In the previous funding period, we focused on identifying the role of the bone marrow (BM) microenvironment in conferring growth, survival, and drug resistance in multiple myeloma (MM) cells. Importantly, we have successfully translated multiple novel agents (bortezomib, lenalidomide) targeting these interactions from the bench to the bedside and FDA approval for treatment of MM. Our prior studies have focused on the cellular components of BM milieu including fibroblasts, osteoclasts, osteoblasts, and endothelial cells. In this renewal application, we will focus on characterizing the role of plasmacytoid dendritic cells (pDCs), predominantly localized in the MM BM, in the pathophysiology of MM. Our data show that pDCs are dysfunctional in MM, since they do not stimulate T cell responses. Importantly, they induce MM cell growth and survival even in the presence of conventional and novel drugs. The current proposal therefore attempts to enhance our understanding of the intercellular interaction of MM cells with pDCs and its therapeutic relevance, and specifically addresses three inter-related hypotheses: 1) the biological behavior of MM cells is modulated by their interactions with pDCs;2) the molecular and functional sequelae of pDC-MM interactions represent potential therapeutic targets;and 3) the aggregate interplay of these interactions in vivo allows for the rational design of novel single and combination targeted therapies. Based on these hypotheses, the current proposal focuses on a set of distinct, yet mutually interacting and complementary.
Specific Aims. We propose: to characterize the role of pDCs in MM cell growth, survival, drug resistance and migration in vitro (Specific Aim 1);to identify the molecular and cellular mechanisms mediating pDC-MM interactions and validate their functional significance and therapeutic relevance (Specific Aim 2);and to validate novel therapies targeting molecular and cellular mechanisms mediating pDC-MM interactions in vivo using MM animal models for evaluation in phase-I/II clinical trials (Specific Aim 3). Overall, these studies will provide the basis for either directly targeting pDCs or blocking the pDC-MM interaction in novel therapeutic strategies for MM to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome.
The theme of this project is to identify the pDC-induced MM cell growth, survival and drug resistance mechanisms within the BM milieu. These studies will provide the basis for either directly targeting pDCs or blocking the pDC-MM interaction in novel therapeutic strategies to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome.
|Das, D Sharma; Ray, A; Das, A et al. (2016) A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells. Leukemia 30:2187-2197|
|Ray, Arghya; Ravillah, Durgadevi; Das, Deepika S et al. (2016) A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol 174:397-409|
|An, Gang; Acharya, Chirag; Feng, Xiaoyan et al. (2016) Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication. Blood 128:1590-603|
|Tagde, Ashujit; Rajabi, Hasan; Bouillez, Audrey et al. (2016) MUC1-C drives MYC in multiple myeloma. Blood 127:2587-97|
|Jiang, H; Acharya, C; An, G et al. (2016) SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia 30:399-408|
|GullÃ , Annamaria; Di Martino, Maria Teresa; Gallo Cantafio, Maria Eugenia et al. (2016) A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells. Clin Cancer Res 22:1222-33|
|Tai, Yu-Tzu; Acharya, Chirag; An, Gang et al. (2016) APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood 127:3225-36|
|Bommarito, Davide; Martin, Allison; Forcade, Edouard et al. (2016) Enhancement of tumor cell susceptibility to natural killer cell activity through inhibition of the PI3K signaling pathway. Cancer Immunol Immunother 65:355-66|
|Ohguchi, Hiroto; Hideshima, Teru; Bhasin, Manoj K et al. (2016) The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nat Commun 7:10258|
|Bae, J; Prabhala, R; Voskertchian, A et al. (2015) A multiepitope of XBP1, CD138 and CS1 peptides induces myeloma-specific cytotoxic T lymphocytes in T cells of smoldering myeloma patients. Leukemia 29:218-29|
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