Armed with an increasingly clear picture of the complex biomolecular mechanisms of disease onset and progression, clinical oncology is poised to realize the promise of personalized medicine by applying multiplexed analytical tools for improved diagnostic, prognostic, and theranostic capabilities. However, there are, in general, a lack of suitable technologies to support multiplexed analyses in the clinic-particularly with respect 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 unraveled through the measurement of multiple biomarker signatures and at both the miRNA and protein level, a wealth of putative biomarkers have been identified that show enhanced predictive value when considered together with panels of other markers. However, many discovery technologies are not amenable to the clinic. For miRNAs, qRT-PCR assays are incredibly sensitive, relatively rapid, and cost effective, yet are only able to quantitte expression of a single target per assay. Conversely, microarrays are readily multiplexable, yet quite slow and expensive. Thus, there exists a pressing need for meso-plex diagnostic capabilities whereby focused panels of 10s of miRNAs can be simultaneously interrogated using rapid, cost effective, and highly scalable technologies. Again, there is a striking gap in analyticl capabilities that limit the translation of multiplexed proteomics into the clinic. The gold standar enzyme-linked immunosorbent assay (ELISA), is typically very sensitive, selective, and cost effective, though most often single-plex. Protein microarrays are highly multiplexable, but generally far less sensitive, less selective, and not amenable to the clinical setting. Emerging multiplexed 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 and multiplexable biomolecular analysis technology, and this application aims to robustly validate this powerful technology for meso-plex cancer diagnostics. Silicon photonic microring resonator arrays, having up to 128 uniquely address-able sensor elements, have been previously utilized to quantitatively detect nucleic acid and protein 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 sensor array chips can be scalably fabricated to allow low cost assays (<$1/measurement). Furthermore, the molecular generality of this methodology will be utilized to simultaneous profile micro-RNA (miRNA) and protein expression from the same clinical sample-a transformative capability. Although applicable to any cancer, the lethal brain cancer glioblastoma multiforme will be the laboratory and clinical model. Well-established miRNA and protein biomarkers 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 with cancer or in remission. A mounting body of evidence suggests that multi-biomarker panels provide detailed levels of diagnostic, prognostic, and theranostic information regarding disease onset, progression, and effective treatment regimens;however, there is a technological void that prevents the translation of this molecular-level insight into the clinic. This application describes a multi-faceted plan to fully validate a transformative technology for molecular cancer diagnostics based upon chip-integrated silicon photonics, filling critical gaps in meso-plex analytics (10s of measurements) for both microRNA and protein diagnostics.
|Wade, James H; Bailey, Ryan C (2014) Refractive index-based detection of gradient elution liquid chromatography using chip-integrated microring resonator arrays. Anal Chem 86:913-9|