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.
|Davis 4th, Richard W; Snyder, Emma; Miller, Joann et al. (2018) Luminol Chemiluminescence Reports Photodynamic Therapy-Generated Neutrophil Activity In Vivo and Serves as a Biomarker of Therapeutic Efficacy. Photochem Photobiol :|
|Cramer, Gwendolyn; Simone 2nd, Charles B; Busch, Theresa M et al. (2018) Adjuvant, neoadjuvant, and definitive radiation therapy for malignant pleural mesothelioma. J Thorac Dis 10:S2565-S2573|
|Ong, Yi Hong; Padawer-Curry, Jonah; Finlay, Jarod C et al. (2018) Determination of optical properties, drug concentration, and tissue oxygenation in human pleural tissue before and after Photofrin-mediated photodynamic therapy. Proc SPIE Int Soc Opt Eng 10476:|
|Ong, Yi Hong; Kim, Michele M; Huang, Zheng et al. (2018) Reactive Oxygen Species Explicit Dosimetry (ROSED) of a Type 1 Photosensitizer. Proc SPIE Int Soc Opt Eng 10476:|
|Zhu, Timothy C; Kim, Michele M; Padawer, Jonah et al. (2018) Light Fluence Dosimetry in Lung-simulating Cavities. Proc SPIE Int Soc Opt Eng 10476:|
|Chandra, Abhishek; Wang, Luqiang; Young, Tiffany et al. (2018) Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis. FASEB J 32:52-62|
|Ong, Yi Hong; Finlay, Jarod C; Zhu, Timothy C (2018) Monte Carlo modelling of fluorescence in semi-infinite turbid media. Proc SPIE Int Soc Opt Eng 10492:|
|Yan, Lesan; Amirshaghaghi, Ahmad; Huang, Dennis et al. (2018) Protoporphyrin IX (PpIX)-Coated Superparamagnetic Iron Oxide Nanoparticle (SPION) Nanoclusters for Magnetic Resonance Imaging and Photodynamic Therapy. Adv Funct Mater 28:|
|Dimofte, Andreea; Finlay, Jarod; Ong, Yi Hong et al. (2018) A quality assurance program for clinical PDT. Proc SPIE Int Soc Opt Eng 10476:|
|Ahn, Peter H; Finlay, Jarod C; Gallagher-Colombo, Shannon M et al. (2018) Lesion oxygenation associates with clinical outcomes in premalignant and early stage head and neck tumors treated on a phase 1 trial of photodynamic therapy. Photodiagnosis Photodyn Ther 21:28-35|
Showing the most recent 10 out of 127 publications