Deconstructing Follicular Lymphoma Elisa Oricchio, Ph.D. 7. Project Summary/Abstract Candidate: I am deconstructing the molecular basis of Follicular Lymphoma (FL), a deadly form of Non- Hodgkin's lymphoma that affects ~ 20,000 Americans per year and that has been scientifically neglected. As a postdoctoral fellow in the laboratory of Dr. Hans-Guido Wendel (MSKCC) I have developed a new murine model of FL and recently reported a new secreted tumor suppressor (EPHA7) against FL1. I now propose further genetic studies aimed to develop better therapies against FL. Owing to a lack of cell lines and animal model, FL has been neglected and there has been no therapeutic progress in decades. My expertise in cancer genetics and my novel mouse model together with a great team of advisers put me in a unique position to make real progress against FL. Before joining Dr. Wendel's group at MSKCC I obtained my Ph.D. in Italy in 2008 working on projects related to DNA damage and mobile genetic elements. My goal is to have an independent scientific career and my laboratory will focus on the biology, genetics and therapy of Non-Hodgkin Lymphoma. To this end, the K99 grant will be the ideal stepping stone and will help my transition to independence. Environment: Memorial Sloan Kettering Cancer Center, the laboratory of Dr. Hans-Guido Wendel (mentor), Dr. Ari Melnick (co-mentor) and my advisory committee establish an ideal environment for my research goals. The Cancer Biology &Genetics program at MSKCC is a prime research venue in the US with leading scientists in various arenas of cancer research. Dr. Wendel and Dr. Melnick are leaders in leukemia and lymphoma research and will act as my mentors. Moreover, I have assembled a team of collaborators (advisory team) consisting primarily of 3 excellent scientists Dr. Koff, Dr. Zelenetz and Dr. Chaganti. Their combined expertise in lymphoma genetics and treatment is unique and will guide my project and its clinical translation. Research Proposal: Follicular lymphoma (FL) is the most common indolent Non Hodgkin's lymphoma. FL is incurable with the conventional chemotherapies and there has been little therapeutic progress in decades. Cytogenetically FL is characterized by the translocation t(14:18) that de-regulates the BCL2 expression. Increased BCL2 expression is not sufficient to drive FL development and progression and I hypothesize that additional genetic events drive FL and open avenues for treatment. My preliminary analyses reveal that several pathways are targets of genomic alterations. In particular cell cycle controls are mutational targets in ~ 50% of FLs and other alterations affect B-cell receptor and immune escape pathways. I will test the biological, clinical and therapeutic implications of frequent genetic alteration in FL.
My specific aims are:
Aim 1) Analysis Of Common Genetic Lesions in FL. I will analyze patient data for copy number changes, mutations, and methylation profile. Based on my preliminary data I will focus on key cell cycle regulators. I have in hand a unique collection of well-annotated clinical samples for genomic analyses.
Aim 2) Genetic studies in a murine model of Follicular Lymphoma I have developed a new mosaic mouse model of FL based on the vavPBcl2 transgenic mouse. This new model recapitulates key aspects of FL genetics and pathology and allows efficient studies of genetic interactions in FL!1"""""""" Aim 3) Preclinical Studies In FL Model In Vivo. My new mouse model of FL1 allows me to directly test how genetic mutations affect FL development and perform highly controlled treatment studies with genetically defined FLs. Overall, this is an innovative genomics study that uses advanced mouse modeling and the analysis of patient specimens to improve the treatment of FL. I have developed a new murine model for FL research and have access to unique collections of FL specimens. My prior work on FL attests to the success of these approaches and proves that I am in a unique position to make real progress in FL research. K99/R00 Career Developmental Grant

Public Health Relevance

Follicular lymphoma (FL) is a significant clinical problem. FLs are very common Non- Hodgkin's lymphomas that do not respond well to chemotherapy. In order to find new possible therapies, we looked at the most frequent chromosomal alterations in Follicular lymphoma patient samples. We observed genomic lesions affecting several oncogenic pathways (e.g. cell cycle regulation, B-cell receptor signaling, immune- response and Nf-kB pathway). In particular, cell cycle regulators are altered in ~ 50% of FL. These lesions are associated with advanced grade and shorter survival;however the underlying biology and implications for therapy have not been studied in this cancer. I will examine how loss of cell cycle control contributes to disease progression and how it affects treatment outcomes. I will also conduct pre-clinical studies of CDK inhibitors and new combination therapies in lymphoma. This study will offer the possibility of new therapies for a large number of FL patients. K99/R00 Career Developmental Grant The written critiques of individual reviewers are provided in essentially unedited form in this section. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Career Transition Award (K99)
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Study Section
Subcommittee G - Education (NCI)
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Schmidt, Michael K
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Sloan-Kettering Institute for Cancer Research
New York
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Oricchio, Elisa; Papapetrou, Eirini P; Lafaille, Fabien et al. (2014) A cell engineering strategy to enhance the safety of stem cell therapies. Cell Rep 8:1677-1685
Oricchio, Elisa; Ciriello, Giovanni; Jiang, Man et al. (2014) Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy. J Exp Med 211:1379-91