Photodynamic therapy (PDT) is approved or in clinical trials for the local treatment of numerous types of malignancies. In the previous funding cycle, detailed spatial analyses of rodent tumors were performed to define the interaction between PDT and tumor physiological properties, including oxygenation and blood flow. These data demonstrate that PDT outcome can be predicted based on individualized monitoring of tumor blood oxygenation or blood flow and thus serve to confirm the therapeutic relevance of intertumor and intratumor heterogeneity. In the renewal of this application, the structural and functional properties of tissue vasculature (vascular microenvironment) will be studied for their effect on cellular, vascular, and molecular responses to PDT. Studies are designed to test the hypothesis that the vascular microenvironment and its accompanying vasoreactivity are effectors of tumor response to PDT. The ability of vascular microenvironment to affect PDT outcome opens the door to methods of altering vascular response in specific vessel types, such as mature vessels, in order to improve treatment efficacy. Accordingly, PDT will be combined with pharmacological modifiers of mature vascular function in an effort to benefit outcome. In clinical studies, the association between vascular maturity and PDT outcome will be investigated for biopsies of non-small cell lung cancer and ovarian cancer from the patients of PDT clinical trials. The studies proposed herein will be performed using many standard biological assays, as well as custom-designed technologies, of which we have substantial experience. Quantitative image analysis of immunohistochemically-stained sections will be used to define vascular microenvironment and PDT effect on spatial distributions of tumor oxygenation and vascular damage. Noninvasive optical spectroscopy (diffuse optical spectroscopy) will be used to longitudinally monitor tumor physiological processes such as oxygenation and blood flow over the course of treatment. Using these techniques the following specific aims will be addressed:
Specific Aim 1. To define how vascular microenvironment affects tumor physiological and cytotoxic responses to PDT.
Specific Aim 2. To define how modulation of vasoreactivity during PDT affects tumor and normal tissue responses.
Specific Aim 3. To explore the association between vascular microenvironment and therapeutic outcome in patients treated with PDT. PUBLIC HEALTH RELEVENCE: The data generated in this proposal will define the effect of vascular microenvironment on vascular, cellular, and therapeutic responses to photodynamic therapy (PDT), and determine how therapeutic outcome may be benefited by modulation of vasoresponse during illumination. The vascular reactivity of mature blood vessels during PDT will be altered using common clinical pharmacological agents, which makes this approach toward therapy optimization highly clinically relevant. In parallel with the preclinical studies, clinical investigation will address the question of how vascular microenvironment affects patient response to PDT, thus providing necessary groundwork for the design of a clinical trial combining PDT with drugs that alter mature vessel reactivity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085831-10
Application #
8228102
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Wong, Rosemary S
Project Start
2000-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
10
Fiscal Year
2012
Total Cost
$299,178
Indirect Cost
$109,224
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
Ceroni, Paola; Lebedev, Artem Y; Marchi, Enrico et al. (2011) Evaluation of phototoxicity of dendritic porphyrin-based phosphorescent oxygen probes: an in vitro study. Photochem Photobiol Sci 10:1056-65
Esipova, Tatiana V; Karagodov, Alexander; Miller, Joann et al. (2011) Two new "protected" oxyphors for biological oximetry: properties and application in tumor imaging. Anal Chem 83:8756-65
Marotta, Diane E; Cao, Weiguo; Wileyto, E Paul et al. (2011) Evaluation of bacteriochlorophyll-reconstituted low-density lipoprotein nanoparticles for photodynamic therapy efficacy in vivo. Nanomedicine (Lond) 6:475-87
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
Busch, Theresa M; Xing, Xiaoman; Yu, Guoqiang et al. (2009) Fluence rate-dependent intratumor heterogeneity in physiologic and cytotoxic responses to Photofrin photodynamic therapy. Photochem Photobiol Sci 8:1683-93
Patel, Hiral; Mick, Rosemarie; Finlay, Jarod et al. (2008) Motexafin lutetium-photodynamic therapy of prostate cancer: short- and long-term effects on prostate-specific antigen. Clin Cancer Res 14:4869-76
Wang, Hsing-Wen; Rickter, Elizabeth; Yuan, Min et al. (2007) Effect of photosensitizer dose on fluence rate responses to photodynamic therapy. Photochem Photobiol 83:1040-8
Busch, Theresa M (2006) Local physiological changes during photodynamic therapy. Lasers Surg Med 38:494-9

Showing the most recent 10 out of 17 publications