Project 4: Photodynamic therapy (PDT) can produce local ischemia during illumination that leads to treatment-limiting hypoxia. Ischemia and hypoxia can limit direct cytotoxicity, as well as alter other aspects of PDT response, for example, effects on signal transduction and immune responses have been documented. Thus, tumor microenvironment during illumination is critical to multiple facets of PDT response that collectively determine therapeutic efficacy. Preliminary data from our clinical trial of pleural-PDT (p-PDT) for mesothelioma detect response-altering ischemia during illumination. P-PDT did not control local recurrence, despite improvement in survival, which could indicate microenvironment-induced limitations in cytotoxicity. In agreement, we measured decreases in local concentrations of total and oxygenated hemoglobin during illumination, respectively indicating treatment-induced ischemia and hypoxia. Furthermore, the addition of surgery to PDT could alter microenvironment because surgery induces the systemic release of pro-inflammatory and vasoactive cytokines. In particular, we found IL-6 induction by surgery to correlate with hypoxia development in thoracic tissues during their subsequent illumination. From these data, we hypothesize that vascular response to intraoperative PDT of the mesothelioma-involved thoracic cavity will determine treatment outcome. Studies will be performed as a part of our Phase II, p-PDT trial, as well as in murine models of intrathoracic and intraoperative PDT.
Aim 1 will ascertain the vascular microenvironment of mesothelioma in patients and evaluate the clinical relevance of procedure-induced hemodynamic change. Our goals include assessment of the vascularization of mesothelioma;measurement of PDT-induced changes in vascular function;and definition of how these factors correlate with local control, toxicities, and survival in p-PDT.
Aim 2 will determine how vascular responses contribute to the efficacy of intraoperative PDT in murine models of mesothelioma.
This Aim will define the consequences of thoracic illumination and surgery-induced cytokine signaling on vessel response to PDT, the importance of this damage to outcome, and the potential to modulate vascular response during p-PDT for therapeutic benefit.
Project 4 From these studies, we will define how vascular damage during intraoperative PDT of large surface areas contributes to multiple aspects of PDT response. These data will be the first of their kind to explore how surgery determines acute vessel response and accompanying therapeutic outcome to PDT. Results will be generalizable to a wide range of PDT applications that are performed in the context of surgery, and will inform on methods to improve existing or develop new protocols that combine surgery with PDT.
|Simone 2nd, Charles B; Cengel, Keith A (2014) Photodynamic therapy for lung cancer and malignant pleural mesothelioma. Semin Oncol 41:820-30|
|Han, Sung Wan; Mesquita, Rickson C; Busch, Theresa M et al. (2014) A Method for Choosing the Smoothing Parameter in a Semi-parametric Model for Detecting Change-points in Blood Flow. J Appl Stat 41:26-45|
|Liang, Xing; Wang, Ken Kang-Hsin; Zhu, Timothy C (2013) Feasibility of interstitial diffuse optical tomography using cylindrical diffusing fibers for prostate PDT. Phys Med Biol 58:3461-80|
|Maas, Amanda L; Carter, Shirron L; Wileyto, E Paul et al. (2012) Tumor vascular microenvironment determines responsiveness to photodynamic therapy. Cancer Res 72:2079-88|
|Friedberg, Joseph S; Culligan, Melissa J; Mick, Rosemarie et al. (2012) Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma. Ann Thorac Surg 93:1658-65; discussion 1665-7|
|Grossman, Craig E; Pickup, Stephen; Durham, Amy et al. (2011) Photodynamic therapy of disseminated non-small cell lung carcinoma in a murine model. Lasers Surg Med 43:663-75|
|Sandell, Julia L; Zhu, Timothy C (2011) A review of in-vivo optical properties of human tissues and its impact on PDT. J Biophotonics 4:773-87|
|Busch, Theresa M; Wang, Hsing-Wen; Wileyto, E Paul et al. (2010) Increasing damage to tumor blood vessels during motexafin lutetium-PDT through use of low fluence rate. Radiat Res 174:331-40|
|Wang, Ken Kang-Hsin; Finlay, Jarod C; Busch, Theresa M et al. (2010) Explicit dosimetry for photodynamic therapy: macroscopic singlet oxygen modeling. J Biophotonics 3:304-18|
|Busch, Theresa M (2010) Hypoxia and perfusion labeling during photodynamic therapy. Methods Mol Biol 635:107-20|
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