Response and Imaging-based Combination Strategies for Optimal PDT

Project Number: 2 P01 CA084203-11A1
Sponsor: NIH/NCI
Award Period: 12/01/1999–12/31/2019

Abstract: 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. This 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). 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 reagents will be heavily influenced by the likelihood of rapid translation to the clinic in Projects 1 and 2. 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 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 NC combinations in preclinical models to steer clinical studies in Project 2 and, in 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.