The Hasan Program Project

Molecular Response and Imaging-based Combination Strategies for Optimal PDT

This is a summary of the Program Project Grant's (P01) annual report for 2010.

Project 1 

Small Molecule Enhancers of Photodynamic Therapy for Skin Cancer. Project leader:  Edward Maytin, M.D. Ph.D.


Specific Aims
    1.  Preclinical studies of nonmelanoma skin cancer (NMSC), i.e., mouse models of human SCC and murine BCC, to establish parameters for tumor preconditioning with methotrexate and Vitamin D.

    2.     Clinical pilot studies

                            (2a):     PpIX microanatomical distribution patterns in different histological subtypes of NMSC.

                            (2b):     Dosimetry tools: To develop a 2-D fluorescence tomographic system to detect PpIX in tumors.

                            (2c):     C/EBP factors as surrogate markers for response to PpIX enhancers in BCC.

    3.     Clinical trial of combination therapy using differentiation-modulating agents and ALA-PDT.

    4.     Mechanistic studies on the role of C/EBP as markers of responsiveness to differentiating agents.

    Publications 

      1. Anand S, Atanaskova N, Wilson C, Hasan T, Maytin EV. Enhancement of protophorphyrinIX and suppression of ferrochelatase levels by  Vitamin D in tumor models of nonmelanoma skin cancer: Implications for tumor response to photodynamic therapy. J Invest Dermatol 2010; 130 (Suppl 1); S137.
      2. Maytin EV, Anand S, Atanaskova N, Wilson C.  Vitamin D as a potential enhancer of aminolevulinate-based photodynamic therapy for nonmelanoma skin cancer.  In: Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XIX, edited by David Kessel,  Proc of SPIE (Intl Soc Optical Engineer). Vol. 7551   [DOI: 10.1117/12.847183].
      3. Warren CB, Lohser S, Wene LC, Pogue BW, Bailin PL, Maytin EV.  Noninvasive fluorescence dosimetry to define protoporphyrin IX production rates in actinic keratoses  ollowing short-contact application of 5-aminolaevulinate (J Biomedical Optics, 2010 Dec issue in press).
      4. GruberJD, Paliwal A, Maytin EV, Hasan T, Pogue BW.  System development for high frequency ultrasound-guided fluorescence quantification of skin layers. Journal of Biomedical Optics, 2010; 15(2) March/April, Issue 026028, 1-5.  [DOI: 10.1117/1.3374040].
      5. Paliwal A, Gruber JD, O'Hara JA, Pogue BW, Hasan T, Maytin EV. Development and validation of a high frequency ultrasound-guided fluororescence tomography system to improve targeting of photodynamic therapy of skin tumors. J Invest Dermatol 2010; 130 (Suppl 1); S131.

        Project 2

        The significance of this project is that it will define the place of PDT in the treatment of non-resectable biliary tract cancer, and investigate a potential new indication for PDT in pancreatic cancer.

        Specific Aims

          1. Does Porfimer sodium PDT improve survival in non-resectable biliary tract cancer (phase III)?

          To determine whether porfimer sodium PDT confers an additional survival benefit over biliary stenting alone in patients with locally advanced or metastatic non-resectable biliary tract carcinoma (BTC). The primary endpoint is overall survival, with secondary endpoints of progression free survival, toxicity and quality of life. Aim 1b: To collect fluorescence (Aurora) data endoscopically (joint with Core C) at the time of PDT, to study the relationship between drug distributions and treatment response in this cancer.

           

          2.  Can Verteporfin PDT can achieve safe and effective necrosis in locally advanced, unresectable pancreatic carcinoma (phase I/II)?

          To determine, in a phase I light dose escalation study, the optimum light dose needed to achieve an appropriate volume of tumor necrosis, as assessed by contrast-enhanced CT (RECIST criteria), around a single treatment location. As part of standard practice, patients will also be offered palliative chemotherapy. Dosimetry measurements from this study will be used to validate the treatment planning of the next phase. Aim 2b: To perform a non-randomized phase II study of verteporfin PDT, using multiple fiber locations under CT guidance and a fixed light dose at each site (determined in Aim 2a), followed by palliative chemotherapy. The clinical endpoints of the study will be: (i) tumor response (by RECIST criteria), (ii) time to disease progression and progression-free survival (PFS), and (iii) quality of life.

            Publications

              1. Pereira SP, Ayaru L, Ackroyd R, Mitton D, Fullarton G, Zammit M, Butruk E, Grzebieniak Z, Messmann H, Ortner MA, Gao L, Sayyarpour F, Trinh M, Spénard J. The pharmacokinetics and safety of porfimer after repeated administration 30-45 days apart to patients undergoing photodynamic   therapy. Aliment Pharmacol Therapy 2010; 32(6): 821-827. PM
              2. Samkoe KS, Chen AA, Rizvi I, O'Hara JA, Hoopes PJ, Pereira SP, Hasan T, Pogue PW. Imaging tumor variation in response to photodynamic   therapy in pancreatic cancer xenograft models. Internat J Rad Onc Biol Phys 2010; 1:251-9 PMCID: PMC2902770
              3. Matull WR, Dhar DK, Ayaru L, Sandanayake NS, Chapman MH, Dias A, Bridgewater J, Webster GJM, Bong JJ, Davidson BR, Pereira SP. R0 butnot R1/R2 resection is associated with better survival than palliative photodynamic therapy in biliary tract cancer. Liv Internat 2010 Sep 16 [Epub ahead of print].
              4. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M,             Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273-81.

                Project 3

                The overall goal of this Project is to develop mechanism-based PDT combination regimens to enhance the efficacy of PDT in preclinical models of pancreatic cancer (PanCa). The overall hypothesis to be tested in this study is that PDT combined with an additional therapy specific to the particular molecular response to PDT, will synergistically enhance treatment efficiency.

                Specific Aims
                1. Can we identify PDT-related molecular targets for combination treatments?The effect of PDT on selected molecular processes will be investigated in physiologically relevant 3-D organotypic cultures.
                2. What are the optimal PDT parameters and potential molecular targets for CPBT in vivo? PDT parameters will be optimized for maximum response in an orthotopic PanCa model
                3. Can mechanism-based PDT combinations enhance treatment outcomes orthotopic models in vivo? Combinations of PDT and targeted therapies will be tested in the orthotopic murine PanCa model guided by the initial selection of biological agents from Aim 1 and by in vivo PDT parameters and molecular target selection from Aim 2. Short term primary tumor burden as well metastasis to lungs, lymph nodes and liver will be the end points to establish the most effective sequence and agent for each molecular target.

                Publications

                1.    Celli JP, Rizvi I, Evans CL, Abu-Yousif AO, Hasan T. Quantitative imaging reveals heterogeneous growth dynamics and treatment-dependent residual tumor distributions in a 3D model for ovarian cancer. Journal of Biomedical Optics (2010), Vol 15(5), September 2010

                2.    Rizvi I, Celli JP, Evans CL, Abu-Yousif AO, Hasan T. Carboplatin efficacy enhanced synergistically by PDT in a 3D model of micrometastatic ovarian cancer. Cancer Research (2010) In Press.        .

                3.    Jonathan P. Celli, Imran Rizvi, Conor Evans, Adnan Abu-Yousif, Tayyaba Hasan. 3D ovarian cancer models: imaging and therapeutic combinations.  Proc. SPIE Vol. 7551, Paper 7551-17 DOI: 10.1117/12.843279

                4.    Conor L. Evans; Imran Rizvi; Jonathan Celli; Adnan Abu-Yousif; Johannes de Boer; Tayyaba Hasan. Visualizing photodynamic therapy response with time-lapse OCT in an in vitro model of metastatic ovarian cancer. Proc. SPIE Vol. 7551, Paper 7551-18 DOI: 10.1117/12.843271

                5.    Celli JP, Spring BQ, Rizvi I, Evans CL, Samkoe KS, Verma S, Pogue BW, Hasan T. Imaging and     Photodynamic Therapy: Mechanisms, Monitoring and Optimization. Chemical Reviews (2010); Vol. 110 (5), 2795–2838. PMID: 20353192, PMCID: PMC2896821

                Project 4

                Specific Aims

                  1.  Can spectral imaging be used to quantify biophysical changes in orthotopic tumors, to allow non-invasive monitoring of therapeutic              response?

                  • This hypothesis will be tested through use of multiwavelength spectral imaging in a pre-clinical animal model of pancreas cancer. The properties which can be measured with this system are related to the vascular compartment (hemoglobin and oxygen saturation) and cellular/stromal     compartments (water and sub-cellular granularity leading to scatter) of the tissue.
                  • The NIR spectral image properties hemoglobin, oxygen saturation, water and scatter will be quantitatively compared to ex vivo microscopy of the same tissues, to independently validate the biological meaning of the images.

                   

                  2.  Can sub-surface NIR fluorescence imaging be implemented in a way which provides quantification of PS concentration in tissue layers?

                  • This hypothesis will be tested in skin and skin tumors through development of a hybrid system approach for in vivo imaging. A multi-strand optical fiber system combined with high frequency ultrasound (HFUS) will be tested. This will be used for PPIX fluorescence quantification, and if successful would augment the Aurora dosimeter by giving spatially resolved information about the PS concentration in skin, having different depth-of-penetration characteristics.
                  • A HFUS system combined with the multi-strand optical fiber system will be used to quantify PPIX fluorescence in layers of tissues, up to 1 cm     thick.
                  • Study of spectral signatures using phantoms, skin raft cultures and skin tumor models, to evaluate the accuracy of the concentration versus         different thicknesses and geometries, to be done collaboratively with Project 1.

                   

                  3. Could the methods developed in Aims 1 and 2 be combined with temporal analysis, to study the use of individualized therapy delivery, as     well as better understand the causes of interanimal variation in drug uptake?

                  • To answer this question this aim will use the experiences and tools developed in the previous two aims to study the feasibility, and first demonstrate correlation between pre-light drug concentration and the treatment effect. This will then lead to individualized light delivery based upon PS imaging.
                  • Establish the accuracy of using online tomographic estimation photosensitizer concentration to predict the response to therapy, and adjust the     light dose to reduce inter-subject variability.

                    Publications

                      1. Pogue BW, Samkoe KS, Hextrum S, O'Hara JA, Jermyn M, Srinivasan S, Hasan T.”Imaging targeted-agent binding in vivo with two probes.” J Biomed Opt. 2010 May-Jun;15(3):030513.PMID: 20614996 
                      2. Gruber JD, Paliwal A, Krishnaswamy V, Ghadyani H, Jermyn M, O'Hara JA, Davis SC, Kerley-Hamilton JS, Shworak NW, Maytin EV, Hasan T, Pogue BW. “System development for high frequency ultrasound-guided fluorescence quantification of skin layers.” J Biomed Opt. 2010 Mar-Apr;15(2):026028.PMID: 20459273
                      3. Samkoe KS, Chen A, Rizvi I, O'Hara JA, Hoopes PJ, Pereira SP, Hasan T, Pogue BW. “Imaging tumor variation in response to photodynamic therapy in pancreatic cancer xenograft models.” Int J Radiat Oncol Biol Phys. 2010 Jan 1;76(1):251-9.PMID: 20005458
                      4. Brian W. Pogue, Subhadra Srinivasan, Kimberley Samkoe, Lei Zak Zheng, Prakash Rai, Zhiming Mai, Sarika Verma, and Tayyaba Hasan Analytic modeling of antibody versus nanocell delivery of photosensitizer Proc. SPIE 7551, 755117 (2010)
                      5. Kimberley S. Samkoe, Scott C. Davis, Subhadra Srinivasan, Martin E. Isabelle, Julia O'Hara, Tayyaba Hasan, and Brian W. Pogue  EGF targeted fluorescence molecular tomography as a predictor of PDT outcomes in pancreas cancer models Proc. SPIE 7551, 75510Q (2010)
                      6. Kimberley S. Samkoe, Shannon K. Hextrum, Omar Pardesi, Julia A. O'Hara, Tayyaba Hasan, and Brian W. Pogue Specific binding of molecularly targeted agents to pancreas tumors and impact on observed optical contrast Proc. SPIE 7568, 75680H (2010)
                      7. Kimberley S. Samkoe, S. K. Hextrum, H. H. Yang, K. Sexton, S. Srinivasan, J. A. O’Hara, T. Hasan, B. W. Pogue, “Quantitatively determining binding of targeted agents in vivo by imaging dual-probe injection can improve efficacy of therapeutic agent delivery” 8th Int. Symp. Photodynamic Therapy and Photodiagnosis in Clinical Practice, Brixen Italy (Oct 2010)
                      8. M. Isabelle, W. S. Klubben, T. He, V. Krishnaswamy, J. A. O'Hara, P. J. Hoopes, S. Pereira, C. A. Mosse, Tayyaba Hasan, Brian W. Pogue,  “Compensated PDT light dose determined by target tissue photosensitizer dosimetry using light-induced fluorescence spectroscopy demonstrates increased efficacy of verteporfin-PDT in xenograft pancreatic cancer”, 8th Int. Symp. Photodynamic Therapy and Photodiagnosis in Clinical Practice, Brixen Italy (Oct 2010)

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