Two critically important areas in oncology are (i) the development of effective treatments that minimize damage to normal tissue, and (ii) the development of treatment strategies that are successful in reducing or eliminating metastatic disease. Cancer chemotherapy can inflict severe damage to normal tissue resulting in devastating side-effects. Metastatic disease is usually refractory to treatment and is a major cause of patients succumbing to cancer. The ability to downregulate specific pathways that are overexpressed and critically important to cancer cells using small interfering RNA (siRNA) technology provides unprecedented opportunities to develop novel cancer-cell specific treatments to target primary and metastatic tumors. The ability to detect the delivery of the siRNA and combine it with the delivery of a chemotherapeutic agent primarily localized within the tumor would be of significant advantage in this quest. We recently developed a prototype agent that allows us to visualize the delivery of a prodrug enzyme, bacterial cytosine deaminase, noninvasively with MRI and optical imaging. With this ability it is possible to time the administration of the nontoxic prodrug 5-fluorocytosine, that is converted by the enzyme to cytotoxic 5-fluorouracil, to coincide with the presence of high concentrations of the enzyme in the tumor and low concentrations in normal tissue, to minimize systemic toxicity. We intend to advance the effectiveness of this strategy by incorporating siRNA targeting of two enzymes, choline kinase and cyclooxygenase-2, that are critically important in breast cancer. The purpose of this application is two-fold. The first is to develop effective cancer treatment strategies utilizing imaged guided prodrug enzyme-siRNA treatment to minimize damage to normal tissue, using preclinical models of breast cancer. The second is to use these strategies, preclinically, to target metastatic lesions. Both MR and optical reporter systems are included in these prototype agents since MR is for clinical translation, whereas the optical reporter is useful for visualizing the incorporation of the enzyme-siRNA conjugate with high-resolution microscopy. The studies proposed in this application can also, in the future, be extended to image-guided targeting of radiation or chemotherapy repair enzymes in combination with prodrug enzyme treatment and radiation therapy.

Public Health Relevance

Our purpose in this application is two-fold. The first is to develop effective treatment strategies utilizing imaged guided prodrug enzyme-siRNA treatment that will minimize damage to normal tissue, thereby reducing or eliminating the damaging side-effects of cancer treatment. The second is to use these strategies to target metastatic lesions, as breast cancer metastasis is refractory to treatment and a major cause of mortality, and there is an urgent need to identify new treatments that are effective at reducing or eliminating metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138515-05
Application #
8468126
Study Section
Special Emphasis Panel (ZRG1-MEDI-A (09))
Program Officer
Tandon, Pushpa
Project Start
2009-07-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$310,286
Indirect Cost
$121,087
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Penet, Marie-France; Shah, Tariq; Bharti, Santosh et al. (2015) Metabolic imaging of pancreatic ductal adenocarcinoma detects altered choline metabolism. Clin Cancer Res 21:386-95
Gadiya, Mayur; Mori, Noriko; Cao, Maria D et al. (2014) Phospholipase D1 and choline kinase-? are interactive targets in breast cancer. Cancer Biol Ther 15:593-601
Penet, Marie-France; Krishnamachary, Balaji; Chen, Zhihang et al. (2014) Molecular imaging of the tumor microenvironment for precision medicine and theranostics. Adv Cancer Res 124:235-56
Penet, Marie-France; Artemov, Dmitri; Farahani, Keyvan et al. (2013) MR - eyes for cancer: looking within an impenetrable disease. NMR Biomed 26:745-55
Pathak, Arvind P; McNutt, Stephen; Shah, Tariq et al. (2013) In vivo "MRI phenotyping" reveals changes in extracellular matrix transport and vascularization that mediate VEGF-driven increase in breast cancer metastasis. PLoS One 8:e63146
Mori, Noriko; Gadiya, Mayur; Wildes, Flonne et al. (2013) Characterization of choline kinase in human endothelial cells. NMR Biomed 26:1501-7
Shah, Tariq; Stasinopoulos, Ioannis; Wildes, Flonne et al. (2012) Noninvasive imaging identifies new roles for cyclooxygenase-2 in choline and lipid metabolism of human breast cancer cells. NMR Biomed 25:746-54
Penet, Marie-France; Winnard Jr, Paul T; Jacobs, Michael A et al. (2011) Understanding cancer-induced cachexia: imaging the flame and its fuel. Curr Opin Support Palliat Care 5:327-33
Glunde, Kristine; Bhujwalla, Zaver M; Ronen, Sabrina M (2011) Choline metabolism in malignant transformation. Nat Rev Cancer 11:835-48
Glunde, Kristine; Bhujwalla, Zaver M (2011) Metabolic tumor imaging using magnetic resonance spectroscopy. Semin Oncol 38:26-41

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