Southern California Institute For Research And Education

GENETIC RISK FACTORS FOR ALCOHOLIC CIRRHOSIS - GENOME-WIDE CASE-CONTROL STUDY

A PROSPECTIVE, RANDOMIZED, CLINICAL TRIAL TO EVALUATE TWO NOVEL THERAPIES, MYCOPH

IDENTIFYING NOVEL THERAPIES TARGETING MERKEL CELL CARCINOMA AND TUMOR MICROENVIRONMENT - ABSTRACT 1 MERKEL CELL CARCINOMA MCC IS AN OFTEN-LETHAL SKIN CANCER WITH INCREASING INCIDENCE AND FEW TREATMENT 2 OPTIONS. THE DISMAL FIVE-YEAR SURVIVAL RATE OF ADVANCED MCC IS LESS THAN 18% AND THE MORTALITY RATE IS 3-TIMES 3 HIGHER THAN MELANOMA. ALTHOUGH IMMUNE CHECKPOINT INHIBITORS (ICI) HAVE BECOME STANDARD OF CARE IN ADVANCED 4 MCC, 50% OF ALL MCC PATIENTS ARE INELIGIBLE FOR ICIS AND RESISTANCE DEVELOPS IN THE MAJORITY OF TREATED PATIENTS. 5 IMPORTANTLY, THERE IS NO THERAPEUTIC ALTERNATIVE FOR THESE PATIENTS. GIVEN THIS URGENT CLINICAL DEMAND, OUR LONG- 6 TERM GOAL IS TO IDENTIFY NOVEL THERAPIES WHICH CAN BE USED TO AUGMENT ICI EFFICACY AND OVERCOME ICI RESISTANCE, 7 OR TO SERVE AS ALTERNATIVE TREATMENTS FOR MCC PATIENTS WHO ARE INELIGIBLE FOR ICIS. UTILIZING MCC CELL LINES 8 ESTABLISHED IN OUR LABORATORY AND HIGH THROUGHPUT DOSE-RESPONSE DRUG SCREENING OF 430 CLINICALLY RELEVANT 9 KINASE INHIBITORS, WE IDENTIFIED FIMEPINOSTAT, THE FIRST-IN-CLASS PI3K/HDAC INHIBITOR, WITH POTENT ANTI-MCC 10 ACTIVITIES. THE OBJECTIVE OF THIS PROPOSAL IS TO DETERMINE THERAPEUTIC EFFICACY OF FIMEPINOSTAT ALONE AND IN 11 COMBINATION WITH ICIS, AND RESOLVE INTRINSIC AND EXTRINSIC MECHANISMS OF ANTI-MCC ACTIVITIES. THE CENTRAL 12 HYPOTHESIS IS THAT FIMEPINOSTAT INHIBITS MCC GROWTH AND PROGRESSION BY TARGETING PI3K AND HDAC EPIGENETIC 13 PATHWAYS, AND BY SENSITIZING TUMOR CELLS TO ICIS THROUGH AUGMENTATION OF ANTITUMOR IMMUNITY IN THE MCC 14 MICROENVIRONMENT. WE WILL TEST THIS HYPOTHESIS BY UTILIZING SYSTEMS-LEVEL APPROACHES INTEGRATING CELLULAR, 15 MOLECULAR AND IMAGING ANALYSES IN SINGLE CELL RESOLUTION TO FULLY STUDY THE FUNCTIONAL COMPLEXITY OF THE MCC 16 ECOSYSTEM IN OUR CLINICALLY RELEVANT ANIMAL MODEL REPRESENTING THE CLOSEST PRECLINICAL MODELS OF HUMAN MCC- 17 IMMUNE MICROENVIRONMENT. THIS SINGULARLY POWERFUL BIOLOGICAL PLATFORM WILL ENABLE US TO STUDY DIRECT EFFECTS OF 18 FIMEPINOSTAT ON TUMORS AND TUMOR-IMMUNE INTERACTIONS AS A MONOTHERAPY AND IN COMBINATION WITH 19 IMMUNOTHERAPY, AS WELL AS UNCOVER NEW INSIGHTS INTO TME-MEDIATED RESISTANCE AND RESPONSE. THE PROPOSED 20 RESEARCH IS SIGNIFICANT BECAUSE SUCCESSFUL COMPLETION OF THE PROJECT WILL LAY FOUNDATION FOR A NEW TREATMENT 21 PARADIGM FOR MCC, OVERCOMING OR CIRCUMVENTING CURRENT LIMITATIONS IN THERAPEUTIC OPTIONS, AND LENDING INSIGHTS 22 INTO IMMUNE RESISTANCE WILL BE APPLICABLE ACROSS HUMAN CANCERS AND IMPROVE PATIENT OUTCOMES.

NON-GENOMIC ACTIONS OF ESTROGEN IN BREAST CANCER

MOLECULAR MECHANISMS OF LYSOSOME SECRETION IN OSTEOCLASTS AND BONE HOMEOSTASIS

ALCOHOL INJURY HEALING, CYTOPROTECTION AND SURVIVIN

IDENTIFICATION OF OSTEOCLAST ENDOCRINE AND PARACRINE COMMUNICATIONS BY SYSTEMS GENETICS APPROACHES - BONE RESORPTION BY OSTEOCLASTS PLAYS A PIVOTAL ROLE IN SKELETON GROWTH, HOMEOSTASIS, AND FRACTURE REPAIR. IN ADULTS, BONE HEALTH IS ENSURED BY BONE REMODELING IN WHICH BONE RESORPTION IS COUPLED AND BALANCED BY BONE FORMATION FROM OSTEOBLASTS. THEREFORE, THE NUMBER AND ACTIVITIES OF OSTEOCLASTS ARE TIGHTLY REGULATED BY SYSTEMIC HORMONES AND PARACRINE FACTORS IN BONE MARROW MICROENVIRONMENT. MEANWHILE, BONE ITSELF IS INCREASINGLY RECOGNIZED AS AN ENDOCRINE ORGAN WHICH CAN MODULATE FUNCTIONS OF OTHER ORGANS IN WHOLE-BODY PHYSIOLOGY. WHILE THE SYSTEMIC FUNCTIONS OF ENDOCRINE FACTORS DERIVED FROM OSTEOBLASTS AND OSTEOCYTES SUCH AS FGF23 AND OSTEOCALCIN HAVE BEEN WELL ESTABLISHED, THE ENDOCRINE FUNCTIONS OF OSTEOCLAST SECRETED PROTEINS REMAIN TO BE UNCOVERED. TO IDENTIFY AND FUNCTIONALLY ANNOTATE ENDOCRINE AND PARACRINE CIRCUITS, WE HAVE DEVELOPED A NOVEL SYSTEMS GENETIC APPROACH, TERMED QUANTITATIVE ENDOCRINE NETWORK INTERACTION ESTIMATION (QENIE), THAT UTILIZES NATURAL VARIATION IN TRANSCRIPT LEVELS ACROSS TISSUES IN MULTIPLE ‘OMICS’ DATASETS TO PREDICT MODES OF ENDOCRINE COMMUNICATION. APPLYING THIS APPROACH TO DATASETS IN THE HYBRID MOUSE DIVERSITY PANEL (HMDP), A COLLECTION OF APPROXIMATELY 100 INBRED STRAINS OF MICE EXHIBITING SUBSTANTIAL DIVERSITY OF MOST CLINICAL TRAITS RELEVANT TO HUMAN DISEASES, WE HAVE UNRAVELED MANY KNOWN ENDOCRINE INTERACTIONS AS WELL AS SEVERAL NOVEL TISSUE-TISSUE CIRCUITS. IN THE PRELIMINARY STUDY LEADING TO THIS PROPOSAL, WE HAVE QUANTITATIVELY MEASURED THE LEVELS OF PROTEINS AND RNAS IN PRECURSOR AND MATURE OSTEOCLASTS BY MASS-SPECTROMETRY BASED PROTEOMIC AND BULK RNA-SEQ. HUNDREDS OF SECRETED PROTEINS IN OSTEOCLAST LINEAGE CELLS HAVE BEEN IDENTIFIED BY THESE ‘OMICS’ STUDIES. WHILE SEVERAL OSTEOCLAST-DERIVED COUPLING FACTORS KNOWN TO STIMULATE OSTEOGENESIS DURING BONE REMODELING ARE IN THE LIST OF OSTEOCLAST SECRETED PROTEINS, THE ENDOCRINE AND PARACRINE FUNCTIONS OF MOST OF THESE NEWLY IDENTIFIED OSTEOCLAST SECRETORY PROTEINS ARE UNKNOWN. BASED ON OUR WORK AND REPORTS BY OTHERS, WE HYPOTHESIZE THAT THE ENDOCRINE AND PARACRINE COMMUNICATIONS OF OSTEOCLASTS PLAY AN IMPORTANT ROLE IN WHOLE BODY AND BONE HOMEOSTASIS UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. TO TEST OUR HYPOTHESIS, WE WILL IDENTIFY NOVEL ENDOCRINE AND PARACRINE CIRCUITS OF OSTEOCLAST LINEAGE CELLS BY THE SYSTEM GENETICS BIOINFORMATIC FRAMEWORK QENIE (AIM 1) AND EXPERIMENTALLY VALIDATE AND FUNCTIONALLY ASSESS THESE OSTEOCLAST-DERIVED FACTORS BY IN VITRO CELL CULTURE AND CO-CULTURE MODELS (AIM 2). SUCCESSFUL ACCOMPLISHMENT OF THE PROPOSED WORK IN THIS APPLICATION WILL FORMULATE NEW HYPOTHESES TO BE TESTED USING IN VIVO ANIMAL MODELS AND IN HUMAN POPULATIONS. THE FINDINGS FROM THIS PROJECT WILL NOT ONLY GREATLY ADVANCE OUR KNOWLEDGE IN OSTEOCLAST BIOLOGY BUT ALSO UNCOVER NEW THERAPEUTIC TARGETS TO TREAT BONE LOSS IN BONE AND OTHER ORGAN DISEASES.

GENETIC RISK FACTORS FOR ALCOHOLIC CIRRHOSIS - GENOME-WIDE CASE-CONTROL STUDY

MECHANISMS INVOLVED IN UREMIC TOXIN MEDIATED DOWN REGULATION OF APOA-I EXPRESSION

ROLE OF RAB PROTEINS IN HSVCT1 CELL BIOLOGY IN INTESTINAL EPITHELIAL CELLS

TAGGING CHEMOKINE SCAVENGER RECEPTOR CXCR7 FOR EARLY DETECTION OF LUNCH CANCER

MONITOR MICRORNA EXPRESSION IN BLOOD AND SALIVA TO DETECT RADIATION-INDUCED CANCER PROGRESSION

TARGET BREAST CANCER STEM CELLS USING A NEW STEM CELL MARKER, LGR5

SOUTHERN CALIFORNIA ALCOHOLIC HEPATITIS CONSORTIUM ADMINISTRATIVE CORE