The complex cancer genetics and the multiple pathways operational in cancer motivate the fundamental hypothesis of this Program: Combination therapies that are mechanistically complementary and directed at non-overlapping molecular targets and pathways will significantly advance cancer treatment outcomes. The current, heavily revised application builds on our own findings, recent advances in the understanding of cancer biology and mechanisms and the progress in imaging technologies, to propose new photodynamic therapy (PDT)-based combination treatments for pancreatic cancer (PanCa) and non-melanoma skin cancers (NMSC). PDT is a photochemistry-based modality that is approved for the treatment of a number of cancer and non-cancer pathologies. Strategically, combinations will be selected such that the first treatment enhances the second. This is achieved by: (i) preconditioning tumors with agents that initiate molecular events that augment PDT and (ii) administering a second treatment specifically tailored to a particular molecular response elicited by the first. This second approach is strengthened by our new nanoconstructs (NCs) capable of simultaneous multi-inhibitor delivery. PDT is a standard component of the combination, while the second modality can be small molecule enhancers, chemo or biologic therapeutics. The choice of the specific combination reagent will be heavily influenced by the likelihood of rapid translation to the clinic in Projects 1 and 2. Toward this gol, we have recruited pharmaceutical industries that are already running clinical trials with reagents that may potentially synergize with PDT. Optical imaging will provide online monitoring of light and photosensitizer dosimetry, treatment planning and molecular response. The Program has 4 projects supported by 3 Cores. Project 1 investigates molecular pathways of small molecules that enhance ALA-PDT to increase therapy response in skin carcinomas in humans. Project 2 uses PDT and combinations ('first in human) to address metastasis in addition to local control by PDT and thus advance the survival and quality of life of patients with PanCa and precancer. Project 3 develops NCs combinations in preclinical models (3D in vitro, orthotopic and genetically engineered mice) to steer clinical studies in Project 2 within the current cycle and, i a more forward looking approach develops targeted multi-inhibitor NCs. Project 4 develops quantitative tools to monitor molecular features of tumor treatment response for integrated dosimetry for standard clinical procedures. Cores provide administration, education, models, instrumentation and technology transfer. Impact: This program positively impacts on the treatment and prevention of two cancers: decreasing mortality and morbidity in PanCa with few therapy options and NMSC with many treatment options but a high incidence, thus putting a heavy societal burden of cost and suffering. These findings could also be translated to other cancers. Scientifically, the tools developed (models, imaging and nanotechnology) provide a platform for the evaluation of new therapeutics and mechanisms.
OF THE PROGRAM OVERVIEW Potential public health benefits: this program impacts on the treatment and prevention of two cancers: decreasing mortality and morbidity in PanCa with few therapy options and an extremely low survival rate and NMSC with many treatment options but a high incidence, thus putting a heavy societal burden of cost and suffering. The mechanistically grounded approach will significantly benefit patient survival and quality of care.
|Pereira, S P; Goodchild, G; Webster, G J M (2018) The endoscopist and malignant and non-malignant biliary obstruction. Biochim Biophys Acta Mol Basis Dis 1864:1478-1483|
|Broekgaarden, Mans; Rizvi, Imran; Bulin, Anne-Laure et al. (2018) Neoadjuvant photodynamic therapy augments immediate and prolonged oxaliplatin efficacy in metastatic pancreatic cancer organoids. Oncotarget 9:13009-13022|
|Huang, Huang-Chiao; Rizvi, Imran; Liu, Joyce et al. (2018) Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery. Cancer Res 78:558-571|
|Huang, Huang-Chiao; Pigula, Michael; Fang, Yanyan et al. (2018) Immobilization of Photo-Immunoconjugates on Nanoparticles Leads to Enhanced Light-Activated Biological Effects. Small :e1800236|
|Wang, Hexuan; Mislati, Reem; Ahmed, Rifat et al. (2018) Elastography can map the local inverse relationship between shear modulus and drug delivery within the pancreatic ductal adenocarcinoma microenvironment. Clin Cancer Res :|
|Obaid, Girgis; Jin, Wendong; Bano, Shazia et al. (2018) Nanolipid Formulations of Benzoporphyrin Derivative: Exploring the Dependence of Nanoconstruct Photophysics and Photochemistry on Their Therapeutic Index in Ovarian Cancer Cells. Photochem Photobiol :|
|Marra, Kayla; LaRochelle, Ethan P; Chapman, M Shane et al. (2018) Comparison of Blue and White Lamp Light with Sunlight for Daylight-Mediated, 5-ALA Photodynamic Therapy, in vivo. Photochem Photobiol 94:1049-1057|
|Pereira, Stephen P; Jitlal, Mark; Duggan, Marian et al. (2018) PHOTOSTENT-02: porfimer sodium photodynamic therapy plus stenting versus stenting alone in patients with locally advanced or metastatic biliary tract cancer. ESMO Open 3:e000379|
|Maytin, Edward V; Kaw, Urvashi; Ilyas, Muneeb et al. (2018) Blue light versus red light for photodynamic therapy of basal cell carcinoma in patients with Gorlin syndrome: A bilaterally controlled comparison study. Photodiagnosis Photodyn Ther 22:7-13|
|Bulin, Anne-Laure; Broekgaarden, Mans; Hasan, Tayyaba (2017) Comprehensive high-throughput image analysis for therapeutic efficacy of architecturally complex heterotypic organoids. Sci Rep 7:16645|
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