Nucleophosmin-anaplastic lymphoma kinase-expressing anaplastic large-cell lymphoma (NPM-ALK+ ALCL) is an aggressive type of T-cell lymphoma. Although it occurs in patients of all ages, NPM-ALK+ ALCL is more frequently seen in young patients, accounting for 20-30% of non-Hodgkin's lymphomas in children and young adults. Patients typically present with advanced-stage disease and generalized involvement of the lymph nodes and other organs including skin, bone marrow, and liver. Currently, there is no effective treatment for this lymphoma, and as in other types of T-cell lymphoma, the treatment of NPM-ALK+ ALCL is primarily based on the CHOP combination chemotherapy regimen. After an initial favorable response to CHOP, up to 40% of NPM-ALK+ ALCL patients eventually have a relapse, develop resistance, and, in many cases, die. At the molecular level, NPM-ALK+ ALCL is characterized by the expression of the chimeric tyrosine kinase NPM-ALK, which induces significant oncogenic effects through interactions with downstream molecules that promote lymphoma cell survival. NPM-ALK is structurally similar to the type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase. IGF-IR plays important roles in promoting the survival of several solid tumors such as breast, prostate, lung, and ovarian cancers. Notably, several of the oncogenic molecules downstream of NPM-ALK also function downstream of IGF-IR. Nevertheless, whether IGF-IR has a functional role in NPM-ALK+ ALCL has not been examined. In preliminary studies we found that the expression of IGF-IR is upregulated in NPM-ALK+ ALCL cell lines compared with normal human T-cells. We also found that IGF-IR and NPM-ALK are physically associated and appear to interact through a reciprocal positive feedback loop to maintain their phosphorylation/ activation. An experimental inhibitor of IGF-IR induced apoptosis and cell cycle arrest and abrogated colony formation in soft agar of NPM-ALK+ ALCL cell lines. On the basis of these preliminary results, we hypothesize that upregulation of IGF-IR and its collaboration with NPM-ALK contribute to the survival of NPM-ALK+ ALCL and, therefore, targeting IGF-IR may be a reasonable strategy for treating this lymphoma.
The specific aims of this proposal are as follows: 1. To identify the mechanisms by which IGF-IR expression is upregulated in NPM-ALK+ ALCL. 2. To characterize the interactions between IGF-IR and NPM-ALK in vitro and in vivo. 3. To examine the in vitro and in vivo preclinical effects of IGF-IR inhibitors currently being used in clinical trials in NPM-ALK+ ALCL. Our results will provide insight into the role of IGF-IR in NPM-ALK+ ALCL. Our long-term goal is to understand IGF-IR-dependent signaling in this aggressive lymphoma in order to devise novel therapeutic strategies. Tactics that antagonize IGF-IR could potentially provide a cure for NPM-ALK+ ALCL patients.
NPM-ALK+ anaplastic large-cell lymphoma (ALCL) is an aggressive type of T-cell lymphoma that commonly affects children and young adults. After initial response to current therapeutics, 30-40% of patients develop a relapse, and death is not uncommon. In this application, we propose to study the role of the type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase in NPM-ALK+ ALCL, and our long-term goal is to understand IGF-IR-dependent signaling in this lymphoma in order to devise effective treatment strategies.
|Mitchell, Jennifer; Tinkey, Peggy T; Avritscher, Rony et al. (2016) Validation of a Preclinical Model of Diethylnitrosamine-Induced Hepatic Neoplasia in Yucatan Miniature Pigs. Oncology 91:90-100|
|Vishwamitra, Deeksha; Curry, Choladda V; Alkan, Serhan et al. (2015) The transcription factors Ik-1 and MZF1 downregulate IGF-IR expression in NPM-ALKâº T-cell lymphoma. Mol Cancer 14:53|
|Irwin, Mary E; Johnson, Blake P; Manshouri, Roxsan et al. (2015) A NOX2/Egr-1/Fyn pathway delineates new targets for TKI-resistant malignancies. Oncotarget 6:23631-46|
|Abdel-Wahab, Reham; Shehata, Samir; Hassan, Manal M et al. (2015) Validation of an IGF-CTP scoring system for assessing hepatic reserve in Egyptian patients with hepatocellular carcinoma. Oncotarget 6:21193-207|
|Vishwamitra, Deeksha; Curry, Choladda V; Shi, Ping et al. (2015) SUMOylation Confers Posttranslational Stability on NPM-ALK Oncogenic Protein. Neoplasia 17:742-54|
|Yang, Lujun; Zhang, Shuangfeng; George, Suraj Konnath et al. (2015) Targeting Notch1 and proteasome as an effective strategy to suppress T-cell lymphoproliferative neoplasms. Oncotarget 6:14953-69|
|Huang, Zhiwei; Fang, Zhijia; Zhen, Hong et al. (2014) Inhibition of type I insulin-like growth factor receptor tyrosine kinase by picropodophyllin induces apoptosis and cell cycle arrest in T lymphoblastic leukemia/lymphoma. Leuk Lymphoma 55:1876-83|
|Lamhamedi-Cherradi, Salah-Eddine; Santoro, Marco; Ramammoorthy, Vandhana et al. (2014) 3D tissue-engineered model of Ewing's sarcoma. Adv Drug Deliv Rev 79-80:155-71|
|George, Suraj Konnath; Vishwamitra, Deeksha; Manshouri, Roxsan et al. (2014) The ALK inhibitor ASP3026 eradicates NPM-ALKâº T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model. Oncotarget 5:5750-63|
|Hamedani, Farid Saei; Cinar, Munevver; Mo, Zhicheng et al. (2014) Crizotinib (PF-2341066) induces apoptosis due to downregulation of pSTAT3 and BCL-2 family proteins in NPM-ALK(+) anaplastic large cell lymphoma. Leuk Res 38:503-8|
Showing the most recent 10 out of 14 publications