In our initial grant, we proposed to optimize intraperitoneal PDT to deal with tumors involving the peritoneal surface. We showed that IP-PDT to the peritoneum was feasible and tolerable, with acceptable toxicity but marginal efficacy. We demonstrated that IP-PDT has a narrow therapeutic ratio reflecting relatively poor ratios of tumor to normal tissue retention of Photofrin. In this renewal, we will study the biological and molecular enhancement of the PDT process by blocking EGF receptor. Preclinical studies show EGFR blockade in combination with PDT improves cytoxicity without increasing normal tissue toxicity. This suggests that inhibiting signal transduction after PDT can improve the therapeutic index of IP-PDT and yield more efficacy without toxicity. In Project 1, we will optimize IP-PDT by using a second generation photosensitizer (BPD) in combination with cetuximab to alter signal transduction in human tumors and thus enhance the therapeutic index of IP-PDT. Project 2 aims to optimize serosal PDT by inhibiting relevant components of signal transduction pathways. This project will define the impact of inhibiting EGF signaling on cytotoxicity and mechanisms of cell death following BPD mediated PDT of ovarian and lung cancer cells. We will use small molecules/antibody inhibitors and siRNA to inhibit EGF receptor and post-receptor signaling pathways. We will study both sequence and timing of PDT and growth factor pathway inhibition to maximize this synergistic effect. Project 3 will study the microenvironmental effects of PDT combined with targeted molecular therapy. We will define the relationship between tumor microenvironment and PDT outcome, with specific attention to the AKT signal transduction pathway looking at Avastin, C225 and nelfinavir. In Project 4, we will look at real-time optical diagnostics of tissue for PDT dosimetry and treatment with major emphasis on characterizing tumor microenvironment brought about by biological targeting while assessing our dosimetry. We have added a new Project 5, of IP-PDT for lung cancer presenting with pleural carcinomatosis. This work has gone on in parallel with our grant but not funded. Our clinical results appear to validate the concept of PDT for treatment of surface malignancies. This program project grant is largely translational and offers a novel and potentially effective therapy for cancers involving serosal surfaces.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA087971-10
Application #
8220975
Study Section
Special Emphasis Panel (ZCA1-GRB-P (O1))
Program Officer
Wong, Rosemary S
Project Start
2000-07-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
10
Fiscal Year
2012
Total Cost
$1,552,554
Indirect Cost
$564,592
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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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