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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA142509-05
Application #
8728776
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
5
Fiscal Year
2014
Total Cost
$168,658
Indirect Cost
$4,919
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Glitza, Isabella C; Lu, Gary; Shah, Rupin et al. (2015) Chromosome 8q24.1/c-MYC abnormality: a marker for high-risk myeloma. Leuk Lymphoma 56:602-7
Wen, Jianguo; Tao, Wenjing; Kuiatse, Isere et al. (2015) Dynamic balance of multiple myeloma clonogenic side population cell percentages controlled by environmental conditions. Int J Cancer 136:991-1002
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
Shi, Qiuling; Wang, Xin Shelley; Li, Guojun et al. (2015) Racial/ethnic disparities in inflammatory gene single-nucleotide polymorphisms as predictors of a high risk for symptom burden in patients with multiple myeloma 1 year after diagnosis. Cancer 121:1138-46
Wang, Xin Shelley; Shi, Qiuling; Williams, Loretta A et al. (2015) Longitudinal analysis of patient-reported symptoms post-autologous stem cell transplant and their relationship to inflammation in patients with multiple myeloma. Leuk Lymphoma 56:1335-41
Parmar, S; Kongtim, P; Champlin, R et al. (2014) Auto-SCT improves survival in systemic light chain amyloidosis: a retrospective analysis with 14-year follow-up. Bone Marrow Transplant 49:1036-41
Chen, Zheng; Orlowski, Robert Z; Wang, Michael et al. (2014) Osteoblastic niche supports the growth of quiescent multiple myeloma cells. Blood 123:2204-8
San-Miguel, Jesús; Bladé, Joan; Shpilberg, Ofer et al. (2014) Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood 123:4136-42
Srkalovic, Gordan; Hussein, Mohamad A; Hoering, Antje et al. (2014) A phase II trial of BAY 43-9006 (sorafenib) (NSC-724772) in patients with relapsing and resistant multiple myeloma: SWOG S0434. Cancer Med 3:1275-83
Ocio, Enrique M; Mitsiades, Constantine S; Orlowski, Robert Z et al. (2014) Future agents and treatment directions in multiple myeloma. Expert Rev Hematol 7:127-41

Showing the most recent 10 out of 79 publications