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 #
5P01CA087971-08
Application #
7760165
Study Section
Special Emphasis Panel (ZCA1-GRB-P (O1))
Program Officer
Wong, Rosemary S
Project Start
2000-07-01
Project End
2013-01-31
Budget Start
2010-04-01
Budget End
2011-01-31
Support Year
8
Fiscal Year
2010
Total Cost
$1,706,206
Indirect Cost
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; Ghogare, Ashwini A; Greer, Alexander et al. (2017) On the in vivo photochemical rate parameters for PDT reactive oxygen species modeling. Phys Med Biol 62:R1-R48
Friedberg, Joseph S; Simone 2nd, Charles B; Culligan, Melissa J et al. (2017) Extended Pleurectomy-Decortication-Based Treatment for Advanced Stage Epithelial Mesothelioma Yielding a Median Survival of Nearly Three Years. Ann Thorac Surg 103:912-919
Penjweini, Rozhin; Kim, Michele M; Zhu, Timothy C (2017) Three-dimensional finite-element based deformable image registration for evaluation of pleural cavity irradiation during photodynamic therapy. Med Phys 44:3767-3775
Ahn, Peter H; Finlay, Jarod C; Gallagher-Colombo, Shannon M et al. (2017) 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 :
Yan, Lesan; Miller, Joann; Yuan, Min et al. (2017) Improved Photodynamic Therapy Efficacy of Protoporphyrin IX-Loaded Polymeric Micelles Using Erlotinib Pretreatment. Biomacromolecules 18:1836-1844
Penjweini, Rozhin; Kim, Michele M; Liu, Baochang et al. (2017) Evaluation of the 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) mediated photodynamic therapy by macroscopic singlet oxygen modeling [J. Biophotonics 9, No. 11-12, 1344-1354 (2016)]. J Biophotonics 10:473-474
Kennedy, Gregory Thomas; Newton, Andrew; Predina, Jarrod et al. (2017) Intraoperative near-infrared imaging of mesothelioma. Transl Lung Cancer Res 6:279-284
Zhu, Timothy C; Kim, Michele M; Ong, Yi-Hong et al. (2017) A summary of light dose distribution using an IR navigation system for Photofrin-mediated Pleural PDT. Proc SPIE Int Soc Opt Eng 10047:
Gemmell, Nathan R; McCarthy, Aongus; Kim, Michele M et al. (2017) A compact fiber-optic probe-based singlet oxygen luminescence detection system. J Biophotonics 10:320-326
Kim, Michele M; Penjweini, Rozhin; Zhu, Timothy C (2017) Evaluation of singlet oxygen explicit dosimetry for predicting treatment outcomes of benzoporphyrin derivative monoacid ring A-mediated photodynamic therapy. J Biomed Opt 22:28002

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