Early cancer detection is not only critical in providing curative therapies for the vast majority of solid malignancies and preventing mortality, but also reducing morbidity and costs. However, most existing strategies for early detection suffer from poor specificity: they are as likely to cause complications and deaths from false positives or overdiagnosis of non-invasive cancers as they are from identifying true cancers at an early stage. Recent data from our own group and others show that Circulating Tumor Cells (CTCs) may be shed in significant numbers into the blood stream of patients with invasive but localized and early-stage cancers. These observations suggest that, rather than being a rare and late event in the evolution of cancer, the presence of CTCs may be an early herald of tumor vascular invasion, preceding a considerable period of time for the eventual establishment of viable distant metastases. Our specific strategy is to develop a highly sensitive digital readout based on RNA in CTCs using the microfluidic CTC isolation approach (CTC-iChip) combined with digital droplet RNA (ddPCR) measurement platform. It is important to note that the CTC-iChip is unique in that it makes no a priori assumption about the type of the tumor cells and as such it applies to all cancers. Detecting tumor lineage specific RNA within noninvasively accessed tumor cells is the technology most likely to be not only highly specific and sensitive but also universal for early detection of invasive cancer. To this end, we have 3 distinct but interrelated Aims.
In Aim I, we will integrate CTC-iChip and digital droplet PCR to develop a highly specific and sensitive RNA-iChip.
In Aim II, we will select two cancers for which sensitive but nonspecific screening tests are currently available, prostate and lung cancer, and we propose to transform these into robust and reliable tests using RNA-iChip that would enable broad screening for invasive and curable cancers.
In Aim III, we propose to develop the point of care RNA-iChip broad dissemination beyond academic medical centers to local hospitals, oncology clinics and to physicians' offices. Success with prostate and lung cancers would have a profound impact in decreasing cancer morbidity and mortality, and open a path toward broad-based early detection of multiple cancers.

Public Health Relevance

The availability of an early diagnosis assay for cancer would empower oncologists as well as non-specialists to make rapid and accurate decisions, make cancer care 'personalized', improve the quality of care, reduce significant disparities that exist in cancer care, and most importantly, save lives. We will develop a point of care technology to diagnose invasive cancers at an early curable stage by detecting RNA signatures derived from circulating tumor cells. Success in this project would transform the early detection and treatment of lung and prostate cancers and establish a strategy for early diagnosis of multiple cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01EB012493-08
Application #
9296141
Study Section
Special Emphasis Panel (ZEB1)
Program Officer
Lash, Tiffani Bailey
Project Start
2010-09-30
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
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Sandlin, Rebecca D; Wong, Keith H K; Tessier, Shannon N et al. (2018) Ultra-fast vitrification of patient-derived circulating tumor cell lines. PLoS One 13:e0192734
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Aceto, Nicola; Bardia, Aditya; Wittner, Ben S et al. (2018) AR Expression in Breast Cancer CTCs Associates with Bone Metastases. Mol Cancer Res 16:720-727
Wong, Keith H K; Tessier, Shannon N; Miyamoto, David T et al. (2017) Whole blood stabilization for the microfluidic isolation and molecular characterization of circulating tumor cells. Nat Commun 8:1733
Fachin, Fabio; Spuhler, Philipp; Martel-Foley, Joseph M et al. (2017) Monolithic Chip for High-throughput Blood Cell Depletion to Sort Rare Circulating Tumor Cells. Sci Rep 7:10936
Zheng, Yu; Miyamoto, David T; Wittner, Ben S et al. (2017) Expression of ?-globin by cancer cells promotes cell survival during blood-borne dissemination. Nat Commun 8:14344

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