Bluestar Genomics reports new method for early pancreatic cancer detection

SAN DIEGO—Bluestar Genomics Inc. has announced the publication of study results reporting a non-invasive way to test for pancreatic cancer. The article, entitled “Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA,” has been published in Nature Communications.

 

According to Kelly Bethel, M.D., chief medical officer of Bluestar Genomics, “Pancreatic cancer is the third leading cause of cancer death in the U.S. and the absence of a robust screening test in clinical care means that this cancer is often detected at an advanced stage, leaving patients with fewer treatment options.”

 

“The Nature Communications publication demonstrates that our technology provides a crucial foundation for the development of a screening test that will set a new standard for liquid biopsies and the future of cancer screening,” added Samuel Levy, Ph.D., CEO and chief scientific officer of Bluestar Genomics, and senior author of the study.

 

The research shows that utilizing Bluestar’s epigenomic technology to analyze blood can effectively identify the presence of pancreatic cancer in patients’ DNA, circulating in their blood. This technique enables precise, non-invasive disease detection, which could lead to more timely treatment and improved patient survival.

 

Published results from a study of 307 patients — including men and women ages 40 or older — showed that Bluestar Genomics’ technology identified distinctive patterns in thousands of genes that could serve as a biomarker for blood-based pancreatic cancer detection. This could enable the development of a future cancer screening test. The study includes application of the detection strategy to novel samples not included in the development set, providing validation that holds promise for early-stage detection in larger patient groups.

 

In pancreatic cancer patients, circulating tumor cells and circulating tumor DNA are shed into the blood and can be easily obtained through a blood draw. This provides a unique potential for early diagnosis, the ability to forecast disease prognosis and the ability to monitor therapeutic response.

 

“The 5hmC [5-hydroxymethylcytosine] signal was readily found to overlap in gene-centric functional regions (enrichment in promoter, exons, UTR and TTS), as well as transposable elements like SINEs (enriched) and LINEs (depleted) (Fig. 1a). Globally, PDAC [pancreatic ductal adenocarcinoma] cfDNA [cell free DNA] cohort had decreased number of peaks compared to non-cancer cfDNA cohort (Fig. 1b), consistent with previous reports of decreased 5hmC in several types of cancer, including pancreatic cancer⁴⁴,” the article states. “Indeed, decreased 5hmC was recently linked to malignant transformation in KRAS mutant pancreatic cells upon deactivation of p53, which are commonly observed in PDAC patients⁴⁵.”

 

“Hydroxymethylcytosine changes in functional regions have also been reported in cfDNA from colorectal²⁵, esophageal^24,46 and lung cancer²⁴,” continues the article. “Consistent with these reports, we observed decreased number of peaks in PDAC cfDNA relative to non-cancer cfDNA. Furthermore, we report PDAC specific gains or losses in hydroxymethylation in functional regions in our data. PDAC specific 5hmC increase in 3’UTR, TTS and exons and 5hmC decrease in promoters detectable in cfDNA (Fig. 1c). These changes were also observed in various pancreatic cancer stages (Supplementary Fig. 1).”

 

“In embryonic stem cells, 5-hydroxymethylation decreases in the promoter region have been shown to associate with elevated gene transcription²⁷. An increase in disease relevant transcription is implicitly supported in our PDAC data by the 5hmC increase in gene-centric features mentioned earlier, as well as an apparent decrease of 5hmC in promoter regions (Fig. 1c),” the article notes. “Taken together, disease specific remodeling of active demethylation in PDAC patients is captured via changes in 5hmC representation.”

 

Current diagnostic methods rely on disease tissue to characterize the condition; Bluestar Genomics’ blood-based 5hmC assay is able to detect signals of disease in a patient’s plasma via DNA-based changes found in gene and gene regulatory regions.

 

“Dynamic changes in chromatin have been shown to control cell development and transition of cells with oncogenic potential⁴⁷. Intersection of our 5hmC data with various chromatin states determined by ChIPseq in PDAC primary tumor tissues revealed 5hmC localization in active chromatin regions, most significantly active TSS and active enhancer regions (Fig. 2a),” explains the article. “Consistent with 5hmC changes over promoters, 5hmC decrease in PDAC cfDNA in active TSS regions also suggests disease specific increases in gene transcription via chromatin modifications, given the permissive transcriptional state associated with H3K4me3⁴⁸.”

 

“Furthermore, we observed 5hmC decrease in weak enhancer regions identified by H3K27ac and H3K4me1 (Fig. 2a),” the article concludes. “While 5hmC patterning around known functional elements of the genome suggests a broader interplay between hydroxymethylation and the epigenetic control of transcriptional processes, these results also indicate that 5hmC in cfDNA can potentially be utilized for non-invasive monitoring of epigenomic dysregulation in PDAC. Additional work will reveal the extent to which models predictive of PDAC can be built from a combination of gene-specific features, genomic loci with different chromatin states and transposable elements detected in cfDNA.”

 

The study results strongly suggest that a clinical test employing newly identified biomarkers could promote more effective early-stage pancreatic cancer screening. This may hold significant value, since many pancreatic cancer patients are asymptomatic until the disease has advanced to a late stage.

 

“This publication demonstrates that the utilization of our epigenetics platform can identify tumor biology in plasma earlier, which can bring the possibility of earlier treatment options to patients, potentially increasing their survival,” noted Gulfem Guler, Ph.D., lead scientist on pancreatic cancer research for Bluestar Genomics, and lead author of the study.

 

Bluestar plans to continue development work on its platform, and to commercialize a test for pancreatic cancer in the coming years.