Multiple myeloma (MM) is still incuable B-cell malignancy affecting more than 14,000 Americans annually. Myeloma tumor cells can survive even the most aggressive treatment available today, leading to disease relapses. The long-term goal of this project is to develop more effective cytostatic therapies to eradicate myeloma cells. We recently made a novel and exciting discovery that anti-?2-microglobulin (?2M) monoclonal antibodies (mAbs) had strong apoptotic activity in both established myeloma cell lines and primary myeloma cells from patients. The mAbs selectively target and kill myeloma cells in coculture with normal hematopoietic cells without damaging normal blood cells, including CD34+ stem cells in vitro, and were active and therapeutic in vivo in xenograft mouse models of myeloma. Anti-?2M mAb-induced apoptosis in myeloma cells were not blocked by high concentrations of soluble ?2M, IL-6, or other myeloma growth and survival factors, and was stronger than apoptosis observed with chemotherapy drugs currently used to treat MM (e.g., dexamethasone). The mAbs induced cell death via inhibiting PI3K/Akt and ERK, activating JNK, and compromising mitochondrial integrity, leading to cytochrome c release and activation of a caspase-9-dependent cascade. Moreover, we also showed that the mAbs may prevent or slowdown bone destruction in patients. Thus, we hypothesize that anti-?2M mAbs may be used as therapeutic agents to treat patients with MM. This grant will elucidate the mechanisms of anti-?2M mAb-mediated protection of myeloma bone disease. We will examine the in vitro effects and mechanism of anti-?2M mAbs on myeloma and bone cells, and elucidate the mechanism of anti-?2M mAb-mediated protection of bone diseases in vivo in myeloma SCID-hu model. These novel studies may lead to the development of anti-?2M mAbs as the first clinically useful and effective therapeutic mAbs for the treatment of MM and potentially other malignancies that express surfacer than apoptosis observed with chemotherapy drugs currently used to treat MM (e.g., dexamethasone). The mAbs induced cell death via inhibiting PI3K/Akt and ERK, activating JNK, and compromising mitochondrial integrity, leading to cytochrome c release and activation of a caspase-9-dependent cascade. Moreover, we also showed that the mAbs may prevent or slowdown bone destruction in patients. Thus, we hypothesize that anti-?2M mAbs may be used as therapeutic agents to treat patients with MM. This grant will elucidate the mechanisms of anti-?2M mAb-mediated protection of myeloma bone disease. We will examine the in vitro effects and mechanism of anti-?2M mAbs on myeloma and bone cells, and elucidate the mechanism of anti-?2M mAb-mediated protection of bone diseases in vivo in myeloma SCID-hu model. These novel studies may lead to the development of anti-?2M mAbs as the first clinically useful and effective therapeutic mAbs for the treatment of MM and potentially other malignancies that express surface ?2M and MHC class I molecules.

Public Health Relevance

The current studies will examine the therapeutic potential of anti-?2-microglobulin (?2M) monoclonal antibodies (mAbs) in myeloma. We recently made a novel and exciting discovery that anti-?2M mAbs had strong apoptotic activity in myeloma cells, and were also active and therapeutic in vivo in xenograft mouse models of myeloma. The mAbs selectively target and kill myeloma cells in coculture with normal hematopoietic cells without damaging normal blood cells. Moreover, our preliminary studies showed that anti-?2M mAbs may also be able to inhibit myeloma-mediated bone destruction in patients. Thus, we hypothesize that anti-?2M mAbs may be used as therapeutic agents to treat patients with myeloma. We propose a series of experiments to examine the mechanisms of mAb-induced apoptosis in myeloma cells, to elucidate the mechanisms of anti-?2M mAb- mediated protection of myeloma bone disease, and to develop strategies to enhance the efficacy of the mAbs to kill myeloma cells. These novel studies will lead to a better understanding of the role of anti-?2M mAbs in myeloma and may provide another avenue for augmenting currently available therapies for treating myeloma and potentially other hematological malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138402-02
Application #
7844847
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
2009-07-01
Project End
2011-12-30
Budget Start
2010-07-01
Budget End
2011-12-30
Support Year
2
Fiscal Year
2010
Total Cost
$319,552
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Zheng, Yuhuan; Wang, Qiang; Li, Tianshu et al. (2016) Role of Myeloma-Derived MIF in Myeloma Cell Adhesion to Bone Marrow and Chemotherapy Response. J Natl Cancer Inst 108:
Li, Yi; Zheng, Yuhuan; Li, Tianshu et al. (2015) Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and polarization in multiple myeloma. Oncotarget 6:24218-29
Zhang, Mingjun; He, Jin; Liu, Zhiqiang et al. (2015) Anti-??-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy. Oncotarget 6:8567-78
Hong, Bangxing; Li, Haiyan; Zhang, Mingjun et al. (2015) p38 MAPK inhibits breast cancer metastasis through regulation of stromal expansion. Int J Cancer 136:34-43
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Lu, Yong; Zhang, Mingjun; Wang, Siqing et al. (2014) p38 MAPK-inhibited dendritic cells induce superior antitumour immune responses and overcome regulatory T-cell-mediated immunosuppression. Nat Commun 5:4229
Hong, Bangxing; Li, Haiyan; Lu, Yong et al. (2014) USP18 is crucial for IFN-?-mediated inhibition of B16 melanoma tumorigenesis and antitumor immunity. Mol Cancer 13:132
Lu, Yong; Hong, Bangxing; Li, Haiyan et al. (2014) Tumor-specific IL-9-producing CD8+ Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers. Proc Natl Acad Sci U S A 111:2265-70
Zhang, Mingjun; Qian, Jianfei; Lan, Yongsheng et al. (2014) Anti-??M monoclonal antibodies kill myeloma cells via cell- and complement-mediated cytotoxicity. Int J Cancer 135:1132-41

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