Combining Next-Generation Sequencing and Advanced Algorithms to Elucidate Tumor Heterogeneity

PROJECT SUMMARY Cancer is one of the leading causes of morbidity and mortality worldwideDriven by advancements in quantifying and characterizing the molecular profile of the tumorcancer therapy is becoming more personalizedselectiveand specificA key factor contributing to the lethalitytherapeutic failureand drug resistance of cancer patientshoweveris intra tumor heterogeneityITHcharacterized by a mixture of tumor cells with different complements of somatic mutationsITH is found in almost every type of cancer and can be highly variablewith up todifferent coding mutations found within primary tumors or between primary and metastatic or recurrence sitesHigh throughput next generation sequencingNGStechnologies are now giving an earlyunprecedented view of intra tumor mutational heterogeneitybut challenges remainCurrent barriers to progress exist in the arena of NGS analytical and computational softwareThere is an immediate need for NGS compatible computational methods that can detect cellular lineages and distinct molecular mechanisms so clinicians can leverage the power of high throughput NGS technology and fulfill the promise of precision oncologyThe objective of this Phase I SBIR project is to explore the clinical feasibility of a novel computational platformOncoGenomic Heterogeneity Softwarethat was designed using licensed technology from Brown University and is the first commercial product of Medley Genomicsa small business that was founded on the overall goal of building novel analytical approaches to define complex genomic heterogeneity and to understand human diseaseThe OncoGenomic Heterogeneity Software platform utilizes innovative analytical approaches to provide estimates of ITH with greater specificityaccuracyand reproducibility than existing solutionsTo explore the clinical feasibility of this technologyMedley Genomics willBuild on current technical validation studies to establish the optimal conditions for utilizing genomic heterogeneity software in primary breast tumorsAimExplore and evaluate the use of genomic heterogeneity software in formalin fixedparaffin embedded breast tumor tissuein comparison with fresh frozen tissueAimand enable the current genomic heterogeneity software to be compatible with cloud based computing and HIPAA compliant systemsAimThe successful conclusion of this study will support a future Phase II SBIR effort thatin collaboration with colleagues at a large academic medical centerwill constitute a clinical effort to retrospectively and then longitudinally evaluate the use of the OncoGenomic Heterogeneity Software package with NGSand possibly single cell sequencingdata to identify and characterize the ITH in primary tumors to inform earlytargeted intervention sin cancer treatmentEnabling this technology has the potential to both streamline and simplify the interpretation of NGS data for evaluating ITH more comprehensivelythus allowing oncologists to prescribe more accurateeffective targeted therapies faster and with more confidence NARRATIVE Precision oncology is the ability to treat cancer patients individuallyin line with the unique mutational profiles of their tumorsThese efforts are thwartedhowevergiven that existing technologiesi enext generation sequencingor NGSare not able to fully account for the heterogeneous nature of tumors current barriers to progress exist in the arena of NGS analytical and computational softwareThis project will advance a novel genomic heterogeneity software platformchampioned by Medley Genomicsthat is based on innovative algorithms and software licensed from Brown Universityand validate its clinical feasibility by characterizing intratumor mutational heterogeneity in primary breast tumorsfresh and paraffin embedded formalin fixed specimensThe purpose of this work is to provide computational solutions that will allow oncologists to further leverage the power of NGS in the clinicand make precision oncology a reality