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
Kim, Michele M; Darafsheh, Arash; Ahmad, Mahmoud et al. (2016) PDT Dose Dosimeter for Pleural Photodynamic Therapy. Proc SPIE Int Soc Opt Eng 9694:96940Y
Sterman, Daniel H; Alley, Evan; Stevenson, James P et al. (2016) Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNα Combined with Chemotherapy. Clin Cancer Res 22:3791-800
Ong, Yi Hong; Zhu, Timothy C (2016) Analytic function for predicting light fluence rate of circular fields on a semi-infinite turbid medium. Opt Express 24:26261-26281
Ghogare, Ashwini A; Miller, Joann M; Mondal, Bikash et al. (2016) Fluorinated Photodynamic Therapy Device Tips and their Resistance to Fouling for In Vivo Sensitizer Release. Photochem Photobiol 92:166-72
Grossman, Craig E; Carter, Shirron L; Czupryna, Julie et al. (2016) Fluence Rate Differences in Photodynamic Therapy Efficacy and Activation of Epidermal Growth Factor Receptor after Treatment of the Tumor-Involved Murine Thoracic Cavity. Int J Mol Sci 17:
Penjweini, Rozhin; Kim, Michele M; Dimofte, Andrea et al. (2016) Deformable medical image registration of pleural cavity for photodynamic therapy by using finite-element based method. Proc SPIE Int Soc Opt Eng 9701:970106
Zhu, Timothy C; Lu, Amy; Ong, Yi-Hong (2016) An improved analytic function for predicting light fluence rate in circular fields on a semi-infinite geometry. Proc SPIE Int Soc Opt Eng 9706:97061D
Penjweini, Rozhin; Kim, Michele M; Liu, Baochang et al. (2016) Evaluation of the 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) mediated photodynamic therapy by macroscopic singlet oxygen modeling. J Biophotonics 9:1344-1354
Penjweini, Rozhin; Kim, Michele M; Finlay, Jarod C et al. (2016) Investigating the impact of oxygen concentration and blood flow variation on photodynamic therapy. Proc SPIE Int Soc Opt Eng 9694:
Gemmell, Nathan R; McCarthy, Aongus; Kim, Michele M et al. (2016) A compact fiber-optic probe-based singlet oxygen luminescence detection system. J Biophotonics :

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