From Translational BNCT Studies in Animals to Clinical

From Translational BNCT Studies in Animals to Clinical Trials Rolf F. Barth, M. D. Department of Pathology The Ohio State University, Columbus, OH 43210, U. S. A.

Identification of Sodium Borocaptate as a Potential Boron Delivery Agent “The discovery of a class of boron compounds, containing the sulfhydryl group, which become fixed to tumor tissue and to serum proteins is presented. A comparison is made between the toxicity and tissue-binding properties of B 12 H 122 - and B 12 H 11 SH 2 -. There are definite indications that SH groups on such anions are potent nucleophiles. Toxicity studies of this latter anion in rabbits are also discussed. ” Biodistribution of Sodium Borocaptate (Na 2 B 12 H 11 SH or “BSH”) Tumor Mean Range 21 ± 17. 8 4. 8 – 61. 5 Blood Brain Mean Range 2. 9 ± 1. 8 1. 0 – 7. 2 0. 9 ± 0. 5 <0. 5 – 2. 0 *Total dose ranged from 140 -175 µg boron/g The attractive tumor-binding properties of BSH lead to a complete pharmacological testing in rabbits. It was determined that slow i. v. injection of a dilute isotonic solution containing a total dose of 200 mg of B/kg was well tolerated. Penetration of Brain and Brain Tumor. VII. Tumor-Binding Sulfhydryl Boron Compounds. Soloway, A. H. , Hatanaka, H. , and Davis, M. A. , Journal of Medicinal Chemistry 10: 714, 1967

Demonstration that BSH Could Be Used to Treat a Murine Brain Tumor Group I. Dose of BSH 100 mg 10 B/ kg i. p. BNCT was initiated 14. 5 hrs after injection with an estimated radiation dose of 1200 rad (c. Gy). Group V. Dose of BSH 100 mg 10 B/ kg i. p. followed by two irradiations with an estimated radiation dose of 740 rad (c. Gy). Boron neutron therapy for transplantable mouse gliomas in 1974. Hasegawa, H. , Mogami, H. , Amano, K. et al. Neutron Capture Therapy, Proceedings of the Second International Sumposium on Neutron Capture Therapy. Ed. Hatanaka H.

Demonstration that BSH Could be Used Clinically to Treat Patients with Gliomas The MST was approx 44 mos and Me. ST survival was 25. 6 mos and the 5 year survival was 58. 3%. Boron-Neutron Capture Therapy for Tumors, Hatanaka H. , in Glioma, eds. Karim, A. B. M. F. , Laws, E. R. Jr. , Springer, 1991.

Demonstration that BNCT Could be Used to Treat a Naturally Occurring Malignant Melanoma in the Skin of a Duroc Pig A. Clinical appearance before BNCT. B. 115 d after BNCT there was complete disappearance of the melanoma. Treatment of malignant melanoma by selective thermal neutron capture therapy using melanoma-seeking compound, Mishima, Y. , Ichihashi, M. , Tsuji, M. et al. , J. Investigative Dermatology, 92(5), Supplement, May 1989.

Demonstration that BNCT Could be Used to Treat an Invasive Melanoma of the Foot c. 2. 5 years after BNCT b. 4. 5 months after BNCT a. Before BNCT The patient, an 85 year old woman with a plantar melanoma, was not a candidate for surgery due to a cardiac problem. She received BNCT using BPA as a fructose complex (170 mg/kg), injected perilesionally. As shown in the photos, there was complete regression without recurrence. Mishima, Y. , Honda, C. , Ichihashi, M. et al. Treatment of Malignant Melanoma by Single Thermal Neutron Capture Therapy with Melanoma-Seeking 10 B-Compounds. The Lancet, II: 388 -389, 1989 Mishima, Y. Selective thermal neutron capture therapy of cancer cells using their specific metabolic activities – melanoma as prototype. Cancer Neutron Capture Therapy Ed. Mishima, Y. Plenum Press, 1996

Demonstration that BPA Could be Used as a Delivery Agent to Treat a Rat Brain Tumor Survival of control and BNCT-treated rats Survival of control and X-irradiated rats Control of intracerebral gliosarcomas in rats by boron neutron capture therapy with p. Boronophenylalanine. Coderre, J. A. , Joel, D. D. , Micca, P. L. Radiation Research 129: 290 -296, 1992.

Demonstration that BPA Could be Used Clinically to Treat Patients with GBMs Time to tumor progression from diagnosis Overall survival times for 37 patients from time of tissue diagnosis Boron neutron capture therapy for glioblastoma multiforme: interim results from the Phase I/II dose -escalation studies. Chanana, A. D. , Capala, J. , Chadha, M. et al. Neurosurgery, 44: 1182 -1192, 1999.

Optimization of Delivery of BPA and BSH Resulted in Enhanced Tumor Uptake 250 mg/kg BPA+30 mg/kg BSH Boron neutron capture therapy of brain tumors: Enhanced survival and cure following blood-brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine. Barth, R. F. , Yang, W. , Rotaru, J. H. et al. Int. J. Radiat Oncol Biol. Phys, 47: 209 -218, 2000.

Dotplot of Boron Values for Individual Rats for Tumor and BAT Int. J. Radiat. Oncol. Biol & Phys. 52: 858 -868, 2002.

Demonstration that Optimized Delivery of BPA and BSH Could Increase Survival Kaplan-Meier survival curves of F 98 glioma bearing rats. The survival times, in days after tumor implantation, are shown for untreated controls (○), irradiated controls (∆), BPA + BSH i. v. (●), BPA + BSH i. c. (▲), and BPA + BSH i. c. + BBB-D (■). Boron neutron capture therapy of brain tumors: Enhanced survival and cure following bloodbrain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine. Barth, R. F. , Yang, W. , Rotaru, J. H. et al. Int. J. Radiat Oncol Biol. Phys, 47: 209 -218, 2000.

Demonstration of the Combined Effect of BPA and BSH for BNCT of SCCVII Murine Tumors “In the present study, the combined BNCT of BPA and BSH showed higher tumor control ability in comparison with BPABNCT or BSH-BNCT. Therefore, this combination is expected to improve the treatment outcome of BNCT significantly by compensating the defects of BPA and BSH with each other. ” The combined effect of boronophenylalanine and borocaptate in boron neutron capture therapy for SCCVII tumors in mice. Ono, K. , Masunaga, S-I. , Suzuki, M. et al. Int. J. Radiat. Oncol. Biol. Phys. 43: 431 -436, 1999.

Survival Curves of Glioma Patients Treated with BNCT Alone or in Combination with XRT Boron neutron capture therapy for newly diagnosed glioblastoma. Kawabata, S. , Miyatake, SI. , Kuroiwa, T. et al. J. Radiat. Res. 50: 51 -60, 2009.

Demonstration that Prolonged Infusion of BPA was Superior to a Short Infusion 10 B distribution in the main tumor mass (MTM) and clusters of tumor cells infiltrating normal brain of F 98 glioma bearing rats. After a 6 hr infusion the 10 B concentration in infiltrating tumor cells had increased by almost 90% relative to 2 or 3 hr infusion. Quantitative imaging and microlocalization of Boron-10 in brain tumors and infiltrating tumor cells by SIMS ion microscopy: relevance to neutron capture therapy. Smith, D. R. , Chandra, S. , Barth, R. F. et al. Cancer Research 61: 8179 -8187, 2001.

Demonstration that Prolonged Infusion of BPA Improved its Pharmacokinetics Average ± standard deviation of 18 patients. Most of the irradiations took place between hours 8 and 9. Boron neutron capture therapy for glioblastoma multiforme: clinical studies in Sweden. Capala, J. , Stenstam, B. H. , Sköld, K. et al. J. of Neuro-Oncol. 62: 135 -144, 2003.

Demonstration that Prolonged Infusion of BPA Resulted in Improved Patient Survival Kaplan-Meier plots of overall survival for the two BNCT studies. Improved clinical efficacy with prolonged infusion was indicated by a longer MST (17. 7 mos) compared to the Brookhaven study (12. 6 mos). Local control of GBM was achieved in the Studsvik study but not the BNL, as shown by neuropathlogical examination following death of the patients. Boron neutron capture therapy for glioblastoma multiforme: advantage of prolonged infusion of BPA-f. Sköld, K. , H-Stenstam, B. , Diaz, A. Z. et al. Acta Neurol. Scand. 122: 58 -62, 2010.

What Are the Limitations of Animal Models? Although animal models can be valuable tools to evaluating new therapeutic approaches, there a number of limitations. 1. No currently available animal brain tumor model exactly simulates human high grade gliomas. This is an inherent limitation in using them to develop an effective therapeutic regimen that can be translated clinically. 2. Therapeutic approaches that may be possible to carry out in an experimental animal such as blood-brain barrier disruption combined with intracarotid injection of BPA and BSH would be very challenging to carry out clinically. 3. Although direct intracerebral administration of a boron delivery agent such as an EGFR targeting monoclonal antibody by means of convection enhanced delivery (CED) can be performed in a rat brain tumor model, it would be difficult to translate this clinically. This is more a problem related to CED, which still is very much a work in progress.

What can be done? • Although considerable time and effort has been expended to develop new boron delivery agents, this has not resulted in any new agent that has been evaluated clinically. This in part is due to the requirement that the boron delivery agent attain a sufficient concentration in the tumor and clear from the blood and normal brain and secondly to the difficulty in obtaining funding for biodistribution studies. Develop multi-investigator, collaborative projects that bring together chemists, biologists and clinicians from the outset. • If government funding is difficult to obtain, then turn to private organizations, foundations, and companies. However, this is easier said than done!

Acknowledgements Albert Soloway Thanks are due to my numerous co-workers over the past 34 years especially, Dr. Willy Yang, and grant support from The National Institutes of Health, the US Department of Energy and the American Cancer Society. Special thanks to Heidi Bosworth for all that she has done to support my research program, including preparation of this power point presentation.