Tumor hypoxia is an important characteristic of solid tumors and a modulator of therapeutic response. Becauseoxygen diffuses 100-150 ?m from blood vessels, fast growing tumors often have two hypoxic regions: achronically hypoxic region in the center of the tumor and a cycling (or acute) hypoxic region within the diffusiondistance. Numerous studies have found that hypoxia, especially its temporal fluctuation, leads to enhanced tumormetastasis and resistance to radiation and drugs. Strategies to reduce hypoxia by increasing delivery of oxygenand decreasing oxygen consumption within the tumor are both being explored to overcome hypoxia-inducedresistance to radiation and drugs. Therefore, there is growing demand for technologies that noninvasivelymeasure tumor oxygenation temporally in vivo to enable advances in drug screening, development andoptimization. However, the relative contributions of chronic hypoxia and cycling hypoxia (CH) as well as thetherapeutic responses are difficult to determine primarily due to the lack of a noninvasive tool to continuouslyquantify the temporal profile of tumor hypoxia in vivo. We have recently developed a side-firing fiber optic sensorand a 1st generation (GEN-1) frequency-domain near-infrared spectroscopy (FD-NIRS) for quantification of tissueoxygenation and total hemoglobin content in model tumors. The flat sensor can be easily and reliably attachedto a tumor surface and thus is an ideal tool for longitudinal monitoring of rodent tumor models and studying anti-hypoxia drugs in vivo.The objective of the proposed project is to develop a 2nd generation (GEN-2) FD-NIRS instrument with improvedspeed and throughputs and validate it for longitudinal assessment of tumor hypoxia and the efficacy ofchemoradiotherapy. We hypothesize that 1) the temporal profiles of hypoxia vary in different breast tumors and2) biguanide drugs (e.g., metformin or phenformin) can reduce the oxygen consumption of breast cancer cells,thus improving their radiosensitivity. The following specific aims will be conducted to test the hypotheses: (1) toconstruct a 2nd generation FD-NIRS instrument with 10x speed and 15-dB better throughputs; (2) to quantify thecharacteristics of tumor hypoxia in orthotopic models of breast cancer; and (3) to assess the efficacy of metforminand irradiation in orthotopic models of breast cancer using the GEN-2 device. Our long-term goal is to developa portable/wearable, low-cost FD-NIRS device that can aid in development and optimization of anti-hypoxiadrugs and chemoradiotherapy. The successful completion of the aims will not only generate new knowledgeabout tumor hypoxia and lay the foundation for subsequent clinical studies to further delineate the role of hypoxiain cancer therapy, but also will enhance the biophotonics research and education at Marquette University.
This research is aimed at developing a noninvasive optical spectroscopy device for continuous assessment oftumor hypoxia and its response to chemoradiotherapy. Specifically; this research develops a secondgeneration frequency-domain near-infrared spectroscopy system with faster speed and improved throughputand validates it for longitudinal assessment of natural hypoxia in orthotopic tumor models of breast cancer andthe efficacy of anti-hypoxia drugs and irradiation in vivo. Tumor hypoxia (lack of oxygen) is an importantcharacteristic of solid tumors and has been long recognized as a major catalyst in the development of tumorresistance to radiation and chemotherapy. Being able to noninvasively and cost-effectively quantify thetemporal profile of tumor oxygenation in vivo will undoubtedly promote the development of optimized andindividualized cancer therapy as well as advance our knowledge about tumor hypoxia.
| Benej, Martin; Hong, Xiangqian; Vibhute, Sandip et al. (2018) Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Proc Natl Acad Sci U S A 115:10756-10761 |
