Tumor hypoxia compromises effectiveness of therapies including radiation and chemotherapy. 02 levels in tumors are spatially heterogeneous and fluctuate over time. The long-term goal of this project is to quantitatively understand processes that govern spatial and temporal distributions of 02 and glucose in human cancers and to use that knowledge to improve therapeutic strategies. This grant will utilize pre-clinical models, theoretical approaches based on experimental data and clinical trials in patients with head and neck cancer to focus on two themes: (A) Characterize and determine underlying causes for fluctuant pO2 (a.k.a. acute hypoxia) at baseline and after radiation exposure and (B) Determine methods to improve tumor pO2 by increasing delivery + reducing 02 consumption. The overall hypothesis of this project is that successful amelioration of hypoxia will require a multifaceted approach that blocks fluctuant pO2, improves O2 delivery and reduces 02 consumption.
Specific Aim 1. We have found that pO2 fluctuations are caused by microvessel red cell flux instability. Further, it is the norm, as opposed to chronic steady state hypoxia. In pre-clinical models, including human tumor xenografts, we will: (la) determine causes for red cell flux instability; (lb) examine intratumoral size distribution and coordination of fluctuant zones of hypoxia and (Ic) compare methods to measure fluctuant pO2.
Specific Aim 2. We have found that 02 breathing + hyperglycemia leads to substantial increase in tumor pO2 yet the most hypoxic regions are refractory. Better knowledge of glucose and 02 transports is needed for optimization. Using animal models and theoretical simulations, we will: 1) establish the effect of hyperglycemia on intracellular and extracellular tumor glucose and lactate concentrations and 2) determine whether the respiratory inhibitor MIBG and/or inorganic phosphate can work cooperatively with hyperglycemia to increase tumor pO2.
Specific Aim 3. Two clinical trials will establish key metabolic and physiologic characteristics of squamous cell carcinoma of the head and neck, The goals are to: (3a) characterize kinetics of fluctuant pO2 for the first time in human cancer, (3b) examine relationships between hypoxia and anaerobic metabolism, and (3c) examine intracellular and extracellular concentrations of glucose and lactate. We believe that this comprehensive approach holds great promise for successfully ameliorating hypoxia in human cancer.
Showing the most recent 10 out of 169 publications
