Noninvasive Imaging of Mitochondria Structure and Function to Predict Therapeutic Response in NSCLC
Abstract
We present a study that seeks to improve the diagnosis and treatment of non-small cell lung cancer (NSCLC) through structural and functional imaging of the mitochondria. The mitochondria are traditionally thought of as cellular power plants that provide the cell with energy. However, we have uncovered that profiling the structural organization of the mitochondria in lung tumors using positron emission tomography (PET) imaging may enable us to predict therapeutic sensitivity or resistance to front-line chemotherapy. Even with the advent of new immune-based therapies, many NSCLC patients still receive chemotherapy and, to date, there are no effective biomarkers available to accurately predict response to chemotherapy before treatment is delivered. This underscores the need to develop biomarkers that may be predictive of therapeutic response at the time of diagnosis. To address these clinical needs, we have developed a PET imaging probe called FTP that measures mitochondrial structure and function in lung tumors. Importantly, we have discovered that tumors that are positive for FTP may be highly responsive to the front-line chemotherapy, cisplatin, whereas tumors that are negative for FTP may be highly resistant. Here, FTP PET imaging promises to inform clinicians as to which patients will fare well on cisplatin therapy and which have tumors that will be unresponsive. Therefore, our first objective will be to test whether FTP is a predictive biomarker of response or resistance to cisplatin. We will use state-of-the-art models of NSCLC for rapid translation of our work into clinical applications. In addition, we examined whether FTP could be used to specifically guide the delivery of drugs that inhibit mitochondria in lung tumors. We performed a screen of lung tumors and discovered the existence of tumor populations that are highly sensitive to drugs that inhibit the mitochondria. Importantly, many of these tumors were positive for FTP. We next labeled our mitochondrial inhibitors with our FTP probe, allowing us to target these drugs to the tumor mitochondria with high affinities and induce tumor cell death. Therefore, our second objective of the proposed study will be to test the effectiveness of FTP PET to guide the delivery of mitochondrial inhibitors to be used as novel anti-cancer agents for the treatment of lung cancer. Here, we present a novel study that employs a biomarker-driven approach that first uses PET imaging to profile mitochondrial structure and function in lung tumors at time of diagnosis. This screening will enable patients to be stratified into cisplatin-responsive and non-responsive populations to better inform oncologists. We reason that FTP PET will also effectively guide the delivery of novel mitochondrial inhibitors. Our approach represents a paradigm shift in the diagnosis and treatment of this disease as we move toward developing personalized therapeutic strategies that couple non-invasive PET imaging with delivery of effective and precise medicines. We propose that the information gleaned by profiling the mitochondrial structure and function in lung tumors will enable oncologists to tailor precise and effective treatments for patients at the time of diagnosis to significantly improve their overall survival and outcome.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810295
Entities
People
- David B Shackelford
Organizations
- United States Army
- University of California, Los Angeles