This proposal addresses the need for the development of efficient boron delivery agents for application in a new treatment modality for intractable brain tumors and other malignancies, boron neutron capture therapy (BNCT). This need arises from advances in the production and availability of high quality neutron beams. BNCT is a binary therapy based on a nuclear reaction which occurs when boron-10 nuclei localized within tumors capture low-energy neutrons to produce high linear energy transfer particles whose cytotoxic effects are confined to the cells in which the drug is retained. Phase I/II BNCT clinical trials are being pursued in the U.S., Europe, and Japan, for the treatment of patients with glioblastomas and melanomas;although there is clear evidence of a therapeutic response to BNCT, the development of new boron delivery drugs with higher tumor cell specificity, uptake and retention will increase the general acceptance of BNCT and provide a very attractive and selective treatment for one of the most therapeutically refractory of all human cancers, high grade gliomas. Our results obtained during the last funding period show that carboranylporphyrins are non-toxic, amphiphilic and deliver therapeutic amounts of boron to animal tumors with moderate selectivity;among the new compounds investigated, two are particularly promising as a boron delivery drug: TOCP and HOCP. Our previous studies also suggest that convection enhanced delivery might be the best method for administration of our compounds.
The specific aims for our revised proposed program are: 1) to conduct animal and in vitro BNCT studies on our most promising boronated porphyrin derivatives;2) to continue the study of the fundamental properties of our first-generation compounds and to develop new analogues with enhanced specificity for tumor targeting and tumor cell uptake;3) to evaluate the in vitro BNCT efficacy of our boronated porphyrin derivatives;4) to evaluate their toxicity and biodistribution in animal models, and 5) to investigate their administration via convection enhanced delivery. Our studies have great medical significance and urgency and should rapidly lead to the discovery of efficient BNCT agents and to clinical trials. Two porphyrin-based molecules are FDA approved for use in another binary cancer therapy, photodynamic therapy, and one of them (Photofrin) is currently being investigated in a Phase II brain tumor trial. There is currently no efficient treatment for high grade gliomas. Despite advances in surgery, radiotherapy and chemotherapy, and aggressive treatments using a combination of these modalities, median life expectancy for adults diagnosed with glioblastomas and anaplastic astrocytomas is generally less than one year. The potential of BNCT will only be realized if new and improved BNCT agents are discovered, synthesized and their properties thoroughly investigated.
Our proposed program is of great relevance to public health since there is currently no efficient treatment for high grade gliomas, which are responsible for over 12,000 deaths in the U.S. each year. BNCT is also a promising method for the treatment of other malignancies, such as difficult to treat malignant melanomas, meningiomas, therapeutically refractory head and neck tumors, and oral cancer. The potential of BNCT will only be realized when we fully understand the factors that limit its effectiveness, develop new strategies and translate the findings from our laboratory to the clinic.
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