Metastatic melanoma has a dismal prognosis, with 10-year survival rates of <10%. A major underlying reason for this is that no systemic treatment provides durable benefit due to development of resistance to current therapies. A new potential strategy for treating melanoma is proposed that exploits differences in oxidative metabolism between cancerous and non-malignant cells to selectively kill melanoma cells. This new mitochondrial-targeted intervention utilizes a class of small molecules, based on triphenylphosphonium (TPP), to selectively increase superoxide levels and oxidative stress-induced melanoma cell killing, relative to normal cells. Our preliminary data demonstrate that TPP-based compounds can be designed to selectively kill melanoma cells relative to normal melanocytes. We further show that TPP-based compounds can be designed to promote melanoma cell death via increased oxidative stress and that the effect can be enhanced with inhibitors of hydroperoxide metabolism. In addition, orally-administered 10-TPP significantly suppressed melanoma tumor growth in mice, with no measurable toxicity. This research is innovative because no other therapy targets differences in mitochondrial oxidative metabolism in melanoma cells vs normal cells to selectively kill melanoma cells. This research is significant because the success of these aims can result in a new treatment paradigm for metastatic melanoma that can potentially provide durable benefit to patients. The central hypothesis is that TPP-based therapies can be developed to selectively kill melanoma cells relative to non-malignant cells by exploiting differences in oxidative metabolism of melanoma cells relative to non-malignant cells. This hypothesis will be tested in three Specific Aims: SA1: Identify TPP structure activity relationships (SAR) and mechanisms that selectively promote cell death and increase oxidative stress in melanoma cells, relative to non-malignant melanocytes. SA2: Determine the potential for TPP based drugs to selectively enhance melanoma cell killing when combined with standard clinically relevant chemotherapeutic agents and/or inhibitors of hydroperoxide metabolism. SA3: Identify TPP SAR as well as routes of administration that could result in the development of effective combined-modality therapies for human melanomas in xenograft models. Successful completion of these studies will identify key design traits of TPP-drugs that selectively promote melanoma cell death vs. normal melanocytes, as well as establish a detailed mechanistic understanding of TPP-based combination therapies that can ultimately lead to well-tolerated protocols for treating metastatic melanoma that can be advanced to human clinical trials.

Public Health Relevance

Emerging evidence of fundamental differences in mitochondrial oxidative metabolism between cancer cells and normal cells has led to the hypothesis that therapeutic agents that selectively target tumor cell mitochondria could be designed to provide effective therapy for metastatic melanoma. The current application will investigate a class of mitochondrial targeted small molecules (based on triphenylphosphonium) that selectively promote cell death and oxidative stress in melanoma cells, relative to normal cells. These studies could lead to the development of novel combination therapies for metastatic melanoma with the potential for broad applicability.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25CA172218-02
Application #
8693967
Study Section
Subcommittee B - Comprehensiveness (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2013-07-02
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Lee, Dongyoul; Li, Mengshi; Bednarz, Bryan et al. (2018) Modeling Cell and Tumor-Metastasis Dosimetry with the Particle and Heavy Ion Transport Code System (PHITS) Software for Targeted Alpha-Particle Radionuclide Therapy. Radiat Res 190:236-247
Nelson, A W; Eitrheim, E S; Knight, A W et al. (2017) Polonium-210 accumulates in a lake receiving coal mine discharges-anthropogenic or natural? J Environ Radioact 167:211-221
Schoenfeld, Joshua D; Sibenaller, Zita A; Mapuskar, Kranti A et al. (2017) O2?- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell 32:268
Li, Mengshi; Zhang, Xiuli; Quinn, Thomas P et al. (2017) Automated cassette-based production of high specific activity [203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer. Appl Radiat Isot 127:52-60
May, D; Nelson, A N; Schultz, M K (2017) Quantitation of lead-210 (210Pb) using lead-203 (203Pb) as a ""Massless"" yield tracer. J Environ Radioact 171:93-98
Rosenblum, James; Nelson, Andrew W; Ruyle, Bridger et al. (2017) Temporal characterization of flowback and produced water quality from a hydraulically fractured oil and gas well. Sci Total Environ 596-597:369-377
Schibler, Jeanine; Tomanek-Chalkley, Ann M; Reedy, Jessica L et al. (2016) Mitochondrial-Targeted Decyl-Triphenylphosphonium Enhances 2-Deoxy-D-Glucose Mediated Oxidative Stress and Clonogenic Killing of Multiple Myeloma Cells. PLoS One 11:e0167323
Nelson, Andrew W; Johns, Adam J; Eitrheim, Eric S et al. (2016) Partitioning of naturally-occurring radionuclides (NORM) in Marcellus Shale produced fluids influenced by chemical matrix. Environ Sci Process Impacts 18:456-63
Mueller, Dirk; Breeman, Wouter A P; Klette, Ingo et al. (2016) Radiolabeling of DOTA-like conjugated peptides with generator-produced (68)Ga and using NaCl-based cationic elution method. Nat Protoc 11:1057-66
Reedy, Jessica L; Hedlund, Devin K; Gabr, Moustafa T et al. (2016) Synthesis and Evaluation of Tetraarylethylene-based Mono-, Bis-, and Tris(pyridinium) Derivatives for Image-Guided Mitochondria-Specific Targeting and Cytotoxicity of Metastatic Melanoma Cells. Bioconjug Chem 27:2424-2430

Showing the most recent 10 out of 19 publications