Tumor Microenvironment, Adaptive Cellular Responses, Tumor Metabolism Summary
Dr. Denko joined the Department of Radiation Oncology at the OSUCCC – James in 2012 after spending 11 years at Stanford University in the department of Radiation Oncology. His NIH-sponsored research has focused on understanding how the stresses with the tumor microenvironment can influence tumor cell malignant progression and the response of solid tumors to therapeutic interventions. These studies have progressed through basic gene expression and cell biologic investigations to model tumor systems, to the initiation of an interventional clinical trial. Current projects are investigating the role of reduced oxygen (hypoxia) and nutrient stress (hypoglycemia) on gene expression and cellular metabolism. By manipulating the cell’s adaptive responses to environmental stress, we hope to cripple tumor cells and increase sensitivity to conventional or targeted therapeutics.
Tumor hypoxia has been recognized for nearly 20 years as a prognostic indicator of poor patient survival. However, clinical attempts to reverse hypoxia by delivering more oxygen have met with disappointing results. There are many physiologic barriers that limit oxygen delivery to the solid tumor, so increased oxygen delivery to the systemic circulation through increased red blood cell mass or inspired oxygen do not result in increase delivery of oxygen to the tumor cells. Chronic hypoxia exists within the tumor because the demand for oxygen within the tumor is greater than the supply that is delivered. We are therefore attempting to approach the problem from a different angle and decrease oxygen consumption within the tumor to bring the supply and demand for oxygen into balance. Using this strategy, metabolic manipulation within tumor cells can result in decreased hypoxia and increased radiation response. These preclinical studies will potentially integrate with future clinical trials. The investigation of drugs that reduce hypoxia and radiosensitize can combine with future studies examining molecular imaging of hypoxia using new 19F PET radiotracers, and novel clinical trials that employ modern hypofractionated SBRT protocols.
A complementary anti-cancer approach has been to exploit our understanding of the adaptive HIF-1/PDHK1 axis to reverse classical tumor metabolism. Since the times of Warburg, scientists have understood that tumor cells are hyperglycolytic with reduced mitochondrial function. In 2006 we identified the HIF-1 target gene pyruvate dehydrogenase kinase 1 as a major inhibitor of mitochondrial glucose oxidation in cells exposed to hypoxia. This adaptive response reduces oxygen consumption when environmental oxygen is limited. We have found that pharmacologic or genetic intervention that blocks this HIF/PDHK1 response has profound effects on the growth of model tumors. Genetic knockdown of PDHK1 using stable ShRNA constructs, or pharmacologic inhibition of PDHK1 function using the pan-PDHK inhibitor dichloroacetate results in the inhibition of the growth of transplanted tumors. The mechanism of this growth inhibition is poorly understood, but appears to be replicated in experiments that have also increased mitochondrial function by alternative means (such as ectopic expression of mitochondrial uncoupling protein UCP1). These preclinical findings have lead to an NIH-funded phase 1 clinical trial examining the use of PDHK inhibitors in the treatment of patients with solid tumors.
As tumors grow, their metabolic needs surpass what is available in the surrounding tissue. This uncontrolled cellular proliferation, along with malformed and dysfunctional tumor vasculature, creates a nutrient- and oxygen-starved environment to which the tumors must adapt to survive and continue growing. To adapt, the cells undergo metabolic changes to compensate for the decrease in nutrients. These changes also decrease cellular oxygen requirements to help alleviate the hypoxic conditions. Overall, these adaptive events have been shown to be poor prognostic factors for patient survival.
Our lab aims to target key intersections in these metabolic pathways so that we may exploit these features of solid tumors. To this end, we aspire to better understand the specific mechanisms responsible for the adaptations so that we may develop targeted therapies and enhance the efficacy of current treatment regimens.
Ioanna Papandreou, PhD – research assistant professor
Ramon Sun, PhD – Pelotonia fellow
Betina McNeil, PhD – post doctoral researcher
Jason Evans, PhD – post doctoral researcher
Shiva Raghuvanshi, MS – research assistant
Wendy O’Neil, DDS – master’s degree student