There is a clear unmet clinical need for a non-invasive real time imaging platform to assess drug target inhibition in order to enhance the therapeutic decision-making process and development of novel anti-cancer therapies. Many of the emerging anti-targeted agents induce arrest of cellular proliferation and tumor growth stabilization rather than tumor shrinkage. This makes early assessment of benefit with conventional imaging challenging, and currently available imaging and tissue-based biomarkers do not provide reliable evidence of target inhibition. Hence, drug developers and clinicians are faced with uncertainty whether tumor growth is due to a pharmacologically ineffective drug or biological tumor resistance. To be able to discern this difference with a non-invasive imaging platform would greatly impact the way we approach patients and develop targeted anti-cancer therapeutics. This is particularly relevant to patients with advanced stage cancer who cannot afford to lose irretrievable time by being exposed to a potentially ineffective agent. The goal of this academic-industrial collaborative research project is to accomplish the clinical translation o the next-generation imaging technology hyperpolarized 13C MRI. Here we propose to address the unmet clinical need of accurately assessing metabolic response of drug target inhibition of the mTOR pathway non-invasively in hormone therapy resistant breast cancer patients with liver metastases in a first ever proof of principle study. In a multidisciplinary approach bringing together UCSF MRI scientists, pharmacists and drug developers, this academic-industrial partnership will translate preclinical findings in hyperpolarized 13C MR imaging into a radiologic imaging tool to accurately assess drug target inhibition by mTOR inhibitors in patients. The partnership with industry will enable the required development of a clinical polarizer with a sterile fluid path (GE Research Circle Technologies), the construction of 13C MRI coils (USA Instruments) and production of sterile 13C labeled agent (Isotec); and ultimately integrate imaging into the development of novel targeted anti- cancer therapeutics (Celgene Corporation and others).

Public Health Relevance

The successful outcome of the proposed project will result in the development and translation into the clinical setting of new methods to enable greatly improved metabolic MR imaging of human cancer. While this project focuses on breast cancer metastases to liver, these new molecular imaging techniques could ultimately benefit the clinical management of other cancers and diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA183071-05
Application #
9437717
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Zhang, Huiming
Project Start
2014-05-12
Project End
2019-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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Milshteyn, Eugene; von Morze, Cornelius; Gordon, Jeremy W et al. (2018) High spatiotemporal resolution bSSFP imaging of hyperpolarized [1-13 C]pyruvate and [1-13 C]lactate with spectral suppression of alanine and pyruvate-hydrate. Magn Reson Med 80:1048-1060
Gordon, Jeremy W; Hansen, Rie B; Shin, Peter J et al. (2018) 3D hyperpolarized C-13 EPI with calibrationless parallel imaging. J Magn Reson 289:92-99
Gordon, Jeremy W; Chen, Hsin-Yu; Autry, Adam et al. (2018) Translation of Carbon-13 EPI for hyperpolarized MR molecular imaging of prostate and brain cancer patients. Magn Reson Med :
Shang, Hong; Sukumar, Subramaniam; von Morze, Cornelius et al. (2017) Spectrally selective three-dimensional dynamic balanced steady-state free precession for hyperpolarized C-13 metabolic imaging with spectrally selective radiofrequency pulses. Magn Reson Med 78:963-975
Ohliger, Michael A; von Morze, Cornelius; Marco-Rius, Irene et al. (2017) Combining hyperpolarized 13 C MRI with a liver-specific gadolinium contrast agent for selective assessment of hepatocyte metabolism. Magn Reson Med 77:2356-2363
Shin, Peter J; Zhu, Zihan; Camarda, Roman et al. (2017) Cancer recurrence monitoring using hyperpolarized [1-13C]pyruvate metabolic imaging in murine breast cancer model. Magn Reson Imaging 43:105-109
Koelsch, Bertram L; Sriram, Renuka; Keshari, Kayvan R et al. (2016) Separation of extra- and intracellular metabolites using hyperpolarized (13)C diffusion weighted MR. J Magn Reson 270:115-123
Shang, Hong; Larson, Peder E Z; Kerr, Adam et al. (2016) Multiband RF pulses with improved performance via convex optimization. J Magn Reson 262:81-90
Sriram, Renuka; Van Criekinge, Mark; DeLos Santos, Justin et al. (2016) Non-invasive differentiation of benign renal tumors from clear cell renal cell carcinomas using clinically translatable hyperpolarized 13C pyruvate magnetic resonance. Tomography 2:35-42

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