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 #
5P50CA142509-04
Application #
8543580
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$163,721
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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
Carballo-Zarate, Adrian A; Medeiros, L Jeffrey; Fang, Lianghua et al. (2017) Additional-structural-chromosomal aberrations are associated with inferior clinical outcome in patients with hyperdiploid multiple myeloma: a single-institution experience. Mod Pathol 30:843-853
Xu-Monette, Zijun Y; Zhang, Mingzhi; Li, Jianyong et al. (2017) PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response? Front Immunol 8:1597
Wan, Wen; Pei, Xin-Yan; Grant, Steven et al. (2017) Nonlinear response surface in the study of interaction analysis of three combination drugs. Biom J 59:9-24
Yu, Li; Tu, Meifeng; Cortes, Jorge et al. (2017) Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease. Blood 129:1658-1668
Nguyen, Tri; Parker, Rebecca; Hawkins, Elisa et al. (2017) Synergistic interactions between PLK1 and HDAC inhibitors in non-Hodgkin's lymphoma cells occur in vitro and in vivo and proceed through multiple mechanisms. Oncotarget 8:31478-31493
(2017) Correction: Integration of Novel Agents into the Care of Patients with Multiple Myeloma. Clin Cancer Res 23:2605
Lee, Hans C; Wang, Hua; Baladandayuthapani, Veerabhadran et al. (2017) RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma. Br J Haematol 177:80-94
Manasanch, Elisabet E; Orlowski, Robert Z (2017) Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol 14:417-433

Showing the most recent 10 out of 190 publications