Targeting ILlRAP in virus-associated malignancies

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Abstract Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi's Sarcoma (KS) and Primary Effusion Lymphoma (PEL), which preferentially arise in immunocompromised patients and lack of effective therapeutic options. KS also represents one of common oral cancers in AIDS patients. PEL represents a rapidly progressing B cell-derived lymphoma with poor prognosis even under the combinational chemotherapy. Interleukin1 (IL1) family represents a major mediator for inflammation and plays an important role in both innate and adaptive immunity. The IL1 receptor accessory protein (IL1RAP) acts as a global regulator of IL1 signaling, including many of IL1 family members such as IL1, IL33 and IL36. However, the role of IL1 receptor/co-receptor and other related ligands, especially IL1RAP, in KSHV pathogenesis and tumorigenesis remains almost unknown. Our preliminary data indicate the elevated levels of many IL1 signaling molecules including IL1RAP in KSHV-infected cells at both latent and lytic conditions. Direct knock-down of IL1 signaling receptors/co-receptors such as IL1R1 and IL1RAP significantly reduce KSHV+ lymphoma cell growth. For clinical implication, both IL1R1 and IL1RAP proteins are found highly expressed in AIDS-KS tissue when compared to normal skin tissue. Based on these data, we hypothesize that the IL1 signaling molecules including IL1RAP have important role in KSHV pathogenesis and tumorigenesis, which may represent attractive therapeutic targets. To address this hypothesis, we propose the following Specific Aims: 1) To identify the functions of IL1RAP in KSHV-infected cells as well as its clinical relevance in KSHV-related malignancies. 2) To explore the therapeutic efficacy of a new IL1RAP antibody, BI- 5041, against KSHV-related malignancies in vivo. Through these efforts, we aim to illuminate putative mechanisms of IL1 signaling (in particular IL1RAP) in KSHV pathogenesis and the development of virus-related malignancies. We will also reveal clinical relevance and implication of IL1 signaling in patients with these virus- associated malignancies. Additionally, these studies will provide a framework for the development of interventional strategies targeting IL1 signaling especially IL1RAP for improving the treatment of KSHV-related malignancies in high-risk immunocompromised patients.