The ubiquitin-proteasome pathway has been validated as a therapeutic target for mulfiple myeloma (MM) by our group and others through the demonstrafion ofthe acfivity of bortezomib in both the relapsed/refractory and up-ft-ont settings. Because of its broad impact on intracellular proteolysis, however, this proteasome inhibitor induces anfi-apoptotic effects at the molecular level that decrease its efficacy, and at the clinical level it induces toxicifies such as peripheral neuropathy that limit its ufility. A more targeted approach, therefore, such as by inhibiting a specific E3 ubiquitin ligase responsible for ubiquitinafion of only a small subset of client proteins, would likely be more effective and better tolerated. We have obtained evidence that second-generation small molecule inhibitors ofthe HDM-2 E3 ligase, which is best known for its role in p53 ubiquitinafion, induce anfi-proliferative effects in MM models irrespective of their p53 status;that these agents activate a p53-dependent type I cell death program, as well as p53-independent type II cell death, or autophagy;and that they interact synergistically with different classes of chemotherapeutics in wild type and mutant p53 backgrounds. These and other findings led us to our central hypothesis, that HDM-2 inhibitors are promising novel agents that can be used as chemosensitizers in a p53 status-adapted approach to personalize MM therapy. To evaluate this possibility, and to translate these agents into the clinic, our proposed specific aims will: 1. Further define the molecular mechanisms of acfion of HDM-2 inhibitors in MM, including their impact on type I and II cell death, and the role of p53 and HDM-2 in these processes;2. Delineate the pathways by which HDM-2 inhibitors sensifize MM to type l-inducing chemotherapeutics such as anthracyclines, death receptor agonists, and Bcl-2 inhibitors in wild type p53 models, and to mTOR inhibitors in mutant p53 models;and 3. Pilot an HDM-2 inhibitor as a single agent in a phase I study evaluafing its impact and mechanism of cell death induction in patients with relapsed/refractory MM in preparafion for later studies of an individualized p53 status-adapted approach.

Public Health Relevance

Mulfiple myeloma is the second most commonly diagnosed hematologic malignancy and remains incurable in the vast majority of pafients. Our preliminary data support the hypothesis that HDM-2 inhibifion is a novel, rational therapeufic strategy against myeloma, which can be individualized to the characteristics of each patient's disease, and the proposed studies will test this central hypothesis both pre-clinically and clinically.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Zhang, Jun; Medeiros, L Jeffrey; Young, Ken H (2018) Cancer Immunotherapy in Diffuse Large B-Cell Lymphoma. Front Oncol 8:351
Ni, Haiwen; Shirazi, Fazal; Baladandayuthapani, Veerabhadran et al. (2018) Targeting Myddosome Signaling in Waldenström's Macroglobulinemia with the Interleukin-1 Receptor-Associated Kinase 1/4 Inhibitor R191. Clin Cancer Res 24:6408-6420
Zhou, Liang; Zhang, Yu; Sampath, Deepak et al. (2018) Flavopiridol enhances ABT-199 sensitivity in unfavourable-risk multiple myeloma cells in vitro and in vivo. Br J Cancer 118:388-397
Davenport, Clemontina A; Maity, Arnab; Baladandayuthapani, Veerabhadran (2018) Functional interaction-based nonlinear models with application to multiplatform genomics data. Stat Med 37:2715-2733
Yao, Z; Deng, L; Xu-Monette, Z Y et al. (2018) Concordant bone marrow involvement of diffuse large B-cell lymphoma represents a distinct clinical and biological entity in the era of immunotherapy. Leukemia 32:353-363
Zhang, Xiaohui; Lee, Hans C; Shirazi, Fazal et al. (2018) Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia 32:2224-2239
Thomas, Sheeba K; Cha, Soung-Chul; Smith, D Lynne et al. (2018) Phase I study of an active immunotherapy for asymptomatic phase Lymphoplasmacytic lymphoma with DNA vaccines encoding antigen-chemokine fusion: study protocol. BMC Cancer 18:187
Xu-Monette, Zijun Y; Zhou, Jianfeng; Young, Ken H (2018) PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood 131:68-83
Purushothaman, Anurag; Bandari, Shyam K; Chandrashekar, Darshan S et al. (2017) Chondroitin sulfate proteoglycan serglycin influences protein cargo loading and functions of tumor-derived exosomes. Oncotarget 8:73723-73732
Holkova, Beata; Yazbeck, Victor; Kmieciak, Maciej et al. (2017) A phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma. Leuk Lymphoma 58:1349-1357

Showing the most recent 10 out of 203 publications