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Development of a low-cost epigenetic screening assay for Pap specimen-based detection of early-stage ovarian cancer in high-risk women

Award Number: R01CA260628
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY With a 5-year survival rate of only 47%, high-grade serous carcinoma (HGSC) remains the most lethal of all types of ovarian cancer. This is a particular concern for women with familial histories or BRCA mutations, who exhibit 20 to 35-fold higher risk of developing HGSC in their lifetime. The high mortality of the disease is largely attributable to the fact that HGSC almost always remains undiagnosed until advanced stages when curative surgery is no longer feasible. Recently, numerous studies have demonstrated that most HGSCs likely originate in the fallopian tubes as precursor lesions called serous tubal intraepithelial carcinomas (STICs) that progress over a period of 6-7 years before rapidly metastasizing to the ovary and surrounding tissues. This suggests there exists a critical window of time in which STIC lesions and early-stage tumors might be detected so that tumor progression can be effectively intercepted before reaching an incurable stage. Recent studies have held out hope by showing that STIC and tumor cells are able to freely travel from the fallopian tubes to the cervix where they can be readily-detected in routinely-collected Pap specimens. Nonetheless, two notable challenges to this approach remain: (1) issues associated with the sensitivity and specificity of current biomarkers that undermine test performance and (2) a cost-effective diagnostic technology with sufficient sensitivity to detect exceedingly-rare copies of biomarkers from early-stage HGSC in complex samples such as Pap specimens. In the present proposal, we seek to address both of these challenges by developing a new type of HGSC screening assay called PapDREAM that is based on the sensitive, cost-effective detection of a novel set of epigenetic biomarkers that we have recently shown to be prevalently and specifically hypermethylated in both early, precursor (STIC) lesions and later-stage HGSC tumors. The PapDREAM assay will employ a unique, digital methylation analysis technique called µ-DREAMing (microfluidic Discrimination of Rare EpiAlleles by Melt) that provides a simple, but highly-effective means of detecting and quantifying rare, aberrantly- methylated DNA, even in challenging samples such as stool, liquid biopsies and Pap specimens. A user- friendly workflow based on common laboratory instrumentation will be developed to enable PapDREAM to be readily translated and performed in various research and clinical settings at a cost of only a few dollars per assay. Ultimately, the PapDREAM assay can be used alone or in combination with other assays to provide an ideal screening method for women at high risk for developing HGSC. We have assembled a multi-disciplinary team with complementary expertise in gynecologic pathology, assay development and DNA methylation bioinformatics to accomplish this goal by achieving the following aims: (1) Evaluate and prioritize methylation biomarkers to be included in the PapDREAM assay, (2) Incorporate µ- DREAMing assays into PapDREAM: a simple, multiplexed digital methylation assay for the detection of early- stage HGSC, and (3) Assess the clinical performance of the PapDREAM assay in Pap specimens.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $406,959 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Detection and Diagnosis Research	000	4	5/2/2024	NON-COMPETING CONTINUATION	$406,959
														Subtotal = $406,959

Issue Date FY: 2023 ( Subtotal = $423,593 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Detection and Diagnosis Research	000	3	6/1/2023	NON-COMPETING CONTINUATION	$423,593
														Subtotal = $423,593

Issue Date FY: 2022 ( Subtotal = $433,937 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Detection and Diagnosis Research	000	2	8/8/2022	NON-COMPETING CONTINUATION	$433,937
														Subtotal = $433,937

Issue Date FY: 2021 ( Subtotal = $443,815 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Detection and Diagnosis Research	000	1	6/14/2021	NEW	$443,815
														Subtotal = $443,815

Grand Total All Awards = $1,708,304

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Development of a low-cost epigenetic screening assay for Pap specimen-based detection of early-stage ovarian cancer in high-risk women

Award Number: R01CA260628

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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