked to DNA mutations.
In a new paper in Clinical Cancer Research, the researchers analyzed in incredible detail the tumor cells from a man with head and neck cancer who agreed to donate his tumor tissue for research. The study shows that their approach, termed functional genomics, has the potential to deliver on the promise of precision oncology by highlighting potential drug targets in the patient’s tumor and helping distinguish the DNA changes that affect cancer survival from those that don’t. They also demonstrated the potential application for use in guiding a patient’s ongoing treatment and provided insight into vulnerabilities that might be found in other patients’ tumors.
The work is supported by the National Cancer Institute’s Cancer Target Discovery and Development, or CTD2, initiative. CTD2, part of the Precision Medicine Initiative announced by former president Barack Obama, aims to uncover new therapeutic targets for cancer. The potential targets from this study will be publicly posted in the CTD2 database of new cancer targets, available to other researchers to further explore.
Drilling down into one patient’s tumor
Every patient’s tumor has traveled a unique path, collecting its own set of genetic alterations that shape its response to different treatments. Kemp, Méndez and the current study’s first authors, Drs. Chang Xu and Olga Nikolova, wanted to dig as deep into the molecular characteristics of a single patient’s tumor as possible. What kinds of mutations had this person’s tumor collected? What are the essential proteins that cells from this specific tumor need to survive? And could any of this information shed light on potentially effective therapies?
“The question was, if we could go into huge detail on one patient, could we imagine a scenario where we could tailor therapy for that patient?” Kemp said. “And unlike most other approaches, which stop at the genomic or descriptive level, with DNA sequencing or gene expression … we take it two steps further and do these in-depth functional assays.”
The patient whose tumor was studied was diagnosed with an aggressive, treatment-resistant head and neck cancer. The patient received cisplatin chemotherapy and radiation after his tumor was surgically removed. The cancer cells were kept alive in laboratory culture, making it possible for Kemp and Méndez’s team to tease out what molecules they relied on to stay alive.
A step beyond genomics
Functional genomics is a three-pronged approach. First, the scientists assess the DNA mutations in the tumor to identify the underlying genetic defects. Next, they determine which of the many thousands of proteins inside a tumor cell are central to keeping the tumor cell alive but are not critical to the survival of normal cells. This is the functional side of functional genomics.
The researchers have developed a method that allows them to remove specific proteins, one by one, to see which are required to keep the tumor cells alive. Many proteins can be removed without affecting the cancer cells, but take away the right one, and the cancer cells will die. This information is combined with the third piece — drug sensitivity screening — to pinpoint existing drugs that might be effective and potential targets for which new drugs could be developed. Using an approach called high-throughput screening, the group can learn about the importance of thousands of different proteins, and the effect of thousands of drugs, at the same time.
Méndez and Kemp had already used the strategy to discover a previously unknown vulnerability in certain head and neck cancers that made them susceptible to a drug that targets a protein known as WEE1. This drug was tested against head and neck cancers in a promising, recently concluded Phase 1 trial.
But beyond pinpointing targets and drugs for future study, Kemp and his colleagues hoped to demonstrate that functional genomics has the potential to be used to tailor treatment for individual patients. Xu, a staff scientist, led the deeply detailed analysis of the patient’s tumor, generating a wealth of information that Nikolova, a computational biologist, developed methods to analyze.
The group found more than 200 gene mutations that conceivably could affect tumor growth or survival, but the incredibly detailed genomic data alone didn’t clarify which mutations might make the tumor susceptible to available therapies.
And, as it turns out, several key vulnerabilities did not arise from changes in the tumor cells’ DNA. When the team ran the two functional assays on the patient’s tumor cells, they found genes that were not mutated nevertheless made good drug targets.
This suggests that in this particular patient, merely sequencing the tumor’s genes could have led oncologists toward ineffectual treatments. In other patients, genomic sequencing may indeed pinpoint drug targets, but functional assays could still help identify new vulnerabilities.
The team’s functional genomics approach “leads directly to solutions, while a DNA sequencing-only approach all too often leads to questions with no answers,” Kemp said.
Accelerating precision medicine
Kemp’s ultimate goal is to bring tailored, effective treatments to patients. In addition to deeply analyzing one patient’s tumor and getting valuable glimpses into what made that tumor tick, he and his team were able to take a first step toward integrating their approach with patients’ ongoing cancer treatment.
Tumor samples from two patients who were participating in the trial of the WEE1 inhibitor were analyzed using the functional genomics approach. The team found that the laboratory results corresponded well with the patients’ responses to therapy, suggesting that the strategy could be used to assess individual patients’ drug sensitivities during treatment.
Unfortunately, the patient who donated his tumor tissue for deep analysis passed away as the team was analyzing the sample. Kemp’s goal is to prevent this from happening again. Now that they’ve worked out the computational methods necessary to analyze such an enormous amount of data, similar analyses will go much, much quicker, he said.
“This is where we feel the urgency to move this forward faster,” he said. While only a handful of genes are currently targeted by cancer drugs, “there are many more genes that could be targeted and we now have the ability to find them.”
