Armed with an increasingly clear picture of the complex biomolecular mechanisms of disease onset andprogression, clinical oncology is poised to realize the promise of personalized medicine by applyingmultiplexed analytical tools for improved diagnostic, prognostic, and theranostic capabilities. However, thereare, in general, a lack of suitable technologies to support multiplexed analyses in the clinic?particularly withrespect to the analysis of disease-relevant miRNA and protein panels, despite their clearly established utility. Complex and aberrant mechanisms underlying cancer onset and progression can only be unraveledthrough the measurement of multiple biomarker signatures and at both the miRNA and protein level, a wealthof putative biomarkers have been identified that show enhanced predictive value when considered togetherwith panels of other markers. However, many discovery technologies are not amenable to the clinic. FormiRNAs, qRT-PCR assays are incredibly sensitive, relatively rapid, and cost effective, yet are only able toquantitate expression of a single target per assay. Conversely, microarrays are readily multiplexable, yet quiteslow and expensive. Thus, there exists a pressing need for meso-plex diagnostic capabilities whereby focusedpanels of 10s of miRNAs can be simultaneously interrogated using rapid, cost effective, and highly scalabletechnologies. Again, there is a striking gap in analytical capabilities that limit the translation of multiplexedproteomics into the clinic. The gold standard enzyme-linked immunosorbent assay (ELISA), is typically verysensitive, selective, and cost effective, though most often single-plex. Protein microarrays are highlymultiplexable, but generally far less sensitive, less selective, and not amenable to the clinical setting. Emergingmultiplexed analysis methodologies offer some improvements but have yet to find widespread clinical utility. Chip-integrated silicon photonic sensor arrays have recently emerged as an inherently scalable andmultiplexable biomolecular analysis technology, and this proposal aims to robustly validate this powerfultechnology for meso-plex cancer diagnostics. Silicon photonic microring resonator arrays, having up to 128uniquely address-able sensor elements, have been previously utilized to quantitatively detect nucleic acid andprotein signatures in multiplexed assay formats and from within complex, clinically-relevant sample matrices.Importantly, the technology has its origin in well-established methods of semiconductor processing and sensorarray chips can be scalably fabricated to allow low cost assays (<$1/measurement). Furthermore, themolecular generality of this methodology will be utilized to simultaneous profile miRNA and protein expressionfrom the same clinical sample?a transformative capability. Although applicable to any cancer, the lethal braincancer glioblastoma multiforme will be the laboratory and clinical model. Well-established miRNA and proteinbiomarkers exist for glioblastoma, thus keeping the proposed efforts entirely on technology validation.
Cancer is the second leading cause of death in the United States with over 12 million Americans living withcancer or in remission. A mounting body of evidence suggests that multi-biomarker panels provide detailedlevels of diagnostic; prognostic; and theranostic information regarding disease onset; progression; andeffective treatment regimens; however; there is a technological void that prevents the translation of thismolecular-level insight into the clinic. This proposal describes a multi-faceted plan to fully validate atransformative technology for molecular cancer diagnostics based upon chip-integrated silicon photonics; fillingcritical gaps in meso-plex analytics (10s of measurements) for both microRNA and protein diagnostics.
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