The broad, long-term goal of this application is to optimize serosal photodynamic therapy (PDT) through the inhibition of relevant components of the signal transduction pathways thereby improving the outcome of patients with pleural and peritoneal spread of cancers. Activation of the epidermal growth factor receptor (EGFR) signaling pathway is thought to limit the effectiveness of PDT as a therapeutic approach. Preliminary data suggest that inhibition of EGFR will increase the therapeutic index of PDT, increasing tumor cell kill without a concomitant increase in normal tissue toxicity. Moreover, while PDT is thought to kill cells primarily through apoptotic mechanisms, augmentation of cancer cell death through inhibition of EGFR signaling may occur through stimulation of necrotic/non-apoptotic cell death pathways. Therefore, this project will focus on defining and characterizing the impact of inhibiting growth factor signaling on the signaling, cytotoxicity and mechanisms of cell death following BPD-mediated PDT of ovarian and lung cancer cells. To maximize the external validity, generalizabilitv and clinical applicability of these findings, experiments will be performed using a panel of ovarian cancer (QvCa) and non-small cell lung cancer (NSCLC) cell lines that includes OVCAR-5 and H460 and also using OVCAR-5 and H460 tumor xenografts. We will use chemical inhibitors and siRNA to inhibit EGFR and its post-receptor signaling partners to investigate the molecular mechanism by which the inhibition of EGFR signaling enhances BPD-mediated PDT cytotoxicity. We will also examine the sequencing and timing PDT and EGFR pathway inhibition in order to maximize the enhancement of BPD-mediated PDT cvtotoxicitv. The specific endooints that will be analyzed in these studies are: 1) Levels and activation of EGFR and related signaling proteins 2} The nucleo-cvtoplasmic distribution of EGFR and its association with nuclear STAT3: 3) The clonogenic survival of cells and tumors. Lastly, we will determine the effect of modulating growth factor signaling on the mechanism of cell death following BPD-mediated PDT in order to further characterize this novel treatment approach and to further identify areas for enhancement of cytotoxicity. The specific endpoints that will be analyzed in these studies are: 1) The percent of cells with apoptotic vs necrotic cell death pheotvpes;2} The expression and activation of cell death-related proteins: 3) The effect on p53. Bax and Bak protein expression on clonogenic cell survival and the percent of cells with apoptotic vs necrotic ceil death pheotypeslhese studies should help us to understand the potential clinical application of combination PDT + growth factor inhibition as a therapeutic approach for patients with serosal malignancies. Given the extremely poor prognosis for patients with spread of either ovarian cancer within the abdominal cavity or NSCLC within the chest cavity, successful clinical application of this treatment approach could lead to a new standard of clinical care in these populations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA087971-09
Application #
8219259
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
9
Fiscal Year
2011
Total Cost
$200,288
Indirect Cost
Name
University of Pennsylvania
Department
Type
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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