PROJECT 1 ABSTRACT Project 1 will develop combination photodynamic therapy (cPDT) for non-melanoma skin cancers (NMSC), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). NMSC are currently treated by surgical excision, but better alternatives are needed, especially for organ transplant patients who develop frequent and aggressive SCC, and for Basal Cell Nevus Syndrome patients who develop hundreds of BCCs. Previously, we discovered that biochemical manipulation with differentiating agents (methotrexate, vitamin D [Vit D], and 5-fluorouracil [5-FU]) enhances heme pathway activity and protoporphyrin IX (PpIX) accumulation. Those findings will now be translated into improved efficacy in the clinic.
AIM 1 will examine cPDT for SCC (the most lethal NMSC) using topical 5-FU prior to ALA and blue light. This is a clinical trial to test whether the combination improves efficacy for SCC in-situ in patients at high risk for aggressive NMSC (patients with organ transplants, or highly photodamaged skin). Skin biopsies and blood will be saved for use in Aim 3.
AIM 2 will investigate cPDT for BCC (the most prevalent of all cancers). PDT is hampered by a nonhomogeneous photosensitizer (PpIX) distribution in tumors, but Vit D pretreatment induces a more homogenous distribution. Patients with BCC will be pretreated with 5-FU, Vit D, or placebo followed by ALA for 4 hr. A skin biopsy will be taken to assess PpIX distribution; tumors will then be treated with red light. Histological clearance of tumors at 3 months will be confirmed by surgical excision.
AIM 3 will investigate new cPDT approaches and new assays to help individualized patient treatments. Liposomal targeting nanoconstructs from Project 3 will be used to deliver small molecule inhibitors against EGFR or VEGF/c-Met (along with photosensitizer BPD) in preclinical models of BCC skin cancer, including a BCC skin explant model from Ptch1 +/- mice. The predictive value of noninvasive monitoring of PpIX in patient skin (using optical tools developed in Project 4), and of measuring p53 levels and thymidine synthase gene alleles, will be tested by correlation with lesion clearance rates in the clinical studies. The preclinical studies will improve understanding of mechanisms and suggest future approaches to individualize the treatments and maximize therapeutic responses to cPDT.

Public Health Relevance

PROJECT 1 NARRATIVE Translation of novel approaches to combination photodynamice therapy, originating from discoveries in the previous round and expanded into clinical trials here (along with additional preclinical experiments), could significantly benefit patients with numerous and recalcitrant skin cancers that cannot be otherwise adequately treated.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Massachusetts General Hospital
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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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