During the previous grant, we successfully completed research on the effects of photodynamic therapy (PDT) on tumor oxygenation and blood flow, with a focus on the treatment-altering consequences of PDT- triggered vasoreactivity during illumination. These studies have identified microenvironmental characteristics such as vessel size and association with extracellular matrix to be response-altering in PDT. Our proposed investigations will build on these findings to more specifically delineate the role of extracellula matrix (ECM) in tumor and vessel responses to PDT, and to assess, both pre-clinically and clinically, how other therapeutic interventions can alter tumor vasculature, potentially creating a more PDT-responsive microenvironment. We hypothesize that tumor ECM is an effector of PDT outcome that can be modulated to improve treatment responsiveness. In studies directed toward this hypothesis, Aim 1 will employ in vitro cultures of endothelial or tumor cells grown on matrix-coated dishes, together with confirmatory studies in animal tumors, to define the mechanisms by which PDT of ECM increases treatment-induced cytotoxicity~ changes in adhesion-dependent survival signaling upon PDT of ECM-associated cells will specifically be considered, as will the anti- angiogenic/angiogenic effect of PDT of ECM.
Aim 2 will test promising approaches to favorably alter ECM deposition in tumors prior to PDT. We will determine if anti-angiogenics or other vessel-modifying drugs can be applied as vascular normalizing agents to increase the sensitivity of tumor vessels to PDT. Also, in another approach, we will evaluate if increases in ECM deposition stimulated by radiation can be exploited by PDT to treat tumors that failed radiation therapy.
Aim 3 will be based in clinical samples for the purposes of studying radiation effects and PDT dependencies on tumor ECM in human malignancies. We will determine the ECM characteristics of radiation-recurrent disease, with a particular focus on collagen IV deposition (chosen based pre-clinical results). Using banked tissue from a completed trial of PDT for peritoneal malignancies, we will confirm the clinical relevance of ECM deposition (including collagen IV) to PDT outcome. In this regard, preliminary data identify the time-to-recurrence after PDT to be longer in patients whose tumors expressed more collagen. In summary, the overall goals of our proposal are to define the mechanisms by which tumor ECM, and in particular the collagen of vascular basement membrane affects outcome to PDT~ to develop clinically-relevant approaches toward priming tumors for PDT through modulation of ECM levels~ and to confirm the relevance of ECM deposition to clinical response to PDT. We will study the ECM of radiation- recurrent tumors because our pre-clinical and clinical data show increased collagen IV deposition in these tumors, and the addition of PDT as second-line therapy for radiation recurrences could be a straightforward and highly effective approach to exploit ECM dependencies in PDT responsive for the benefit of patients who otherwise have limited therapy choices.
Tumor microenvironment, including abnormalities in the structure and function of its blood vessels, represent a major limitation in the successful application of many treatments, including photodynamic therapy (PDT). We have identified specific components of vascular extracellular matrix (ECM) that affect PDT, and propose to study the mechanisms by which tumor ECM alters responsiveness to therapy, as well as define approaches by which it can be altered to be more responsive to PDT. One such approach involves taking advantage of the expected increases in tumor ECM after recurrence to definitive radiation~ ultimately, the addition of PDT as a second-line therapy based on ECM expression in radiation-recurrent tumors would embody a rationally-designed and stepwise approach to treatment that actually exploits the 'failed' radiation response to provide for more effective treatment by another modality (i.e. PDT) in patients who otherwise have limited therapy choices.
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