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

Fast-Track proposals will be accepted.

Direct-to-Phase II will not be accepted.

Number of anticipated awards: 3–5

Budget (total costs, per award):
Phase I: $300,000 for 9 months;
Phase II: $2,000,000 for 2 years

It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

The deadline for receipt of all contract proposals submitted in response to this solicitation has expired. It was: November 5, 2014 by 4:30 PM ET.


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 indicate 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 a 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 biomarker 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, using 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 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 feasible.

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 are not limited to, cfNA concentration, fragmentation pattern, microsatellite stability, DNA methylation, tumor-specific sequences, DNA mutations, or tumor-derived RNA. The sources of cfNAs can be from plasma, serum, urine, sputum, or other types of body fluids or effusions. In Phase I, the development of a molecular diagnostic assay should focus on proof of concept. In Phase II, the assay developed in Phase I will be validated in the clinical setting under a plan developed with the NCI project officer.

Project Goals

The goal of the project is to develop a cfNA-based assay for clinical use in the evaluation of cancer diagnosis, prognosis, and/or response to therapy. The levels of sensitivity and specificity required will depend on the clinical question and the unmet need(s) that will be addressed with the proposed assay. 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 should 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 choice (e.g., plasma, serum or/and urine) for detection of a cancer or cancer 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 a lesion that was detected via CT imaging).
  • Deliver to NCI the SOPs of the cfNA-based assay for cancer diagnosis, prognosis, and/or response to therapy.
  • Demonstration of a plan that is necessary to file a regulatory application.

Phase II Activities and Expected Deliverables

  • Demonstrate that the assay 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.
Updated Date: 
June 24, 2015