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Circulating exosomal RNA as a biomarker in melanoma. Association of Women Surgeons October 15th, 2016 Genevieve M. Boland, MD, PhD Assistant Professor, Harvard Medical School Assistant in Surgery, Massachusetts General Hospital A lot has changed in a very short period of time. Molecularly-targeted therapy Immunotherapy Circulating Biomarkers in Cancer CTCs ctDNA Exosomes Proteins Westphal et al. 2015 Exosomes: Defined By Size AETHLON MEDICAL INC Bence Gyorgy et al. Cell. Mol. Life Sci. 2011 Exosomes in Cancer Bobrie et al, 2011 RNA is Concordant: Cells vs Exosomes RPMI 7951 Cells RPMI 7951 Exo 100 90 A375 Cells A375 Exo Allele Fraction (%) 80 Sk mel 2 Cells Sk mel 2 Exo 70 Sk mel 30 Cells Sk mel 30 Exo 60 MeWo Cells MeWo Exo 50 40 30 20 10 0 BRAF V600E BRAF V600E NRAS Q61R NRAS Q61R NRAS Q61K NRAS Q61K 400 p<0.0001 pg BRAF V600E/ng RNA 250 * 300 200 100 0 Normal 200 Pt Number 150 36 280 100 370 50 Melanoma 0 PRE-RESECTION 16000 Electron Microscopy pg BRAF V600E/ng RNA Exosome Concentration x107 Patient-Derived Exosome Characterization POST-RESECTION Palliative Rsxn Definitive Rsxn 14000 Pre-resection Post-resection 12000 10000 Patient Number 8000 6000 4000 2000 0 410 214 356 383 166 Pt Number RNA is Concordant: Tumor vs Exosomes Immune/Hematologic Metabolic Exosome Profile Reflects Response to aPD1 • Pre- and On-treatment exosomes (n=20) of responders and non-responders to aPD1 • Statistically significant differences (p<0.05) in pre- to on- change between responders and non-responders • 111 genes, including 8 miRNA and markers of immune activation (e.g. IFN-gamma) • Expansion cohort and validation ongoing Exosome RNA Correlates with Tumor Mutations BRAF Exosomal RNA NRAS Triple WT NF1 CKIT Immunotherapy: predictive signature of response to aPD1 Immunotherapy responsive Exosomal RNA Immunotherapy non-responsive Future Directions • Examine the use of tumor mutations to assess minimal residual disease and identify a high-risk subset of surgical patients • Expand the cohort of immunotherapy patients to validate our immunotherapy response signature • Clinical trial of the use of exosomes as a marker of high-risk or residual disease is surgically resected melanomas • Clinical trial of exosomal profiling to predict/correlate with response to immunotherapy Acknowledgements • Boland Lab, MGH – – – – – – Bill Michaud, PhD Sonia Cohen, MD, PhD Jessica Cintolo-Gonzalez, MD Ali Rabi, MD, PhD Roman Alpatov, PhD Tabea Moll, MS • Flaherty Lab, MGH – – – – Marc Hammond Hans Vitzhum Deborah Plana Benchun Miao, PhD • Collaborators: • • • • • • • Fisher Lab, CBRC, MGH David Panka, PhD, BIDMC Soldano Ferrone, MD, PhD, MGH Darrell Borger, PhD, MGH Ryan Corcoran, MD, PhD, MGH Nir Hacohen, PhD, MGH/Broad Institute Manolis Kellis, PhD, MIT/Broad Institute • Larry Zhang • Alvin Shi, PhD
