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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-J (O1))
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Dana-Farber Cancer Institute
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Cholujova, Danka; Bujnakova, Zdenka; Dutkova, Erika et al. (2017) Realgar nanoparticles versus ATO arsenic compounds induce in vitro and in vivo activity against multiple myeloma. Br J Haematol 179:756-771
Hideshima, Teru; Cottini, Francesca; Nozawa, Yoshihisa et al. (2017) p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma. Blood 129:1308-1319
Feng, Xiaoyan; Zhang, Li; Acharya, Chirag et al. (2017) Targeting CD38 Suppresses Induction and Function of T Regulatory Cells to Mitigate Immunosuppression in Multiple Myeloma. Clin Cancer Res 23:4290-4300
Yin, Li; Tagde, Ashujit; Gali, Reddy et al. (2017) MUC1-C is a target in lenalidomide resistant multiple myeloma. Br J Haematol 178:914-926
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
Ohguchi, Hiroto; Hideshima, Teru; Bhasin, Manoj K et al. (2016) The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nat Commun 7:10258
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
Stroopinsky, Dina; Kufe, Donald; Avigan, David (2016) MUC1 in hematological malignancies. Leuk Lymphoma 57:2489-98
An, Gang; Acharya, Chirag; Feng, Xiaoyan et al. (2016) Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication. Blood 128:1590-603
Amodio, Nicola; Stamato, Maria Angelica; Gullà, Anna Maria et al. (2016) Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma. Mol Cancer Ther 15:1364-75

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