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Cell-Free Nucleic Acid-Based Assay Development for Cancer Diagnosis

The evidence that cell-free circulating DNA is present in cancer patient?s blood was first reported over half century ago.  Since then studies that addressed the clinical significance of the cell free DNA quantification in plasma/serum for cancer diagnosis have grown steadily.  Research findings indicated that most patients with solid tumors in lung, breast, prostate, colon, cervix, ovary, testes, and bladder have increased DNA levels that allow for discriminating patients with malignancies from those with non-malignant disease.  The first application of cell free circulating nucleic acids (cfNA) in the diagnosis and prognosis of cancer was demonstrated in 1977 when higher level of circulating DNA was detected in the serum of cancer patients; these levels decreased in response to radiation therapy. 
In recent years, it has been recognized that circulating DNA may be altered in fragmentation pattern, microsatellite stability, and DNA methylation. In addition, the cfNA sequences may be mutated and tumor-specific allowing for increased sensitivity and specificity in evaluation and detection of cancer compared to mere quantification of cfNA levels.  Besides circulating cell free DNA, evidence has indicated that tumor-derived RNA, (especially the quantification of the tumor-derived microRNA in plasma/serum) may be an excellent biomarkers for the diagnosis and prognosis of cancer.  Furthermore, alterations of cfNA are also found in other sources of body fluids or effusions such as urine or sputum.  Clearly, cfNA as a biomarker, which is easily accessible, reliable, and reproducible, can offer many advantages in their implementation into clinical use.
To date, however, there are no currently effective cfNA-based assays that are approved for clinical use in the diagnosis or prognosis of cancer. The low abundance of cfNA from all body fluids and effusions remains a major challenge in the assay development.  Many early developments need to be further verified and validated before they can be translated to clinical use. With the latest technology advancement in sample collection, processing, and analysis for nucleic acids, the likelihood of clinical utilization of cfNA becomes more reachable. 
The purpose of this initiative is to provide much needed support for the development of a cfNA-based assay for cancer diagnosis and/or prognosis.  The selected applicants will develop an assay for detection of cancer or its subtype, so that cancer or subtypes can be identified specifically.  Since a single alteration in cfNA may not be sufficient to detect a specific cancer, offerors are encouraged to use a panel of cfNA alterations that could be more robust for their assay development.  The cfNA alterations may include, but not limited to, cfNA concentration, fragmentation pattern, microsatellite stability, and DNA methylation, tumor-specific sequences, DNA mutations or tumor-derived RNA.  The sources for cfNAs can be from plasma, serum, urine, sputum or other types of body fluids or effusions.  In Phase I, the development of molecular diagnostic assay should focus on proof of concept.  In Phase II, the assay developed in Phase I will be validated in the clinic setting under a plan developed with the NCI project officer.
Program Goals
The goal of the project is to develop a cfNA-based assay for clinical use in the evaluation of cancer diagnostics, prognostics, and response to therapy. The levels of sensitivity and specificity required will depend on the clinical question and unmet need the assay is attempting to answer.  The assay may also be used to provide a better mechanistic understanding of tumor development and progress with the idea that this knowledge may lead to better therapeutic targets and improve patient outcome.  Preference will be given to the assays that are platform driven, meaning that the technology platform should be portable and easily used for diagnosis of multiple cancer types.
To apply for this topic, offerors need to outline and indicate the clinical question and unmet clinical need that their assay will address. Offerors are also required to use validated cfNA markers.  This solicitation is not intended for biomarker discovery. 
Phase I Activities and Expected Deliverables
?       Select one or a set of validated cfNA markers with samples of a choice (e.g., plasma, serum or/and urine) for detection of a cancer or subtype (e.g., breast cancer or triple negative breast cancer).  If novel or proprietary markers are used, offerors must show that the markers have been validated.
?       Develop an assay to identify these markers effectively to distinguish the cancer samples from healthy samples.  The offerors should also demonstrate that the assay is able to differentiate the cancer from other cancer types.

Demonstrate high reproducibility and accuracy with the assay.
Demonstrate high specificity and sensitivity of the assay.  Specificity and sensitivity will depend on the application (e.g., high specificity will be required if the assay is used to provide specific molecular information for the lesion that was detected by CT imaging).
Deliver to NCI the SOPs of the cfNA-based assay for cancer diagnosis.

?       Demonstration of a plan that is necessary to file a regulatory application.
Phase II Activities and Expected Deliverables

Demonstrate the assay that enables a test to be finished within one day.
Validate the assay in the clinical setting.
Submit a regulatory application to obtain approval for clinical application.

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