The ultimate success of disease genome projects, such as The Cancer Genome Atlas (TCGA) project ultimately depends on our ability to rapidly translate the massive amounts of data generated into more effective biomarkers and treatment strategies. Using a functional genomics platform that we established to harvest the yield of TCGA we have uncovered 1) genotype--‐matched tumor suppressor microRNAs for multiple cancers, 2) new druggable targets uncovered from the microRNA regulated transcriptome and 2) microRNA--‐regulated gene signatures that can more accurately stratify patients in terms of clinical outcomes than genes or
microRNAs alone.
To rapidly customize therapeutic strategies to suit individual genomes we have added a high-‐throughput functional validation arm that combines microRNAs and siRNAs delivered on gold nanoparticles (Ghosh et al. 2012) and 3D culture models of ovarian and breast cancer. Our functional genomic platform is easily scalable and designed us to rapidly screen the complete set of microRNAs and siRNAs to significantly mutated genes in cancer genomes to 1) gain a systems-‐level understanding of cancer and 2) to identify critical driver of oncogenic pathways to uncover new drug
Targets and 3) identify combinations of microRNAs and drugs to suit individual genomes. To rapidly translate our findings into clinical practice we have collaborated with Dr. Esther Chang at the Lombardi Cancer Center to use their FDA approved, Phase I passed, tumor-‐targeted nanolipsomal delivery vehicle scL to achieve complete remission of ovarian cancer in 40% and extend disease free survival in 60% of pre-‐clinical models of ovarian cancer. Genomic studies established that when used in combination with first-‐line chemotherapy and new drugs like BH3-‐mimetic ABT-‐737 TS microRNAs can transform the treatment of recurrent chemo-‐resistant ovarian cancer by acting as a circuit breaker to intercept diverse signaling pathways driving metastatic progression and chemo-‐resistance.