About MeEducational Background:Dr.
Moore is a graduate from
the University of Alberta. He obtained his MD in 1986 with distinction and laude
and completed his urology residency in 1993. Dr.
Moore also has a PhD in Experimental Surgery, completing this during his residency. As part of his education background, Dr.
Moore completed a fellowship with the Royal College of Physicians and Surgeons and with the American College of Surgeons.
We have investigated the mechanism of action of Porphyrin (5-ALA/PpIX, Photofrin and BPD-MA) and Hypocrellin mediated PDT and photodetection (PD). With these investigations we have gained an understanding of the current limitations to successful clinical application of PDT (J. Urol 167(4):1848-53, 2002; Urol. Oncol. 7(3):125-132, 2002; J. Urol. 2003 Jan;169(1):352-6). Although the use of 5-ALA PD is fairly common in Europe it has been slow to gain acceptance for routine use in North America. Photofrinä (HpD) remains the only clinically licensed photosensitizer for urological PDT. The newer generation photosensitizers have had dramatic improvements in potentency but lack tumor specificity. With Dr. Lown's expertise on perylenequinonoid pigments (Hypocrellins), isolated from the fungus Hypocrella bambusae (Diwu and Lown, J Photochem Photobiol 18:131, 1993) we have previously carried out in-vitro and in-vivo assays on synthetic derivatives of these pigments. Site-directed modifications to improve absorption in the red spectral region (690nm), phototoxicity and pharmacokinetics were achieved. We identified 3 derivatives of Hypocrellin B (HB) that had low dark toxicity and excellent photopotentiation of tumor cell killing, and biodistribution similar to HpD, but with more rapid clearance from the skin (within 48 hours). This represented a substantial improvement over HpD (Photochem and Photobiol 65:714-722, 1997; Cancer Chemotherapy and Pharmacology, 37:343-350, 1996). These investigations supported development of Hypocrellins as clinical photosensitizers and a patent was obtained (Lown JW, Moore RB, Miller GG: Substituted Perylenequinones for Use in Photodynamic Therapy. SN 60/009,912. January, 1996). AltaRex Corp. initially took on the commercialization of these compounds, then Altachem Pharma Ltd. took over the patent and further development of these drugs. This has lead to an industrial partner to support further development of these compounds and strategies to treat prostate cancer (PCa)
Further research accomplishments related to preclinical PDT investigations have been the development of a light delivery apparatus that allows tissue characterization and real time dosimetry for intra arterial photosensitization. This has lead to a patent (Tulip J, Moore RB, Dickey D: Switched PDT Apparatus and Treatment Methods. US Patent # 60/464/656) and commercialization through Altachem Pharma Ltd. To accomplish this, modeling of light dosimetry was carried out in phantoms, our rat prostate tumor and dog models, and human cystoprostatectomy specimens. Key to this was the development of a novel approach for characterizing tissue using angular radiance (Barajas et al. Phys. Med. Biol. 42(9):1675-1687, 1997). We found that an interstitial light source implanted in tissue produces an angular radiance (light flux at a specific angle, W/m2 sr) that becomes progressively isotropic as a function of distance. The anisotropy in the angular radiance as a function of distance is sensitive to variations in the optical coefficients, such that measurements of angular radiance yield information about these coefficients. With this finding, we have solved the P-3 approximation which allows us to generate real-time 3 dimensional (3-D) isodose plots (Dickey et.al. Phys Med Biol 46:2359-2370, 2001; SPIE Proceedings J.B.O. 4156:181-88, 2000). With this ability to characterize tissue in 3-D (Dickey et al., Phys. Med.Biol., in press) we further refined our light delivery apparatus to switch between optical sources and detectors complete with spectrometer to monitor drug levels (Dickey et.al., Journal of Biomedical Optics, in press). These refinements have resulted in less toxicity and greater efficacy in our animal models. In the Dunning Prostate model we have shown increased efficacy with both BPD and HBD using the switched light apparatus (Xiao Z,etal. Abst. Can. J. Urol. CUA Annual Meeting, June, 2003). In the dog model we have shown selective intra arterial delivery of HBD and BPD with therapeutic ratios of >100:1 between prostate and surrounding tissue (Moore RB, etal. Abst. Can. J. Urol. CUA Annual Meeting, June, 2003).
Other significant research has included the development and characterization of a transplantable orthotopic rat bladder tumor model of superficial transitional cell carcinoma (TCC) (British J. Cancer, 81(4):638-46, 1999). The development of this model was a major accomplishment. This publication had the greatest number of requests for reprints and we have helped establish this model in several other laboratories. The model has been highly sought by other labs because of its reproducibility and well characterized TCC phenotype. Prior to this model the only models were carcinogen induced which yielded variable tumor phenotypes, with variable latencies or a mouse model that was too small to work with. Utilizing this model we have systematically evaluated 5-ALA uptake and conversion to PpIX (Photochem. Photobiol. 67(5):573-583, 1998; J Urol 167(4):1848-53, 2002) and response to PDT following intravesical administration (J. Urol. 169(1):352-6, 2003; Brit. J. Urol. Int. 92(1):125-30, 2003). This information has been used to guide clinical trials on PDT of TCC using the Storz D-Light source. This model has also allowed us to conduct preclinical studies on other intravesical therapies (i.e. BCG and Reovirus, Hanel et.al. J. Urol. In press).
Using the same methodologies we also developed a transplantable orthotopic model of human MGHU-3 TCC xenografted into nude rats. This model however is unreliable with low engraftment, long and variable latencies and costly. With this model we studied immunoliposomal delivery of photosensitizers. Despite showing targeting of the immunoliposomes we were unable to demonstrate a selective advantage.
We have also developed an in-vitro bladder tumor model and characterized it for testing topical drug delivery. This model has been used to test targeted drug delivery for several novel intravesical therapies (Selective Reovirus Killing of Bladder Cancer in a Co-Culture Spheroid Model. Virus Research 93:1-12, 2003; Selective Cytotoxicity of Gemcitabine in Bladder Cancer Cell Lines. Anticancer Drugs 13(6):557-66, 2002; and Immunoliposomal Targeting of Transitional Cell Carcinoma with 48-127 mAb. Manuscript under revision). This model system has supported our ex-vivo studies on human Equilibrative Nucleoside Transporter 1 (hENT1) protein in transitional cell carcinoma (Mulder KE, et.al.Urol., in press), and intravesical Reovirus ( Hanel EG, et. al. J. Urol. In press). These studies have lead to proposing separate clinical trials with intravesical gemcitabine and reovirus.
Based on the pioneering work of Dr. Patrick Lee, we have extended our research on topical application in the treatment of bladder to head and neck cancers. We have shown that irrigation of wounds with reovirus markedly reduces recurrence of squamous cell carcinoma (Brookes, JT. etal., Reovirus Salvage of Squamous Cell Cancer Contaminated Wounds. J. Otolaryngology, In Press)
In collaboration with Drs. Charlie Hao, Wilson Roa and Martin Gleave we have been investigating TRAIL and antisense oligonucleotides (asODNs) for the treatment of bladder and prostate cancer. This work has been extended from Dr. Hao’s research on glioma cell lines and Dr. Gleave’s research on apoptosis in PCa with androgen withdrawal. We have shown that combination of TRAIL and asODNs to Bcl2, Clusterin, and telomerase enhance apoptosis in some TCC cell lines. A lot of the preliminary research was conducted by our AHFMR summer students (Johnson E., etal., and Marani S., etal. U of A 36th Annual Student Research Day). Both of these students won awards for their presentations. We are currently funded by NCIC to conduct preclinical studies on intravesical molecular treatment of bladder cancer.
In the field of transplantation we are investigating reverse oncologic strategies to make differentiated cells proliferate in a controlled fashion. We have investigated and shown that senescence, as evident by telomere shortening, may have an important role in the longevity of renal allografts (J. Am. Soc. Nephol. 11:444-453). This finding has generated a great deal of interest in molecular strategies to over come this replicative limitation to chronic low-grade immunologic injury. We are currently studying nonviral means of gene transfection (liposomal) to introduce telomerase into endothelial cells, the prime target of chronic injury in allograft nephropathy (Young ATL, etal. In-Vitro Senescence Occurring in Normal Human Endothelial Cells can be rescued by Ectopic Telomerase Activity. Transplantation Proc 35(7):2483-5, November 2003). The overall aim is to genetically modify the allograft during ex-vivo perfusion prior to transplantation. We have also extended this strategy to islet cell transplants (Young AT, etal. Assessment of different transfection parameters in efficiency optimization. Cell Transplantation, In Press). This strategy would possibly allow the expansion of these single cell transplants and reduce the need for multiple donors for one successful islet transplant. Also in transplantation we are studying the co-transplantation of serotoli cells and islet cells. These serotoli or sustanticular cells prevent immunologic injury to the islet cells by way of FAS –FAS ligand interaction. This research is currently funded by the Kidney Foundation of Canada.