Multiple myeloma (MM) affected 14,400 new patients with in the United States in 2001, with 50,000 total patients, and unfortunately remains incurable despite conventional and high dose chemotherapy. In past studies sponsored by this grant in our Jerome Lipper Multiple Myeloma Center, we have characterized the role of growth factors in MM pathogenesis and derived novel therapies to improve patient outcome based upon targeting cytokines and their signaling cascades both in the MM cell as well as its bone marrow (BM) microenvironment. To achieve this goal, we have developed systems for studying the growth, survival, and drug resistance mechanisms intrinsic to MM cells. Importantly, we have also developed both in vitro systems and in vivo animal models to characterize mechanisms of MM cell homing to BM, as well as cytokines promoting MM cell growth and drug resistance in the BM milieu. These model systems have allowed for the development of several promising biologically-based therapies, including thalidomide (Thal) and its immunomodulatory analogs (IMiDs), proteasome inhibitor PS 341, and arsenic trioxide (As2O3). Once preclinical promise has been demonstrated, we have rapidly translated these laboratory studies to phase I and II clinical trials to evaluate their clinical utility and toxicity. Importantly, ongoing gene array studies of samples obtained from patients treated on these protocols is directed to identify in vivo targets and mechanisms of drug action on the one hand, versus mechanisms of drug resistance on the other. These studies have suggested the critical role of cytokines in growth, survival, drug resistance, and migration of MM cells, providing the framework for validating their role in MM pathogenesis and as targets for novel therapies, as proposed in this competitive renewal application with the following three specific aims:
Specific Aim 1 To characterize the role of growth factors in mediating growth, survival, drug resistance, and migration of MM cells in vitro;
Specific Aim 2 To validate the signaling events mediating cytokine-induced growth, survival, drug resistance, and migration of MM cells as therapeutic targets;
and Specific Aim 3 To validate novel therapeutics targeting in vivo cytokine-induced signaling cascades in animal models for evaluation in phase I/II clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA050947-12
Application #
6574138
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Howcroft, Thomas K
Project Start
1990-12-01
Project End
2008-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
12
Fiscal Year
2003
Total Cost
$299,250
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Gullà, A; Hideshima, T; Bianchi, G et al. (2018) Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia 32:996-1002
Ray, A; Das, D S; Song, Y et al. (2018) Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma. Leukemia 32:843-846
Guang, Matthew Ho Zhi; McCann, Amanda; Bianchi, Giada et al. (2018) Overcoming multiple myeloma drug resistance in the era of cancer 'omics'. Leuk Lymphoma 59:542-561
Anderson, Kenneth C (2018) Promise of Immune Therapies in Multiple Myeloma. J Oncol Pract 14:411-413
Downey-Kopyscinski, Sondra; Daily, Ellen W; Gautier, Marc et al. (2018) An inhibitor of proteasome ?2 sites sensitizes myeloma cells to immunoproteasome inhibitors. Blood Adv 2:2443-2451
Tai, Yu-Tzu; Lin, Liang; Xing, Lijie et al. (2018) APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: therapeutic implications. Leukemia :
Bae, J; Hideshima, T; Zhang, G L et al. (2018) Identification and characterization of HLA-A24-specific XBP1, CD138 (Syndecan-1) and CS1 (SLAMF7) peptides inducing antigens-specific memory cytotoxic T lymphocytes targeting multiple myeloma. Leukemia 32:752-764
Song, Y; Li, S; Ray, A et al. (2017) Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Oncogene 36:5631-5638
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
Zhang, Li; Tai, Yu-Tzu; Ho, Matthew Zhi Guang et al. (2017) Interferon-alpha-based immunotherapies in the treatment of B cell-derived hematologic neoplasms in today's treat-to-target era. Exp Hematol Oncol 6:20

Showing the most recent 10 out of 252 publications