54,000 new cases of renal cell cancer (RCC) are diagnosed each year in the US and approximately 13,000 patients succumb to the disease annually. Recently, anti-angiogenic therapy has produced modest gains, whereas chemotherapy has had no impact in this tumor type. It is therefore clear that novel alternatives are sorely needed. Here we propose to study a novel therapeutic approach to renal cancer that may also yield a technique to rapidly assess treatment response and hence aid in the selection of an appropriate course of treatment. Fermentative glycolysis is common to many solid tumors but has a key role in a subset of renal cancers resulting from mutations in Von-Hippel Lindau (VHL) deficient tumors which occurs in the majority of RCC (as it leads to hypoxia inducible factor (HIF) stabilization). We propose to study renal cancer therapies that seek to reverse the Warburg effect. This can be accomplished through reactivation of the mitochondria in activating PDH (pyruvate dehydrogenase), which facilitates pyruvate entry into tricarboxylic acid cycle (TCA). The enzyme PDH can be activated by a small molecule inhibitor, dichloroacetate (DCA) that blocks pyruvate dehydrogenase kinase (PDK), which in turn negatively regulates PDH. Hence molecular pathways influencing pyruvate's metabolic fate may, in turn, impact tumor survival. The key feature of this proposal is to redirect the fate of pyruvate into the Krebs cycle, so that tumor cells will be preferentially harmed. To date, however, there has been no in vivo methodology to determine whether DCA or other methods of redirecting the fate of pyruvate are in fact accomplishing their goal in vivo. Hyperpolarized magnetic resonance imaging is an emerging technology that may provide such a biocorrelate. Here we propose to use hyperpolarized pyruvate as a tool for assessing the response RCC tumors to therapies that aim to reverse the Warburg effect. Our major working hypothesis is that administration of DCA will result in decreased lactate formation in an orthotopic mouse model of renal cell carcinoma, and that this """"""""pharmacodynamic"""""""" measurement will correlate with decreased tumor burden in this model. Using a variety of doses and schedules for DCA administration, we will collect non-invasive imaging data using hyperpolarized carbon-13 labeled pyruvate. Hence our specific aims are as follows;
Aim 1 : To correlate non-invasive imaging data with various DCA doses (""""""""the pilot study"""""""").
Aim 2 : To correlate these imaging measurements of pyruvate metabolism after chronic DCA treatment with tumor burden, tumor proliferation and apoptotic indices, and PDH phosphorylation status in this model (""""""""the longitudinal study""""""""). The importance of these studies is that they will allow for efficient translation into the clinic of drugs that affect the fate of pyruvate, which may provide a whole new approach to cancer therapeutics.
Fermentative glycolysis (conversion of pyruvate to lactate) is common to many solid tumors but has a key role in renal cancers resulting from mutations in Von-Hippel Lindau (VHL). Studies have demonstrated that in VHL-deficient clear cell renal carcinoma, hypoxia inducible factor (HIF-1) mediates increased glucose uptake, increased lactate production, and decreased respiration. In this proposal we bring together a team of radiologists, physicists, pathologists, and cancer scientists to help accomplish this goal using a state of the art technology known as hyperpolarizing MRI. In particular, we present pre-clinical data showing that this approach is indeed feasible and that we have a validated preclinical renal cancer animal model available to us. We propose to test whether the in vivo administration of dichloroacetate (DCA) results in decreased formation of lactate from pyruvate in this animal model and whether this flux measurement correlates with decreased tumor burden. The importance of these studies is that it will allow for efficient translation into the clinic of drugs that affect the fate of pyruvate, a whole new approach to cancer therapeutics.
|Lee, Hyang Yeon; Parkinson, Elizabeth I; Granchi, Carlotta et al. (2017) Reactive Oxygen Species Synergize To Potently and Selectively Induce Cancer Cell Death. ACS Chem Biol 12:1416-1424|
|Seth, Pankaj; Csizmadia, Eva; Hedblom, Andreas et al. (2017) Deletion of Lactate Dehydrogenase-A in Myeloid Cells Triggers Antitumor Immunity. Cancer Res 77:3632-3643|
|Hu, Hai; Juvekar, Ashish; Lyssiotis, Costas A et al. (2016) Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton. Cell 164:433-46|
|Xie, Han; Hanai, Jun-Ichi; Ren, Jian-Guo et al. (2014) Targeting lactate dehydrogenase--a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metab 19:795-809|