Project Grant R01CA292639

TARGETING RETROTRANSPOSONS FOR IMPROVED TREATMENT OF REFRACTORY CHILDHOOD CANCER - DESPITE NOTABLE IMPROVEMENTS IN CHILDHOOD CANCER SURVIVAL RATES, PATIENTS WITH RELAPSED OR REFRACTORY DISEASE FACE GRIM PROSPECTS, AND CHILDHOOD CANCER REMAINS THE COMMONEST CAUSE OF DEATH FROM DISEASE IN CHILDREN. THIS PROGRAM AIMS TO TACKLE THIS ISSUE, FOCUSING PRIMARILY ON THE CHALLENGING PEDIATRIC CANCER, HIGH-RISK NEUROBLASTOMA (NB), A TUMOR OF THE SYMPATHETIC NERVOUS SYSTEM WHICH ACCOUNTS FOR UP TO 15% OF CHILDHOOD CANCER DEATHS AND IS THE COMMONEST SOLID TUMOR OF YOUNG CHILDREN. RECENT RESEARCH BY OUR INTERNATIONAL COLLABORATIVE TEAM HAS REVEALED A NOVEL MECHANISM OF CANCER DRUG RESISTANCE LINKED TO EPIGENETIC ACTIVATION OF LINE1 (L1) RETROTRANSPOSONS. WE HAVE PROVIDED PRELIMINARY EVIDENCE THAT THESE RETROTRANSPOSONS CAN BE EFFECTIVELY TARGETED BY EXISTING NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIS), OFFERING A PROMISING AVENUE FOR REPURPOSING THESE SAFE AND EFFECTIVE ANTIVIRAL AGENTS AS POTENTIAL TREATMENTS FOR REFRACTORY TUMORS. WHILE THE SIGNIFICANCE OF RETROTRANSPOSON ACTIVATION HAS BEEN ESTABLISHED IN VARIOUS ADULT CANCER TYPES, A SUBSTANTIAL KNOWLEDGE GAP EXISTS CONCERNING ITS ROLE IN PEDIATRIC MALIGNANCIES. CLOSING THIS GAP IS IMPERATIVE, AS CONTROLLING RETROTRANSPOSON ACTIVATION WITH NRTIS, AND POTENTIALLY ALSO WITH IMMUNOTHERAPEUTIC APPROACHES, HOLDS SUBSTANTIAL POTENTIAL FOR SIGNIFICANTLY IMPROVING TREATMENT OUTCOMES FOR PEDIATRIC CANCERS, INCLUDING REFRACTORY NB. OUR PROGRAM SEEKS TO EXPLORE THE FEASIBILITY OF RETROBIOME-TARGETED PHARMACOLOGICAL AND IMMUNOTHERAPEUTIC STRATEGIES IN NB. THIS EXPLORATION WILL BE GUIDED BY A COMPREHENSIVE ASSESSMENT OF RETROTRANSPOSONS' ACTIVITIES AND THEIR IMPACT ON TUMOR CHARACTERISTICS, IN NB AND ALSO IN ALL OTHER SOLID TUMORS OF CHILDHOOD, EMPLOYING A UNIQUE AND EXTENSIVE RANGE OF PRECLINICAL MODELS AND CLINICAL SAMPLES WITH ASSOCIATED COMPREHENSIVE CLINICAL AND MOLECULAR DATA. OUR PROGRAM CAPITALIZES ON A LONGSTANDING, FRUITFUL COLLABORATION BETWEEN US AND AUSTRALIAN TEAMS, DRAWING UPON OUR COMPLEMENTARY EXPERTISE IN BASIC AND TRANSLATIONAL SCIENCE. WE ALSO BUILD UPON OUR TEAMS' FOUNDATIONAL RESEARCH ON THE EPIGENETIC CONTROL OF RETROTRANSPOSONS IN CANCER, THEIR RECOGNITION BY HUMORAL AND T CELL IMMUNITY, AND THE POTENTIAL DRUGGABILITY OF RETROTRANSPOSON-INDUCED MALIGNANT TRAITS, PARTICULARLY DRUG RESISTANCE. OUR SPECIFIC AIMS ARE AS FOLLOWS: (SA1) TO COMPREHENSIVELY CHARACTERIZE RETROTRANSPOSON ACTIVITY IN NB AND OTHER SOLID TUMORS OF CHILDHOOD, AND ASSESS ITS POTENTIAL THERAPEUTIC AND DIAGNOSTIC SIGNIFICANCE, (SA2) TO INVESTIGATE THE IMPACT OF RETROTRANSPOSON DEREPRESSION ON NB TREATMENT RESISTANCE AND THE POTENTIAL OF REVERSE TRANSCRIPTASE INHIBITORS TO ENHANCE REFRACTORY NB TREATMENT OUTCOMES IN PRECLINICAL MODELS AND (SA3) TO EXPLORE IMMUNE RESPONSES TO L1 RETROTRANSPOSON ANTIGENS AND EVALUATE THE EFFICACY OF ANTI-L1 IMMUNOTHERAPY IN PRECLINICAL NB MODELS. THE OUTCOMES OF THE PROPOSED PROGRAM WILL GUIDE THE RATIONAL DESIGN OF FUTURE PHARMACOLOGICAL AND IMMUNOTHERAPEUTIC INTERVENTIONS FOR REFRACTORY NB AND SUBSEQUENTLY OTHER POORLY CURABLE PEDIATRIC CANCERS.