FOURTEENTH A N N U A L S Y M P O S I U M

Institute of Chemical Biology & Drug Discovery “Frontiers of Chemical Biology and Drug Discovery: Nucleic Acid-Based Medicine” ...... Thursday, October 8, 2020  Via Zoom ......

Distinguished Speakers

Dr. George Calin, The University of Texas MD Anderson Center Dr. Richard Gregory, Harvard University Dr. Lin He, University of California, Berkeley Dr. Jingfang Ju, Stony Brook University Dr. Adrian Krainer, Cold Spring Harbor Laboratory Dr. Vivek Mittal, Weill Cornell Medicine Dr. Jennifer Petter, Arrakis Therapeutics

Poster Sessions  Poster Awards

Stony Brook University/SUNY is an affirmative action, equal opportunity educator and employer. 10090247

From the Director ICB&DD’s History and Mission

The primary objective of the he ICB&DD was established in 2004 with Stony Institute of Chemical Biology & Brook University’s institutional support as well Drug Discovery (ICB&DD) is to as the NYSTAR Faculty Development Award. One establish and sustain a world- of ICB&DD’s strengths is that it has been founded by class “Center of Excellence” in reorganizing existing exceptional talents on campus, and chemical biology and drug thus the core of the institute is a well proven entity with discovery at Stony Brook University. The rapid and an excellent track record. ICB&DD is open to a wide range impressive advancements in of collaborative research programs with pharmaceutical chemical biology during the and biotechnology industrial firms. Members of ICB&DD last decade have clearly are from the departments of Chemistry, Pharmacological demonstrated that solutions for a vast majority of Sciences, Medicine, Molecular Genetics and medical problems rely on the understanding of the Microbiology, Biochemistry and Cellular Biology, molecular basis of diseases, therapeutic targets, drug Physiology and Biophysics, Applied Mathematics and actions, and drug resistance. ICB&DD promotes highly Statistics, Oral Biology and Pathology, Cancer Center, productive interdisciplinary and collaborative research Center for Structural Biology, Center for Infectious among chemists, biologists, medicinal chemists, pharmacologists, and physicians to tackle major Diseases, and Brookhaven National Laboratory. In biomedical problems to find solutions including the addition, ICB&DD has two core laboratories located in the discovery of novel therapeutic drugs and innovative Chemistry Building: Analytical Instrumentation diagnostic tools. Laboratory and Discovery Chemistry Laboratory.

Iwao Ojima, Director, Institute of Chemical Biology ICB&DD has three major programs: Structural and & Drug Discovery Computational Biology Program, Infectious Diseases

Dr. Iwao Ojima received his B.S., M.S., and Ph.D. (1973) degrees Research Program, and Cancer Research Program. In from the University of Tokyo, Japan. He joined the Sagami Institute addition, ICB&DD has two strategic Research of Chemical Research and held a position of Senior Research Laboratories on Cancer Stem Cell Research and Anti- Fellow until 1983. He joined the faculty at the Department of inflammatory Research. ICB&DD collaborates with the Chemistry, State University of New York at Stony Brook first as Stony Brook University Cancer Center to develop a Associate Professor (1983), was promoted to Professor (1984), Cancer Therapeutics Program. ICB&DD integrates the Leading Professor (1991), and then to Distinguished Professor existing strengths at Stony Brook University in the basic (1995). He served as the Department Chairman from 1997 to 2003. He has been serving as the founding Director for the Institute of medical sciences as well as medicinal chemistry and Chemical Biology and Drug Discovery (ICB&DD) from 2003. He brings in complementary expertise from outside to has a wide range of research interests in synthetic organic and explore drug discovery and development. At present, medicinal chemistry as well as chemical biology, including ICB&DD focuses on drug discovery in therapeutics for discovery and development of anticancer agents, antimicrobials, cancer, infectious diseases, neurodegenerative diseases and targeted drug delivery systems. His awards and honors include and inflammation. Arthur C. Cope Scholar Award (1994), E. B. Hershberg Award for

Important Discoveries of Medicinally Active Substances (2001), the Medicinal Chemistry Hall of Fame (2006), ACS Award for Through ICB&DD connections, a number of collaborative Creative Work in Fluorine Chemistry (2013), and E. Guenther research teams have been created and research Award in the Chemistry of Natural Products (2019) from the proposals have successfully acquired grants from NIH and American Chemical Society; the Chemical Society of Japan Award other funding agencies. (Total grant funding > 61M). (1999); Outstanding Inventor Award (2002) from the Research Currently, there are 11 ongoing ICB&DD-designated Foundation of the State University of New York; Elected Fellow of projects (Total funding: $21M). J. S. Guggenheim Memorial Foundation, the American Association for the Advancement of Science, the New York Academy of Sciences, the American Chemical Society and the National Academy of Inventors.

ICB&DD 14th Annual Symposium Thursday, October 8, 2020 via Zoom

Join Zoom Meeting https://stonybrook.zoom.us/j/92056653486?pwd=UlRIb00weWFSZzFFSEVjZFRGZy85UT09 Meeting ID: 920 5665 3486 Passcode: 300041

“Frontiers of Chemical Biology and Drug Discovery: Nucleic Acid-Based Medicine”

9:15 am to 9:30 am Opening Remarks Dr. Jingfang Ju, Professor of Pathology, Stony Brook University Renaissance School of Medicine. Chair, Symposium Organizing Committee Dr. Kenneth Kaushansky, Dean, Stony Brook University Renaissance School of Medicine Dr. Iwao Ojima, Distinguished Professor and Director, Institute of Chemical Biology and Drug Discovery, Stony Brook University

9:30 am to 10:15 am Moderator: Dr. Chia-Hsin (Lori) Chan Dr. George A. Calin, Professor, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Center “About Chomsky, Non-codingRNAs and Cancer Therapy”

10:15 am to 11:00 am Moderator: Dr. Jingfang Ju Dr. Richard I. Gregory, Professor and Chairman, Department of Pediatrics Stem Cell Biology, Harvard Medical School “Role of the Epitranscriptome in Gene Regulation and Cancer”

11:00 am to 11:45 am Moderator: Martin Kaczocha Dr. Jingfang Ju, Professor, Department of Pathology, Stony Brook University Renaissance School of Medicine “Development of miRNA Based Platform Technology for Cancer Therapeutics”

11:45 am to 1:00 pm Lunch and Poster Session via Zoom

1:00 pm to 1:45 pm Moderator: Adam Rosebrock Dr. Lin He, Professor, Department of Molecular & Cell Biology, University of California, Berkeley “Friends or Foes, Retrotransposons in Mammalian Preimplantation Development”

1:45 pm to 2:30 pm Moderator: Elizabeth Boon Dr. Adrian Krainer, St. Giles Foundation Professor, Cold Spring Harbor Laboratory (CSHL) and Deputy Director of Research at CSHL Cancer Center “From Base Pairs to Bedside: Antisense Modulation of RNA Splicing”

2:30 pm to 3:30 pm Student Poster Session via Zoom

3:30 pm to 4:15 pm Moderator: John Haley Dr. Vivek Mittal, Professor of Cardiothoracic Surgery and Director, Neuberger Berman Foundation Lung Cancer Laboratory, Weill Cornell Medicine “Metastasis Suppressor miRNAs in Triple Negative Breast Cancer”

4:15 pm to 5:00 pm Moderator: Peter Tonge Dr. Jennifer C. Petter, Founder and CSO, Arrakis Therapeutics “Drugging RNA with Small Molecules” 5:00 pm to 5:05 pm Closing Remarks: Dr. Martin Kaczhocha 5:05 pm to 5:10 pm Announcement of Poster Awards: Dr. Chia-Hsin (Lori) Chan 5:10 pm to 5:30 pm Short Presentations by the Award Winners Speakers

Dr. George A. Calin received both his Dr. Richard I. Gregory is a Professor in M.D. and Ph.D. degrees at Carol Davila the Department of Biological Chemistry University of Medicine in Bucharest, and Molecular Pharmacology at Harvard Romania. After working in cytogenetics Medical School, and the Department of as an undergraduate student with Dr. Pediatrics Stem Cell Biology Chair. He is Dragos Stefanescu in Bucharest, he principal investigator in the Stem Cell completed a cancer genomics training in Program, Division of Hematology/ Dr. Massimo Negrini’s laboratory at the Oncology at Boston Children’s Hospital. University of Ferrara, Italy. In 2000 he He is also co-Director and executive became a postdoctoral fellow at Kimmel committee member of the Harvard Cancer Center in Philadelphia, PA, and while working in Dr. Initiative for RNA Medicine (HIRM), faculty member of the Carlo Croce’s laboratory, Dr. Calin was the first to discover the Dana–Farber/Harvard Cancer Center, and principal faculty link between microRNAs and human cancers, a finding member of The Harvard Stem Cell Institute (HSCI). The considered a milestone in microRNA research history. He is laboratory’s research on RNA regulatory mechanisms has led to presently a Professor in the Experimental Therapeutics and several breakthrough findings and is funded in part by an Leukemia Departments at M. D. Anderson Cancer Center in Outstanding Investigator R35 award from the National Cancer Houston and studies the roles of microRNAs and other non- Institute. Current research is focused on RNA modifications, coding RNAs in cancer initiation and progression and in immune the so-called ‘epitranscriptome’ in cancer biology. Of particular disorders, as well as the mechanisms of cancer predisposition relevance are our recent findings that provide insight into the role linked to non-codingRNAs. Furthermore, he explores the role of and mechanism of the N6-methyladenosine (m6A) body fluid miRNAs as potential hormones and biomarkers, as methyltransferase (MTase) METTL3 in the control of mRNA well as new RNA therapeutic options for cancer patients. Simply, translation, and the first evidence that METTL3 is dysregulated in he is having fun making discoveries, publishing, and from time to cancer and can function as an oncogene to promote cellular time, getting funded grants! transformation and tumorigenesis. These early insights paved the way for the emergence of the ‘epitranscriptome’ and cancer field “About Chomsky, Non-codingRNAs and Cancer Therapy” and represent the basis for our ongoing efforts to elucidate the role of the molecular and cellular mechanisms of the epitranscriptome in cancer and to identify pharmacological MTase inhibitors The world of non-coding RNAs (ncRNAs) is composed of an towards the development of new drugs targeting the enormous and growing number of transcripts ranging in length epitranscriptome as a cancer therapy. Dr. Gregory is a scientific from tens of bases to tens of kilobases, involved in all biological co-founder and scientific advisory board member of Twentyeight- processes and altered in expression and/or function in many types Seven Therapeutics, and Epitoire Therapeutics. of human disorders. The premise of this review is the concept that ncRNAs, like many large proteins, have a multi-domain “Role of the ‘Epitranscriptome’ in Gene Regulation and architecture that organizes them spatially and functionally. As Cancer” ncRNAs are beginning to be imprecisely classified into functional families, we review here how their structural properties might The emerging field of ‘epitranscriptomics’ is offering new insights inform their functions with focus on structural architecture- into the biological and pathological roles of different RNA function relationship. We will describe the properties of modifications. Methylation of transfer RNAs (tRNAs), ribosomal “interactor elements” involved in direct physical interaction with RNAs (rRNAs), and messenger RNAs (mRNAs) can play nucleic acids, proteins or lipids, and of “structural elements” important roles in cancer and the relevance of certain directing their wiring within the “ncRNA interactor networks” methyltransferases as possible therapeutic targets is just beginning through the emergence of secondary and/or tertiary structures. We to be appreciated. The RNA methyltransferase METTL1 catalyzes suggest that spectrums of “letters” (ncRNA elements) are the N7-methylguanosine (m7G) modification of tRNAs, mRNAs, assembled into “words” (ncRNA domains) that are further and microRNA precursors. However, the role of METTL1 and its organized into “phrases” (complete ncRNA structures) with cofactor WDR4 in cancer remains largely unexplored. Here we functional meaning (signaling output) through complex reveal the oncogenic role of METTL1/WDR4. METTL1 is “sentences” (the ncRNAs interactor networks). This semiotic frequently amplified and overexpressed in cancers and correlates analogy can guide the exploitation of ncRNAs as new therapeutic with poor patient survival. METTL1 depletion in cancer cells targets through the development of IE-blockers and/or SE-lockers causes decreased abundance of m7G-modified tRNAs, altered cell that will change the interactor partners’ spectrum of proteins, cycle, and inhibits oncogenicity. Conversely, METTL1 RNAs, DNAs or lipids and consequently influence disease overexpression induces cell transformation and cancer. phenotypes. Mechanistically, we find increased abundance of certain m7G- modified tRNAs including tRNA-Arg(TCT), and increased translation of mRNAs including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, expression of tRNA-Arg(TCT) is elevated in many cancer types, correlates with patient survival, and overexpression of this tRNA enhances reporter mRNA translation and induces oncogenic transformation. Thus, METTL1/WDR4-mediated m7G tRNA modification drives oncogenic transformation, thereby highlighting METTL1 as a promising anti-cancer target. Speakers

Dr. Jingfang Ju is is a Professor of Dr. Lin He is the Thomas and Stacey Pathology of Renaissance School of Siebel Distinguished Chair Professor at Medicine, Co-Leader of Oncogenic Drives University of California, Berkeley. She and Mechanisms of Carcinogenesis received her B.S. in Biology from Program of Stony Brook Cancer Center, Tsinghua University and her Ph.D. from Stony Brook University. Professor Ju Stanford University under the mentorship received his B.S. in chemical engineering of Dr. Greg Barsh. Dr. He was a from Northeastern University in China in postdoctoral fellow at Cold Spring 1989, his Ph.D. from University of Harbor Laboratory with Dr. Greg Southern California in 1996 and Hannon, before joining the faculty at postdoctoral studies as a National Institute of Health fellow in the University of California, Berkeley in 2008. Currently, Dr. Lin He Department of Pharmacology at Yale University (1996-99). He is a professor in the Molecular and Cell Biology Department at was a senior scientist and team leader at CuraGen Inc. He joined University of California, Berkeley. Her lab is interested in the pathology faculty at Stony Brook University in 2008. He is the functional characterization of non-coding elements, including Co-Founder of Curamir Therapeutics Inc in 2019. He is the miRNAs, lncRNAs and retrotransposons, in mammalian genomes. inventor of miRNA based cancer therapeutic platform technology The number of protein-coding genes clearly fails to correlate with and he holds a number of patents in this field. The primary and the developmental and pathological complexity in mammals. Her long term interests in Professor Ju’s laboratory are in research group's overall research interest is to understand the understanding the mechanisms of cancer chemoresistance unique biological functions and molecular regulation of various mediated by non-coding RNA. He has over 100 academic non-coding RNAs and transposable elements in development and publications. In addition to having an NIH/NCI funded disease. Her postdoctoral work has identified some of the first translational research laboratory, he was a recipient of the miRNAs in key oncogene and tumor suppressor pathways. Studies GlaxoSmithKline Oncology Clinical Research Scholar Award. from her own lab have extended beyond mere identification of functionally important miRNAs; Her group aims to understand the “Development of miRNA Based Platform Technology for distinct biological functions and molecular regulation conferred Cancer Therapeutics” by miRNAs, long ncRNAs and retrotransposons in development and disease using an interdisciplinary approach combining mouse Resistance to chemo- and radiation therapy is a major issue for a genetics, genomics, imaging studies, cell biology, and molecular successful outcome of cancer treatment due to tumor biology. Their studies have provided important insights on the heterogeneity and highly plastic nature. Mounting evidence fundamental molecular mechanisms that govern the unique showed that post-transcriptional and translational controls functional complexity of the non-coding genome. mediated by various regulatory molecules, such as RNA binding proteins and non-coding RNAs (e.g. miRNAs), are critically “Friends or Foes, Retrotransposons in Mammalian important. To investigate the impact of miRNAs in Preimplantation Development” chemoresistance to fluoropyrimidines and antifolates, we discovered that miR-192 and miR-215 suppresses the expression Retrotransposons have successfully colonized their host genomes of both thymidylate synthase and dihydrofolate reductase. The during evolution, constituting nearly 40% of the genome. While expression of miR-215 was significantly associated with most retrotransposons are silenced during mammalian colorectal cancer patient survival. Our recent studies have shown development, specific retrotransposons are activated in that several miRNAs (e.g. miR-502, miR-506, miR-194, miR-140, preimplantation embryos. A number of these retrotransposons miR-129, miR-15a) act as tumor suppressor. miR-129 inhibits exhibit gene regulatory functions, acting as alternative promoters, several important targets such as E2F3, TS, and BCL2 in exons and polyadenylation signals to proximal host genes. Here, I colorectal cancer. We have developed unique strategy of will discuss retrotransposon reactivation in mouse preimplantation modifying miRNAs such as miR-129 and miR-15a mimics with development and its functional importance in normal superior stability, efficacy, and ease of delivery. miR-129 mimic development. More importantly, I will discuss the evolutionary was able to eliminate 5-FU resistant colon cancer stem cells. miR- significance of our findings, which suggest that retrotransposons 129 mimic can block colon cancer metastasis in vivo. We also could be employed by the host genome to achieve gene regulatory show that miR-15a mimic is a potent inhibitor for pancreatic roles to generate evolutionarily conserved gene isoforms. cancer by suppressing Wee1, Chk1, Yap1 and BMI-1. This new strategy represents a significant advancement in the development of a nontoxic and highly potent miRNA based cancer therapeutics for treating colorectal cancer, pancreatic cancer and beyond. Given the significant role of miRNAs in many aspects of tumor development such as proliferation, autophagy, cell cycle control, invasion, EMT and maintained tumor stem cell phenotype, we remain hopeful that miRNA based therapeutics, diagnosis and prognosis may emerge in the near future to benefit patients.

Speakers

Dr. Adrian R. Krainer is the St. Giles Dr. Jennifer C. Petter is the Founder Foundation Professor at Cold Spring and Chief Scientific Officer of Arrakis Harbor Laboratory and Deputy Director Therapeutics. Previously, Dr. Petter of Research at the CSHL Cancer Center. was Vice President of Chemistry at He received a Ph.D. in Biochemistry from Celgene, Vice President of Drug Harvard University in 1986, working with Discovery at Avila Therapeutics, Vice Professor Tom Maniatis on pre-mRNA President of Research at Mersana splicing mechanisms. He continued his Therapeutics, Director of Small research on splicing as a Cold Spring Molecule Drug Discovery at Biogen, Harbor Fellow, mentored by Dr. Richard Section Head in Oncology Chemistry at J. Roberts, and joined the faculty at Cold Spring Harbor in 1989. Sandoz/Novartis, and Assistant Professor of Chemistry at the In addition to studying splicing regulation, his laboratory is University of Pittsburgh. Dr. Petter graduated from Dartmouth engaged in the development of mechanism-based targeted College with an AB in chemistry. She earned her PhD in organic therapies to correct or modulate alternative splicing in genetic chemistry at Duke University with Ned Porter, and was a post- diseases and cancer. This work has resulted to date in 215 doctoral fellow in Ron Breslow’s group at Columbia University. publications and seven issued patents. In collaboration with Ionis Dr. Petter has ushered multiple compounds into the clinic for the Pharmaceuticals and Biogen, Dr. Krainer’s laboratory developed treatment of cancer, cardiovascular disease, autoimmune nusinersen (Spinraza), which corrects the splicing defect in the disorders, and sepsis. SMN2 gene and became the first approved therapy for spinal muscular atrophy. Dr. Krainer is a co-founder, Director, and Chair “Drugging RNA with Small Molecules” of the SAB of Stoke Therapeutics. He was elected to the National Academy of Sciences, the National Academy of Medicine, the RNA is upstream of all biology and thus presents a vast array of National Academy of Inventors, and the American Academy of therapeutically attractive targets. Most therapeutic agents that Arts & Sciences. Recent awards include the 2019 Life Sciences bind directly to RNA are either antibiotics blocking bacterial Breakthrough Prize, the 2019 Lifetime Achievement Award of the ribosome function or oligonucleotides with their attendant RNA Society, the 2019 International Prize for Translational pharmaceutical limitations. At Arrakis we have identified Neuroscience, the 2019 Speiser Award in Pharmaceutical druggable RNA sub-structures in mRNA with complex tertiary Sciences, the 2020 Ross Prize in Molecular Medicine, and the folds and drug-like small molecules that bind to those structures 2020 Takeda & NYAS Innovators in Science Senior Scientist selectively. In addition to highlighting some of the unique Award in Rare Diseases. challenges of drugging RNA, this presentation will highlight the central role played by chemical biology in advancing ligands “From Base Pairs to Bedside: Antisense Modulation of RNA toward therapeutic value against this novel class of targets. Splicing”

We are developing mechanism-based therapeutics, combining knowledge about RNA-splicing regulation and antisense technology. We previously developed nusinersen (Spinraza), an antisense oligonucleotide (ASO) that modulates alternative splicing of SMN2 exon 7, restoring normal levels of functional SMN protein in the context of spinal muscular atrophy (SMA). Nusinersen was approved in 2016 as the first drug for SMA; it modifies the disease course and prevents its onset if treatment is initiated pre- symptomatically. We recently found that a nusinersen-like ASO promotes repressive histone marks, resulting in a more compact chromatin at the SMN2 locus; this in turn reduces the transcription- elongation rate, which promotes exon 7 skipping, opposing the ASO’s effect at the RNA level. Histone deacetylase (HDAC) inhibitors result in removal of the repressive marks and a more open chromatin, neutralizing the ASO’s inhibitory effect. Thus, HDAC inhibitors potentiate the ASO’s therapeutic effect on SMN2 splicing. We are also developing splice-switching ASOs for cancer therapy. Pyruvate kinase M2 (PKM2) is upregulated in cancer and drives the Warburg effect. PKM2 is an alternative-splice isoform of PKM, and a potential therapeutic target. ASOs that switch PKM splicing from PKM2 to the more active PKM1isoform alter glucose metabolism and inhibit the growth of human hepatocellular carcinoma (HCC) cells. Furthermore, our lead ASO and a surrogate mouse-specific ASO inhibit tumorigenesis in orthotopic-xenograft and genetically- engineered HCC mouse models, respectively. This preclinical study establishes the potential of ASO-based PKM splice-switching as a therapy for liver cancer.

Speakers

Dr. Vivek Mittal, Ph.D is the Ford-Isom clinical translation, we used multilayered gold nanoparticles (NPs) Professor of Cardiothoracic. He is also the carrying the microRNA mimetic (miR708-NP) which targeted the Director of the Neuberger Berman SOX2/OCT4 cancer cells with tumor-initiating properties, Foundation Lung Cancer Laboratory and enhanced metastatic potential, and marked sensitivity to miR-708 Professor of Cell and Developmental treatment. These studies support the potential of oligonucleotide- Biology at Weill Cornell Medical College based targeted therapy for TNBC. in New York. Previously, Dr. Mittal held faculty appointments at Cold Spring NOTES______Harbor Laboratory and State University of ______New York, Stony Brook. Dr. Mittal ______lectures widely to diverse audiences throughout the world and has ______been published in leading journals including Science, Nature, ______Cancer Cell, PNAS, and other leading peer-reviewed journals and ______textbooks. He contributes to NIH study sections and has chaired ______sessions at prominent national conferences and symposiums. His research is supported by funds from the National Cancer Institute ______and foundations, and several national and international patents ______have emerged from his discoveries. Research in Dr. Mittal’s lab ______is focused around the lung as a central organ to study de novo lung ______carcinogenesis, as well as the initiation and progression of ______metastatic lesions derived from extrapulmonary neoplasms ______including breast cancer. The program integrates clinical and basic ______science to foster innovative research for the prevention, detection, ______and treatment of cancer. A major aim is to understand cancer cell ______intrinsic and extrinsic programs that regulate tumor growth and ______metastasis. Cancer cell intrinsic programs include aberrant ______signaling pathways, which are investigated at several levels ______including transcriptional regulation, epigenetic regulation, and ______regulation by small regulatory RNAs. Cancer cell extrinsic ______programs include the contribution of the tumor microenvironment; by dissecting the complexity of various stromal cell types ______that comprise the microenvironment we unravel heterotypic ______reciprocal signaling between the stromal cells and tumor epithelial ______compartments that contribute to tumor progression. Dr. Mittal is ______interested in understanding how these two programs are integrated ______to regulate key tumorigenic processes including angiogenesis, ______inflammation, epithelial to mesenchymal transition, therapeutic ______resistance, metastasis initiation and progression. A major aim is to ______rapidly validate insights obtained from these investigations in ______preclinical and clinical settings, and to determine the diagnostic ______and therapeutic potential of candidate molecules in collaboration ______with clinicians. Dr. Mittal’s research continues to produce ______discoveries with implications in the development of novel stromal ______targets for prognosis and drug design. ______Metastasis Suppressor miRNAs in Triple Negative Breast ______Cancer ______Triple-negative breast cancer (TNBC) patients exhibit the worst clinical outcome due to its aggressive clinical course and higher Please note: this event is being photographed and/or videotaped rate of metastasis compared to other breast cancer subtypes. Given and your image may be used in connection with the advertising and a conspicuous lack of FDA approved targeted therapies for promotion of Stony Brook University and/or Stony Brook University TNBC, identification of effective therapeutics is an urgent clinical Medical Center. priority. We have discovered a series of miRNAs that are abundantly expressed in primary breast cancer; however, their expression is significantly lost in metastatic lesions. We have designated them as “metastasis suppressors” as restoring their expression in the “miRNA-deficient” metastatic cell has the potential to impair metastasis. Using an integrated preclinical and clinical approach, we have demonstrated epigenetic regulation of the miRs, and have identified the mechanisms by which these miRs contribute to metastasis suppression. To further

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