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Identifying new drug targets is imperative to combat metastasizing cancers in the future as existing therapies may turn ineffective and a reserve of novel treatment options may save lives, time, and resources.

Two Potential Drug Targets Identified in Cervical Cancer Trial

ARID1A and PIK3CA could serve as potential targets for drug development

NRG Oncology

Formed to conduct oncologic clinical research and to broadly disseminate study results for informing clinical decision making and healthcare policy. It brings together the National Surgical Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG)—each recognized internationally as a research leader.

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Published:Mar 29, 2023
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NRG Oncology GOG-0240, a Phase 3, randomized trial, demonstrated the statistically and clinically significant survival benefit of incorporating bevacizumab with chemotherapy for women with recurrent and metastatic cervical carcinoma (NCT00803062). GOG-0240 was a proof of concept in anti-angiogenesis therapy and a proof of principle in supportive care and led directly to an indication for bevacizumab in this disease in over 60 countries. 

Whole genome sequencing and whole exome sequencing of tumor samples obtained in GOG-0240 suggest that ARID1A and PIK3CA could represent potential targets for drug development in the recurrent/metastatic cervical cancer space. These results were presented by lead author, Anjali Y. Hari, MD, of the University of California Irvine, CA, during the late-breaking oral session of the Society of Gynecologic Oncology’s (SGO) Annual Meeting in March 2023. 

“Although the adoption of anti-angiogenesis therapy and immunotherapy have fulfilled previously unmet clinical needs in advanced cervical cancer, nearly all patients will ultimately progress, creating new populations in need of novel treatment. This study, by identifying two promising targets, could potentially lead to new treatment options,” stated Hari.

Phase 3 GOG-0240 trial: execution and findings

From April 6, 2009, and January 3, 2012, the Phase 3 GOG-0240 trial enrolled 452 patients, who provided 112 tumor samples with sufficient DNA and RNA for mutational analysis. 

In this study, DNA/RNA were co-extracted from FFPE samples after a central pathology review at the NRG Biospecimen Bank at Nationwide Children’s Hospital in Columbus, OH. DNA/RNA analytes were shipped to the New York Genomic Center and the University of North Carolina for whole genome sequencing, whole exome sequencing, RNA sequencing, and microRNA sequencing.

Mutational frequencies were compared with those reported in the Cancer Genome Atlas (TCGA) and potential molecular targets for biological therapy were identified. Pattern recognition, mutational clusters, and bioinformatics steps are in progress. 

More than 35,917 total mutations were identified, and above 90 percent of mutations identified from DNA were present in RNA sequences when the expression level was sufficient. Similar to early-stage cases from the TCGA, PIK3CA (an integral component of the mTOR pathway that modulates angiogenic factors) was mutated in 28 out of 112 (25 percent) advanced/recurrent GOG-0240 specimens. 

Median overall survival (OS) among PIK3CA mutants was 15.4 months (HR 1.0; 95 percent CI 0.61–1.62) and median progression-free survival (PFS) was 7.5 months (HR 0.85; 95 percent CI 0.54–1.34).

A significantly higher frequency of ARID1A mutants (previously reported to increase tumor mutational load and sensitivity to immunotherapy) was observed in 19 of 112 GOG-240 samples (17 percent) compared with TCGA (5 percent, p < 0.005). Median OS among ARID1A mutants was 14.3 months (wild-type 17.1 months; HR 1.18; 95 percent CI 0.67–2.06) and median PFS was 5.3 months (wild-type 6.9 months; HR 1.0; 95 percent CI 0.59–1.68).

The trial results demonstrated that ARID1A and PIK3CA are potential targets and should be considered for drug development through clinical trials in the recurrent/metastatic cervical cancer space. 

Concerning these results, Hari said, “We hope that the ongoing bioinformatics, mutational clustering, and pattern recognition incorporating RNA sequencing and microRNA analysis will identify additional potentially druggable targets and further increase our understanding of gene expression in advanced cervical cancer.”

- This press release was originally published on the NRG Oncology website