Preliminary Findings on the Use of Targeted Therapy with Pazopanib and Other Agents in Combination with Sodium Phenylbutyrate in the Treatment of Glioblastoma Multiforme

Stanislaw R. Burzynski^*, Tomasz J. Janicki, Gregory S. Burzynski, Sheldon Brookman

Burzynski Clinic, Houston, USA.

DOI: 10.4236/jct.2014.514144                

Abstract

The most common and aggressive type of brain tumor is glioblastoma multiforme (GBM). The prognosis for GBM remains poor with a five-year survival rate between 1% and 2%. The prospects for patients with recurrent GBM (RGBM) are much worse, with the majority dying within 6 months. This publication provides a brief description of the treatment of 11 GBM patients treated with sodium phenylbutyrate (PB) in combination with pazopanib, m-TOR inhibitors, and other agents. The treatment was associated with tolerable side effects and resulted in objective responses in 54.5% of cases (complete response 18.2%, partial response 36.3%) and 27.3% cases of stable disease. The preferable treatment regimen consisted of PB, pazopanib, dasatinib, everolimus, and bevacizumab (BVZ). For various reasons not all patients were compliant with the treatment regimen. In patients who strictly complied with the treatment plan, all responded as CR or PR. Based on preliminary findings, the authors propose further phase I/II clinical trials with PB in combination with pazopanib, dasatinib, everolimus, and BVZ in patients with RGBM who failed standard surgery, radiation therapy and chemotherapy. With proper dose reductions, the treatment appears to be well-tolerated. Molecular profiling of patient subgroups with favorable genomic signatures may help to select patients for future studies.

Keywords

Gliobastoma Multiforme, Personalized Targeted Agents, Sodium Phenylbutyrate, Treatment of Glioblastoma Multiforme

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Ostrom, Q.T., Gittleman, H., Farah, P., Ondracek, A., Chen, Y., Wolinsky, Y., et al. (2013) CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States 2006-2010. Neuro-Oncology, 15, ii1-ii56. http://dx.doi.org/10.1093/neuonc/not151
[2]	Ohka, F., Natsume, A. and Wakabayashi, T. (2012) Current Trends in Targeted Therapies for Glioblastoma Multiforme. Neurology Research International, 2012, Article ID: 878425. http://dx.doi.org/10.1155/2012/878425
[3]	Olson, J.J., Nayak, L., Ormond, D.R., Wen, P.Y., Kalkanis, S.N. and Ryken, T.C. (2014) The Role of Targeted Therapies in the Management of Progressive Glioblastoma. Journal of Neuro-Oncology, 118, 557-599. http://dx.doi.org/10.1007/s11060-013-1339-4
[4]	Stupp, R., Mason, W.P., van den Bent, M.J., Weller, M., Fisher, B., Taphoorn, M.J.B., et al. (2005) Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. New England Journal of Medicine, 352, 987-996. http://dx.doi.org/10.1056/NEJMoa043330
[5]	Stupp, R., Hegi, M.E., Mason, W.P., van den Bent, M.J., Taphoorn, M.J., Janzer, R.C., et al. (2009) Effects of Radiotherapy with Concomitant and Adjuvant Temozolomide versus Radiotherapy Alone on Survival in Glioblastoma in a Randomized Phase III Study: 5-Year Analysis of the EORTC-NCIC Trial. Lancet Oncology, 10, 459-466. http://dx.doi.org/10.1016/S1470-2045(09)70025-7
[6]	Burzynski, S.R. (1976) Antineoplastons: Biochemical Defense against Cancer. Physiological Chemistry and Physics, 8, 275-279.
[7]	Burzynski, S.R. (1986) Antineoplastons—History of the Research (I). Drugs under Experimental Clinical Research, 12, 1-9.
[8]	Burzynski, S.R. (2004) The Present State of Antineoplaston Research (1). Integrative Cancer Therapies, 3, 47-58. http://dx.doi.org/10.1177/1534735403261964
[9]	Burzynski, S.R. (2006) Treatments for Astrocytic Tumors in Children: Current and Emerging Strategies. Pediatric Drugs, 8, 167-168. http://dx.doi.org/10.2165/00148581-200608030-00003
[10]	Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Marszalek, A. (2014) The Response and Survival of Children with Recurrent Diffuse Intrinsic Pontine Glioma Based on Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Brainstem Glioma. Childs Nervous System, 30, 2051-2061. http://dx.doi.org/10.1007/s00381-014-2401-z
[11]	Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Marszalek, A. (2014) A Phase II Study of Antineoplastons A10 and AS2-1 in Children with High-Grade Glioma. Final Report (Protocol BT-06) and Review of Recent Trials. Journal of Cancer Therapy, 5, 565-577. http://dx.doi.org/10.4236/jct.2014.56065
[12]	Burzynski, S.R., Janicki, T.J. and Burzynski, G.S. (2014) A Phase II Study of Antineoplastons A10 and AS2-1 in Adult Patients with Recurrent Glioblastoma Multiforme: Final Report (Protocol BT-21). Journal of Cancer Therapy, 5, 946-956. http://dx.doi.org/10.4236/jct.2014.510100
[13]	Burzynski, S.R., Janicki, T.J., Burzynski, G.S., Marszalek, A. and Brookman, S. (2014) A Phase II Study of Antineoplastons A10 and AS2-1 in Children with Recurrent, Refractory or Progressive Primary Brain Tumors—Final Report (Protocol BT-22). Journal of Cancer Therapy, 5, 977-988. http://dx.doi.org/10.4236/jct.2014.510102
[14]	Burzynski, S.R., Burzynski, G.S. and Janicki, T.J. (2014) Recurrent Glioblastoma Multiforme—A Strategy for Long-Term Survival. Journal of Cancer Therapy, 5, 957-976. http://dx.doi.org/10.4236/jct.2014.510101
[15]	Brusilow, S.W., Danney, M., Waber, L.J., Batshaw, M., Burton, B., Levitsky, L., et al. (1984) Treatment of Episodic Hyperammonemia in Children with Inborn Errors of Urea Synthesis. New England Journal of Medicine, 310, 1630-1634. http://dx.doi.org/10.1056/NEJM198406213102503
[16]	Iannitti, T. and Palmieri, B. (2011) Clinical and Experimental Applications of Sodium Phenylbutyrate. Drugs in R & D, 11, 227-249. http://dx.doi.org/10.2165/11591280-000000000-00000
[17]	Burzynski, S.R. and Patil, S. (2014) The Effect of Antineoplastons A10 and AS2-1 and Metabolites of Sodium Phenylbutyrate on Gene Expression in Glioblastoma Multiforme. Journal of Cancer Therapy, 5, 929-945. http://dx.doi.org/10.4236/jct.2014.510099
[18]	Sturm, D., Witt, H., Hovestadt, V., Khuong-Quang, D.A., Jones, D.T., Konermann, C., et al. (2012) Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma. Cancer Cell, 22, 425-437. http://dx.doi.org/10.1016/j.ccr.2012.08.024
[19]	Phuphanich, S., Baker, S.D., Grossman, S.A., Carson, K.A., Gilbert, M.R., Fisher, J.D., et al. (2005) Oral Sodium Phenylbutyrate in Patients with Recurrent Malignant Gliomas: A Dose Escalation and Pharmacologic Study. Neuro-Oncology, 7, 177-182. http://dx.doi.org/10.1215/S1152851704000183
[20]	Chang, S.M., Kuhn, J.G., Robins, H.I., Schold, S.C., Spence, A.M., Berger, M.S., et al. (1999) Phase II Study of Phenylacetate in Patients with Recurrent Malignant Glioma: A North American Brain Tumor Consortium Report. Journal of Clinical Oncology, 17, 984-990.
[21]	Weller, M., Cloughesy, T., Perry, J.R. and Wick, W. (2013) Standards of Care for Treatment of Recurrent Glioblastoma—Are We There Yet? Neuro-Oncology, 15, 4-27. http://dx.doi.org/10.1093/neuonc/nos273
[22]	Prados, M.D. (2014) “We Will Know if When We See It”; Bevacizumab and Glioblastoma. Neuro-Oncology, 16, 469-470. http://dx.doi.org/10.1093/neuonc/nou036
[23]	Gerber, N.K., Goenka, A., Turcan, S., Reyngold, M., Makarov, V., Kannan, K., et al. (2014) Transcriptional Diversity of Long-Term Glioblastoma Survivors. Neuro-Oncology, 16, 1186-1195. http://dx.doi.org/10.1093/neuonc/nou043