Currently, hyperthermia used for radiosensitization of tumors is usually administered locally at the site of the tumor, at relatively high temperatures. Moreover, because of technical application difficulties, the first heating dose is usually delivered after the first radiation dose, and is administered infrequently in comparison to radiation fractions. However, there is growing evidence that the biological rationale for locally applied, high temperature hyperthermia is faulty. Moreover, maintaining and monitoring a state of intense hyperthermia locally, even for short durations, has been challenging for the physicist, radio-therapist and the patient. In contrast, we assert, based on our experience exploring the effects of thermal stress on host tissues and tumors, that regional or systemic treatment of normal organs and tissues with a mild, physiologically relevant, hyperthermia (between 38.5 - 39.5oC) can result in significant radiosensitization of tumors. We have observed that mild systemic hyperthermia induces selective and long term increases in tumor vascular perfusion and we propose that this is the result of powerful (and rapidly reversible) thermoregulatory mechanisms in normal vasculature which eventually force collapsed non-functional tumor vessels lying downstream of normal vascular beds to receive blood. Specifically, we have strong evidence that mild systemic heating can significantly and selectively increase tumor vascular perfusion over a relatively long period of time, decrease tumor interstitial fluid pressure and significantly sensitize tumors to subsequent radiotherapy. The overall goal of this new grant proposal is to address the mechanistic and pre-clinical questions that arise from our preliminary data. Specifically, we will test the overall hypothesis that normal thermoregulatory mechanisms can be exploited to selectively increase perfusion of tumor vasculature, thus greatly enhancing tumor oxygenation without further increasing oxygenation of normal tissues.
The Specific Aims of this proposal are to: 1) Test the hypothesis that mild, systemic thermal stress selectively increases tumor vascular perfusion and oxygenation while decreasing interstitial fluid pressure, 2) Test the hypothesis that pretreatment of animals with mild systemic thermal therapy will significantly enhance the anti-tumor efficacy of radiation therapy without increasing normal tissue sensitivity and 3) Compare short and long-term effectiveness of pre-treatment with mild thermal stress followed by radiation therapy among different clinically relevant animal tumor models, including spontaneous tumors, patient-derived tumors, and orthotopic and metastatic tumors. Our research team is uniquely qualified to conduct this research and we have designed these aims to support rapid implementation of rationally designed clinical trials based upon the newly defined biological basis for the use of hyperthermia as a radiation sensitizer defined in this proposal.

Public Health Relevance

We are proposing a feasible new strategy that can significantly enhance the sensitivity of solid tumors to radiation therapy and result in immediate clinical impact. This approach (which does not require complex physics of local heat delivery) depends upon the response of normal vasculature to mild temperature shifts (i.e., thermoregulation), which we hypothesize will increase the perfusion of downstream blood vessels in tumors, thus increasing oxygenation. This proposal will address critical issues which must be addressed for the optimal design of new clinical trials utilizing the property of thermoregulation in patients who will receive radiation therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Wong, Rosemary S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Roswell Park Cancer Institute Corp
United States
Zip Code
Povinelli, Benjamin J; Kokolus, Kathleen M; Eng, Jason W-L et al. (2015) Standard sub-thermoneutral caging temperature influences radiosensitivity of hematopoietic stem and progenitor cells. PLoS One 10:e0120078
Lee, Chen-Ting; Kokolus, Kathleen M; Leigh, Nicholas D et al. (2015) Defining immunological impact and therapeutic benefit of mild heating in a murine model of arthritis. PLoS One 10:e0120327
Winslow, Timothy B; Eranki, Annu; Ullas, Soumya et al. (2015) A pilot study of the effects of mild systemic heating on human head and neck tumour xenografts: Analysis of tumour perfusion, interstitial fluid pressure, hypoxia and efficacy of radiation therapy. Int J Hyperthermia 31:693-701
Leigh, Nicholas D; Kokolus, Kathleen M; O'Neill, Rachel E et al. (2015) Housing Temperature-Induced Stress Is Suppressing Murine Graft-versus-Host Disease through ?2-Adrenergic Receptor Signaling. J Immunol 195:5045-54
Repasky, Elizabeth A; Eng, Jason; Hylander, Bonnie L (2015) Stress, metabolism and cancer: integrated pathways contributing to immune suppression. Cancer J 21:97-103
Eng, Jason W-L; Reed, Chelsey B; Kokolus, Kathleen M et al. (2015) Housing temperature-induced stress drives therapeutic resistance in murine tumour models through ?2-adrenergic receptor activation. Nat Commun 6:6426
Eng, Jason W-L; Kokolus, Kathleen M; Reed, Chelsey B et al. (2014) A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response. Cancer Immunol Immunother 63:1115-28
Kokolus, Kathleen M; Spangler, Haley M; Povinelli, Benjamin J et al. (2014) Stressful presentations: mild cold stress in laboratory mice influences phenotype of dendritic cells in naïve and tumor-bearing mice. Front Immunol 5:23
Messmer, Michelle N; Kokolus, Kathleen M; Eng, Jason W-L et al. (2014) Mild cold-stress depresses immune responses: Implications for cancer models involving laboratory mice. Bioessays 36:884-91
Eng, Jason W-L; Reed, Chelsey B; Kokolus, Kathleen M et al. (2014) Housing temperature influences the pattern of heat shock protein induction in mice following mild whole body hyperthermia. Int J Hyperthermia 30:540-6

Showing the most recent 10 out of 20 publications