The long-term goal of my proposal is to explore combination chemotherapies utilizing Photodynamic Therapy (PDT) with the precursor aminolevulinic acid (ALA) to the natural photosensitizer Protoporphyrin IX (PplX). ALA is an early component in the heme synthesis pathway that, through a series of enzymatic conversions becomes PplX. PDT is a minimally invasive cancer treatment which utilizes the interaction between a photoactivatable agent (i.e. PplX), light and oxygen to form reactive oxygen species and cause tissue damage. PDT using ALA induced accumulation of PplX is a useful method in treating cancer but advances need to be made so ALA-PDT treatment is available to a broader range of cancers. This proposal attempts this by combining ALA-PDT first with an inhibitor of the c-Met tyrosine kinase receptor and second with a vascular disrupting agent (VDA), DMXAA. Previous research has shown the c-Met receptor interacts with an adaptor protein, RanBPM, which interacts with and is involved in cellular localization of rate-limiting enzyme in the heme synthesis pathway, Porphobilinogen Deaminase (PBGD). The first hypothesis proposes that if c-Met receptor activation is decreased more RanBPM will be free to interact with PBGD, thus causing a greater PDT effect by increasing PplX. PDT causes tissue destruction through three mechanisms: direct cell kill, vascular shutdown and immune response. The second hypothesis is in response to research showing ALA-PDT has minimal effects on vasculature shutdown. The hypothesis is that combining a VDA with ALA- PDT will increase efficacy.
Aim 1 :
This aim will explore the effect of combining ALA-PDT with an inhibitor of the c-Met receptor in vitro in various cancer cell lines using both K252a (Calbiochem) and PHA-665752 (Pfizer) as the inhibitors.
Aim 2 :
This aim i ncludes use of inhibitor of the c-Met receptor, PHA-665752 (Pfizer), in vivo in combination with topical ALA-PDT, exploring the effect of the combination and aiming to optimize the treatment.
Aim 3 :
The final aim will examine the benefits of combining DMXAA with ALA-PDT in vivo. The survival of animals will be monitored in anticipation that the combined treatment will improve survival over either therapy alone, in hopes of finding a synergistic anti-tumor effect. It will also use multiple imaging techniques (microPET, fMRI fluorescence microscopy) to visualize the vasculature of the mice post- treatment. The overall goal of this proposal is to improve the treatment of cancer by exploring ways to enhance the cure-rate of ALA-PDT. This will be beneficial as ALA-PDT is used in multiple disciplines which include dermatology, urology and gastroenterology; by understanding and exploiting the interactions of the combinations, the benefits in cancer research, in addition to these other areas of research, will be immense. ? ? ?
| Marrero, Allison; Becker, Theresa; Sunar, Ulas et al. (2011) Aminolevulinic acid-photodynamic therapy combined with topically applied vascular disrupting agent vadimezan leads to enhanced antitumor responses. Photochem Photobiol 87:910-9 |
