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TCGA's Ovarian Cancer Study Points to Range of PGx Strategies, Potential Role for PARP Inhibitors

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By Molika Ashford

The Cancer Genome Atlas Research Network has published a detailed picture of the genomic changes in a highly aggressive form of ovarian cancer that suggests a broad range of genomically guided treatment strategies for the disease.

According to the group's paper, published in Nature this week, their analysis of advanced-stage, high-grade serous ovarian cancer, or HGS-OvCa, "sets the stage for approaches to the treatment of HGS-OvCa in which aberrant genes or networks are detected and targeted with therapies selected to be effective against these specific aberrations."

In all, the TCGA team identified 68 genes that could be targeted by existing US Food and Drug Administration-approved or experimental compounds, and singled out PARP inhibitors as a drug class with particular potential. The study also provides a potential basis for subtype-based diagnostics to stratify patients according to their cancer's genomic variation, as well a preliminary gene signature with prognostic potential.

The full catalog of aberrations reflects analysis of mRNA and microRNA expression, DNA copy number, and promoter methylation in 489 HGS-OvCa samples, as well as whole-exome sequencing of 316 of the samples. The analysis found TP53 mutations in 96 percent of the tumors, as expected, and lower prevalence somatic mutations in nine other genes, as well as miRNA and methylation changes showing four distinct expression subtypes.

The study also found that more than 20 percent of the tumors had mutations in the BRCA1 and BRCA2 genes that were associated with better survival odds than patients with wild-type versions of the genes.

The goal of the TCGA, which began as a three-year pilot in 2006, is to completely characterize more than 20 tumor types, or which serious ovarian adenocarcinoma is the second.

The authors noted in the Nature paper that new therapeutic approaches are a "central goal" of the TCGA, and said that several aspects of the study findings point toward possible pharmacogenomic targets.

Paul Spellman, a research scientist at Lawrence Berkeley National Laboratory and lead author on the paper, told PGx Reporter this week that though the study found many candidate genes that could be linked with available therapeutics, these treatments would be considered off-label if applied to ovarian cancer currently.

"If you look at the structure of the genome, there are a large number of regions that have copy number changes, and a significant number of genes… are potential candidates for therapeutic intervention, in the sense that they have drugs in the pipeline. But none of them are indicated for ovarian cancer now to the best of my knowledge," he said.

In particular, the study suggests that PARP inhibitors may be a promising therapy for HGS-OvCa. It has already been established that cells with mutated or methylated BRCA1 or mutated BRCA2 are responsive to PARP inhibitors, so the fact that around 20 percent of the samples in the study had germline or somatic mutations in BRCA1/2, and 11 percent lost BRCA1 expression through DNA hypermethylation, points toward PARP inhibitors as a potential treatment. Furthermore, the TCGA team identified genomic alterations in other homologous recombination genes that indicate sensitivity to PARP inhibitors, including amplification or mutation of EMSY, focal deletion or mutation of PTEN, hypermethylation of RAD51C, mutation of ATM or ATR, and mutation of Fanconi anaemia genes.

In total, the team found that approximately 50 percent of the serious ovarian cancer samples in the study exhibited genomic alterations linked to response to PARP inhibitors — a finding, the authors wrote, that provides a rationale for "clinical trials of PARP inhibitors targeting tumors with these homologous recombination-related aberrations."

"We think this is one of the first chances to have a very good catalog of the exact fraction of cases that have mutations in all the components that might be involved … So the prevalence in those pathway mutations in ovarian cancer shows that something like half of the cases might be candidates for PARP inhibition," Spellman said.

Several drug firms are developing PARP inhibitors to treat cancer. AstraZeneca's PARP inhibitor olaparib is being developed in ovarian cancer and the company has partnered with Myriad Genetics to use the firm's BRACAnalaysis test to stratify patients in clinical trials based on their BRCA gene mutation status.

Strategies for combining drugs might also result from the research, he added, though "the impact of the study on indicating combination therapies probably has more to do with identifying and helping to identify targets." Since many of the genetic changes were seen in less than ten percent of samples, the proportion of patients with two unique, currently actionable targets might be low, he said.

At the same time, he said, "I think the idea of combination therapy has a lot of appeal in sort of a pathway model sense where people are looking, for example, at feedback loops and want to turn off one [gene] that causes cells to rewire themselves, and turn on another that works in with a second drug."

"In this case… the prevalent events we have are ones we already know about: p53 and the BRCA pathway. Those are the only things that are really more than 25 percent frequency."

But, Spellman suggested, if drugs were developed to interfere with p53 inactivation, for example, they could provide one half of an effective treatment combination. Other signaling pathways identified by the study, NOTCH and FOXM1, might also be promising targets, he said.

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Overall, the study offers a broad genomic picture that could inform a variety of future treatment options and diagnostic development strategies, according to the researchers.

BRCA1 and 2 each showed germline mutations in about ten percent of the study samples and had somatic mutations in an additional three percent, Spellman said. The group also found other genes with mutations that were recurrent, though less frequently, including, NF1, RBI and CDK12. The analysis also identified 113 significant focal copy number aberrations and promoter methylation events involving 168 genes.

Interestingly, the study also shed new light on the role that BRCA1/2 variations play in survival. "If either of the BRCA1 and BRCA2 genes is mutated, there is improved survival duration. However, if BRCA1 activity is instead reduced by methylation, there is no improved survival duration," the authors wrote.

"What was surprising is that many people I think expected that methylation of BRCA 1 — which is a very common event in ovarian cancer, ten percent frequency or more — would behave very similarly to mutation of BRCA1 and BRCA2, and what we found is that it doesn't. We found that BRCA1 methylation behaves like wild type BRCA1," said Spellman.

"I think there [are] two interpretations of that," he said. One interpretation is that "that there is something fundamentally different" about methylation of BRCA1 activity.

The other option, which Spellman favors, is that BRCA1 methylation is "easier to escape," meaning that "the tumors that want to restore BRCA1 [find it] much easier to adapt to demethylating BRCA1 and restoring activity than if you have a somatic or germline mutation in the gene that inactivates it," he said.

In addition to identifying potential drug targets, the TCGA researchers also identified a 193-gene transcriptional signature that predicted overall survival, with 108 genes correlated with poor survival, and 85 with good.

The team validated the predictive power of the signature on an independent set of 255 TCGA samples, as well as three independent sets of expression data. They wrote that the signature showed statistically significant association with survival in all validation sets.

The researchers also examined mRNA and miRNA expression in the tumor samples.

Combining gene expression measurements for 11,864 genes from three platforms (Agilent, Affymetrix HuEx and Affymetrix U133A), the researchers identified approximately 1,500 genes as "intrinsically" variable. Four clusters, the researchers wrote, could be considered separate expression subtypes of HGS-OvCa.

In the paper, the group describes these subtypes as "immunoreactive," "differentiated," "proliferative," and "mesenchymal," based on the genes present in each cluster and on earlier research on molecular subtypes of ovarian cancer.

While molecular subtypes of breast cancer have been adopted for diagnostic testing in assays like the PAM50 test, the same may not be immediately true of ovarian cancer subtypes because these types have not yet been linked with unique treatments, Spellman said.

"PAM50 is useful because it segregates patients with clinically distinct treatment regimens," he said. "For high-grade serous ovarian cancer there are no real viable alternatives today. In the future, as we learn more about the distinct biology of the disease, it might be possible."

The data from TCGA's analysis is freely available to anyone who can demonstrate a scientific rationale for their use and can maintain patient privacy in regard to the samples. Spellman declined to mention any specific companies that have expressed interest in the data toward drug or diagnostic development.

With the serious ovarian cancer study complete, TCGA plans to move on to 20 or so other tumor types. These further studies will be funded using money from the 2009 American Recovery and Reinvestment Act.

Spellman said the group is already pushing forward. "We expect to see final data on colon, kidney, rectal and ductal breast carcinomas very shortly," he said.

All those cancer types have had all their samples accrued, he said. "It’s a matter of months between when the samples are accrued to when the data are available … and we expect that a number of papers will be submitted in the remainder of 2011 and hope to see quite a number coming out in 2012 on other tumor projects."


Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at mashford [at] genomeweb [.] com.

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