The long-term goal of this project is to develop 1H MRS and MRI methods for prediction and detection of therapeutic response of non-Hodgkin's lymphoma (NHL), a prevalent malignancy whose incidence has increased by more than 90% since 1950 that ranks fourth in overall economic impact. A multi-institutional clinical study in which the PI is participating has already demonstrated that 31P MRS can predict about 2/3 of the tumors that fail to exhibit a complete clinical response, but this method is limited to relatively large superficial tumors. Our approach has been to develop proton imaging and spectroscopy methods that are capable of early detection of response in all patients. During the first funding cycle of this grant we examined a xenograft model, DLCL2, of diffuse large B-cell lymphoma (DLBCL), the most common form of NHL affecting about 1/3 of all patients. We have evaluated the utility of 1H MRS measurements of total choline and lactate and 1H MRI (diffusion-weighted and T2-weighted with dynamic contrast-enhanced and T1A-weighted) in this tumor. We have examined the response to multiple clinically relevant therapies including: combination chemotherapy with Cyclophosphamide, Hydroxydoxorubicin, Oncovin and Prednisone (CHOP), CHOP plus Bryostatin 1 (CHOPB), Rituximab alone, Rituximab plus CHOP and radiation therapy. The most exciting results from these studies are: 1) significant decreases in lactate detected within one cycle of CHOP that correlated with decreased tumor proliferation;2) regional changes in the apparent diffusion constant and in T2 corresponding to areas of response in the tumor;3) design and implementation of a novel hybrid pulse sequence for 1H imaging of lactate utilizing multi-slice Hadamard spatial encoding and chemical shift imaging via a selective multi-quantum coherence transfer. This sequence was developed on the animal scanner and has now been translated to a clinical scanner and applied to an NHL patient. The objectives of the current proposal are 1) to define the mechanisms underlying therapy associated decreases in lactic acid, 2) to define the mechanism leading to MRI-detected regional response of the tumor, and 3) to extend the study to more responsive DLBCL xenograft models and to follicular lymphoma, the next most common form of NHL. We will employ a number of sophisticated and innovative methods to achieve these goals including 1) use of a two- compartment model to distinguish between changes in steady-state lactate concentration due to changes in glycolysis and washout, 2) determination if FDG-PET imaging and DCE MRI, which are more readily available in the clinic than 13C MRS, can distinguish between changed in lactate levels due to alterations in glycolytic rate or due to a change in the rate of lactate elimination, 3) 17O imaging methods to image perfusion and oxygen consumption simultaneously and 4) validation of a metabolic network model for 13C NMR by predicted and experimental oxygen consumption rates. We will also explore in depth possible mechanisms that could contribute to regional therapeutic response in the tumor.

Public Health Relevance

This project is directed towards developing NMR methods for prediction and early detection of therapeutic response of individual patients with non-Hodgkin's lymphoma (NHL), one of the prevalent forms of human cancer. A clinical program in which we participate has already developed a 31P NMR method for predicting about 2/3 of the tumors that will fail to respond to conventional treatment. This method, however, is limited to patients with large superficial tumors. Here we are developing much more sensitive 1H NMR methods that can be used for early detection of response in all NHL patients. The same methods should be applicable to other prevalent forms of human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA101700-08
Application #
8236871
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Menkens, Anne E
Project Start
2003-07-01
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
8
Fiscal Year
2012
Total Cost
$358,748
Indirect Cost
$130,971
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Xu, H N; Zhao, H; Mir, T A et al. (2013) CHOP THERAPY INDUCED MITOCHONDRIAL REDOX STATE ALTERATION IN NON-HODGKIN'S LYMPHOMA XENOGRAFTS. J Innov Opt Health Sci 6:1350011
Xu, He N; Mir, Tahreem A; Lee, Seung-Cheol et al. (2013) Mapping the redox state of CHOP-treated non-Hodgkin's lymphoma xenografts in mice. Adv Exp Med Biol 789:243-9
Lee, Seung-Cheol; Marzec, Michal; Liu, Xiaobin et al. (2013) Decreased lactate concentration and glycolytic enzyme expression reflect inhibition of mTOR signal transduction pathway in B-cell lymphoma. NMR Biomed 26:106-14
Lee, Seung-Cheol; Poptani, Harish; Delikatny, E James et al. (2011) NMR metabolic and physiological markers of therapeutic response. Adv Exp Med Biol 701:129-35
Lee, Seung-Cheol; Poptani, Harish; Pickup, Stephen et al. (2010) Early detection of radiation therapy response in non-Hodgkin's lymphoma xenografts by in vivo 1H magnetic resonance spectroscopy and imaging. NMR Biomed 23:624-32
Mellon, Eric A; Lee, Seung-Cheol; Pickup, Stephen et al. (2009) Detection of lactate with a hadamard slice selected, selective multiple quantum coherence, chemical shift imaging sequence (HDMD-SelMQC-CSI) on a clinical MRI scanner: Application to tumors and muscle ischemia. Magn Reson Med 62:1404-13
Lee, Seung-Cheol; Delikatny, Edward J; Poptani, Harish et al. (2009) In vivo (1)H MRS of WSU-DLCL2 human non-Hodgkin's lymphoma xenografts: response to rituximab and rituximab plus CHOP. NMR Biomed 22:259-65
Huang, Ming Q; Pickup, Stephen; Nelson, David S et al. (2008) Monitoring response to chemotherapy of non-Hodgkin's lymphoma xenografts by T(2)-weighted and diffusion-weighted MRI. NMR Biomed 21:1021-9
Lee, Seung-Cheol; Huang, Ming Q; Nelson, David S et al. (2008) In vivo MRS markers of response to CHOP chemotherapy in the WSU-DLCL2 human diffuse large B-cell lymphoma xenograft. NMR Biomed 21:723-33
Pickup, Stephen; Lee, Seung-Cheol; Mancuso, Anthony et al. (2008) Lactate imaging with Hadamard-encoded slice-selective multiple quantum coherence chemical-shift imaging. Magn Reson Med 60:299-305

Showing the most recent 10 out of 11 publications