The overall goal of this grant application is to acquire the opportunity to develop the knowledge and skills to become an independent physician-scientist who effectively translates bench studies to the clinic. Establishing a solid research foundation is one of the key elements with this approach. Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) is an aggressive malignant lymphoma of T/null-cell immunophenotype. It frequently affects children and young adults, and an estimated 40-50% of the patients fail current therapeutics. Janus kinase 3 (Jak3) is a protein tyrosine kinase with biologic functions related to cell survival and tumorigenesis. Our preliminary studies showed that Jak3 is constitutively activated in ALK+ ALCL cell lines and that inhibition of Jak3 decreases cell viability due to apoptosis and cell cycle arrest. Our preliminary studies also showed that Jak3 and ALK are physically associated and that inhibition of Jak3 decreases ALK kinase activity. Further, we found that ALK+ ALCL patients with tumors expressing activated Jak3 tend to have a lower survival rate than in ALK+ ALCL patients with tumors lacking the expression of activated Jak3. In addition, we demonstrated that IL-9 contributes to Jak3 activation by showing that IL-9 receptor-( and IL-9 are expressed in ALK+ ALCL cell lines and in most human primary tumors. Moreover, an anti-IL-9 neutralizing antibody decreased levels of activated Jak3 in and soft agar colony formation of ALK+ ALCL cells. Our preliminary studies also demonstrated that a major physiologic inhibitor of Jak3, SHP1, is absent or gene methylated in ALK+ ALCL cell lines and in most human tumors. Transfection of SHP1 into ALK+ ALCL cells induced downregulation of activated Jak3 levels. On the basis of these results, we hypothesize that constitutive activation of Jak3 by multilevel dysregulation plays an important role in the pathogenesis of ALK+ ALCL.
The specific aims of this proposal are to 1) define the pathogenetic role of Jak3 in ALK+ ALCL and 2) establish the biologic and clinical significance of Jak3 activation in tumors from ALK+ ALCL patients. The global aim of the proposed studies is to identify Jak3 as a potential therapeutic target in ALK+ ALCL patients;
this aim i s in complete agreement with the mission of M.D. Anderson Cancer Center of bringing novel therapeutics to the clinic. The balanced program of mentored research and career development proposed in this application will provide the applicant with a solid foundation for a successful career as an independent investigator in cancer biology. Relevance to public health: ALK+ ALCL is an aggressive type of cancer that commonly affects children and young adults. Our preliminary results showed that the enzyme Jak3 plays an important role in the development and progression of ALK+ ALCL. The direct aim of the proposed studies is to validate Jak3 as a therapeutic target in patients afflicted with this dreadful disease. ? ? ?
