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 of 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).
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.
|Shin, Peter J; Larson, Peder E Z; Uecker, Martin et al. (2015) Chemical shift separation with controlled aliasing for hyperpolarized (13) C metabolic imaging. Magn Reson Med 74:978-89|
|Aggarwal, Rahul; Grabowsky, Jennifer; Strait, Noah et al. (2014) Impact of patient ethnicity on the metabolic and immunologic effects of PI3K-mTOR pathway inhibition in patients with solid tumor malignancies. Cancer Chemother Pharmacol 74:359-65|
|von Morze, Cornelius; Carvajal, Lucas; Reed, Galen D et al. (2014) Directly detected (55)Mn MRI: application to phantoms for human hyperpolarized (13)C MRI development. Magn Reson Imaging 32:1165-70|