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Preliminary Findings on the Use of Targeted Therapy in Combination with Sodium Phenylbutyrate in Advanced Malignant Mesothelioma: A Strategy for Improved Survival

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DOI: 10.4236/jct.2014.512116    1,796 Downloads   2,136 Views   Citations

ABSTRACT

Advanced malignant mesothelioma (MM) is among the most aggressive and difficult-to-treat diseases. Industrialization and exposure to asbestos is the main causative factor for the dramatic increase in the incidence of MM, which carries a poor prognosis and a median survival of less than 12 months. Combination chemotherapy offers only palliative results; however, targeted therapy carries more promise for future successful treatment. This paper presents preliminary findings of improved overall survival (OS) using a combination of sodium phenylbutyrate (PB) with various chemotherapeutic and targeted agents in advanced MM. The data suggest using a strategy of simultaneous interruption of signal transduction involving RAS-MEK-ERK, PI3K-AKT, mTOR, Merlin, and angiogenesis pathways and interference in cell cycle and epigenetic processes. Complete response was determined in 15.4% and stable disease in 46.2% in the group of 13 evaluable patients. Median OS for MM was higher compared to other treatments (17 months compared to between 6 and 12.1 months). The longest surviving patient continues to be in complete response and in excellent condition for over 12.5 years from the treatment start. These findings are only preliminary and validation of the results using a well-designed phase I/II trial in advanced MM is proposed.

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Burzynski, S. , Janicki, T. , Burzynski, G. and Brookman, S. (2014) Preliminary Findings on the Use of Targeted Therapy in Combination with Sodium Phenylbutyrate in Advanced Malignant Mesothelioma: A Strategy for Improved Survival. Journal of Cancer Therapy, 5, 1127-1144. doi: 10.4236/jct.2014.512116.

References

[1] Sekido, Y. (2013) Molecular Pathogenesis of Malignant Mesothelioma. Carcinogenesis, 34, 1413-1419. http://dx.doi.org/10.1093/carcin/bgt166
[2] Robinson, B.W.S. and Lake, R.A. (2005) Advances in Malignant Mesothelioma. New England Journal of Medicine, 353, 1591-1603. http://dx.doi.org/10.1056/NEJMra050152
[3] Vogelzang, N.J., Rusthoven, J.J., Symanowski, J., Denham, C., Kaukel, E., et al. (2003) Phase III Study of Pemetrexed in Combination with Cisplatin versus Cisplatin Alone in Patients with Malignant Pleural Mesothelioma. Journal of Clinical Oncology, 21, 2636-2644.
http://dx.doi.org/10.1200/JCO.2003.11.136
[4] Sekido, Y. (2011) Inactivation of Merlin in Malignant Mesothelioma Cells and the Hippo Signaling Cascade Dysregulation. Pathology International 61, 331-344.
http://dx.doi.org/10.1111/j.1440-1827.2011.02666.x
[5] Zucali, P.A., Ceresoli, G.L., De Vincenzo, F., Simonelli, M., Lorenzi, E., et al. (2011) Advances in the Biology of Malignant Pleural Mesothelioma. Cancer Treatment Reviews, 37, 543-558.
http://dx.doi.org/10.1016/j.ctrv.2011.01.001
[6] Jean, D., Daubriac, J., Le Pimpec-Barthes, F., Galateau-Salle, F. and Jaurand, M.-C. (2012) Molecular Changes in Mesothelioma with an Impact on Prognosis and Treatment. Archives of Pathology & Laboratory Medicine, 136, 277-293. http://dx.doi.org/10.5858/arpa.2011-0215-RA
[7] Mossman, B.T., Shukla, A, Heintz, N.H., Verschraegen, C.F., Thomas, A. and Hassan, R. (2013) New Insights into Understanding the Mechanisms, Pathogenesis, and Management of Malignant Mesotheliomas. American Journal of Pathology, 182, 1065-1077.
http://dx.doi.org/10.1016/j.ajpath.2012.12.028
[8] Greillier, L., Marco, S. and Barlesi, F. (2011) Targeted Therapies in Malignant Pleural Mesothelioma: A Review of Clinical Studies. Anti-Cancer Drugs, 22, 199-205.
http://dx.doi.org/10.1097/CAD.0b013e328341ccdd
[9] Burzynski, S.R. (1969) Investigations on Unknown Ninhydrin-Reacting Substances in Human Blood Serum. I. Attempts at Identification of Three Such Substances. Experientia, 25, 490-491.
http://dx.doi.org/10.1007/BF01900774
[10] Burzynski, S.R. (1976) Antineoplastons: Biochemical Defense against Cancer. Physiological Chemistry and Physics, 8, 275-279.
[11] Burzynski, S.R. (1986) Antineoplastons—History of the Research (I). Drugs under Experimental and Clinical Research, 12, 1-9.
[12] Burzynski, S.R. (1986) Synthetic Antineoplastons and Analogs. Drugs of the Future, 11, 679-688.
[13] Burzynski, S.R. (2004) The Present State of Antineoplaston Research (1). Integrative Cancer Therapies, 3, 47-58. http://dx.doi.org/10.1177/1534735403261964
[14] 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
[15] 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 Antineoplaston A10 and AS2-1 in Patients with Brainstem Glioma. Childs Nervous System, Published Online. http://dx.doi.org/10.1007/s00381-014-2401-z
[16] 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 and Review of Recent Trials. Journal of Cancer Therapy, 5, 565-577. http://dx.doi.org/10.4236/jct.2014.56065
[17] 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
[18] 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
[19] Brusilow, S.W., Danney, M., Waber, L.J., Batshaw, M., Burton, B., 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
[20] Phuphanich, S., Baker, S.D., Grossman, S.A., Carson, K.A., Gilbert, M.R., 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
[21] 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
[22] Burzynski, S.R., Burzynski, G.S. and Janicki, T.J. (2014) Recurrent Glioblastoma Multiforme, a Strategy for Long-Term Survival. Journal Cancer Therapy, 5, 957-976.
http://dx.doi.org/10.4236/jct.2014.510101
[23] Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Brookman, S. (2014) Preliminary Findings on the Use of Targeted Therapy in Combination with Sodium Phenylbutyrate in Recurrent Advanced Pancreatic Cancer—A Potential Strategy for Improved Survival. Journal Cancer Therapy, in Press.
[24] Middleton, G.W., Smith, I.E., O’Brien, M.E.R., Norton, A., Hickish, T., Priest, K., et al. (1998) Good Symptom Relief with Palliative MVP (Mitomycin-C, Vinblastine and Cisplatin) Chemotherapy in Malignant Mesothelioma. Annals of Oncology, 9, 269-273.
http://dx.doi.org/10.1023/A:1008236010868
[25] Nowak, A.K., Byrne, M.J., Williamson, R., Ryan, G., Segal, A., Fielding, D., et al. (2002) A Multicentre Phase II Study of Cisplatin and Gemcitabine for Malignant Mesothelioma. British Journal of Cancer, 87, 491-496. http://dx.doi.org/10.1023/A:1008236010868
[26] Scherpereel, A., Astoul, P., Baas, P., Berghmans, T., Clayson, H., De Vuyst, P., et al. (2010) Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the Management of Malignant Pleural Mesothelioma. European Respiratory Journal, 35, 479-495. http://dx.doi.org/10.1183/09031936.00063109
[27] Dazzi, H., Hasleton, P.S., Thatcher, N., Wilkes, S., Swindell, R. and Chatterjee, A.K. (1990) Malignant Pleural Mesothelioma and Epidermal Growth Factor Receptor (EGFR). Relationship of EGFR with Histology and Survival Using Fixed Paraffin Embedded Tissue and the F4, Monoclonal Antibody. British Journal of Cancer, 61, 924-926. http://dx.doi.org/10.1038/bjc.1990.207
[28] Cortese, J.F., Gowda, A.L., Wali, A., Eliason, J.F., Pass, H.I. and Everson, R.B. (2006) Common EGFR Mutations Conferring Sensitivity to Gefitinib in Lung Adenocarcinoma Are Not Prevalent in Human Malignant Mesothelioma. International Journal of Cancer, 118, 521-522.
[29] Garland, L.L., Rankin, C., Gandara, D.R., Rivkin, S.E., Scott, K.M., Nagle, R.B., et al. (2007) Phase II Study of Erlotinib in Patients with Malignant Pleural Mesothelioma: A Southwest Oncology Group Study. Journal of Clinical Oncology, 25, 2406-2413. http://dx.doi.org/10.1200/JCO.2006.09.7634
[30] Jackman, D.M., Kindler, H.L., Yeap, B.Y., Fidias, P., Salgia, R., Lucca, J., et al. (2008) Erlotinib plus Bevacizumab in Previously Treated Patients with Malignant Pleural Mesothelioma. Cancer, 113, 808-814. http://dx.doi.org/10.1002/cncr.23617
[31] Mathy, A., Baas, P., Dalesio, O. and Van Zandwijk, N. (2005) Limited Efficacy of Imatinib Mesylate in Malignant Mesothelioma: A Phase II Trial. Lung Cancer, 50, 83-86.
http://dx.doi.org/10.1016/j.lungcan.2005.04.010
[32] Porta, C., Mutti, L. and Tassi, G. (2007) Negative Results of an Italian Group for Mesothelioma (g.I.Me.) Pilot Study of Single-Agent Imatinib Mesylate in Malignant Pleural Mesothelioma. Cancer Chemotherapy and Pharmacology, 59, 149-150. http://dx.doi.org/10.1007/s00280-006-0243-4
[33] Dudek, A., Pang, H., Kratzke, R.A., Otterson, G.A., Vokes, E.E. and Kindler, H.L. (2010) CALGB 30601: A Phase II Study of Dasatinib (D) in Patients (pts) with Previously Treated Malignant Mesothelioma (MM) (Abstract 7037). Journal of Clinical Oncology, 28.
[34] Dowell, J.E., Lan, C., Gerber, D., Hughes, R., Yan, J., Xie, Y., et al. (2009) Pemetrexed, Cisplatin and Bevacizumab in Patients with Advanced Malignant Mesothelioma: A Multi-Center Phase II Trial (Abstract b1.2). Journal of Thoracic Oncology, 4, S319.
[35] Nowak, A.K., Millward, M., Francis, R.J., Hasani, A., Van Der Schaaf, A.A., Seguard, T., et al. (2010) Final Results of a Phase II Study of Sunitinib as Second-Line Therapy in Malignant Pleural Mesothelioma (MPM) (Abstract 7036). Journal of Clinical Oncology, 28.
[36] Janne, P.A., Wang, X.F., Krug, L.M., Hodgson, L., Vokes, E.E. and Kindler, H.L. (2007) Sorafenib in Malignant Mesothelioma (MM): A Phase II Trial of the Cancer and Leukemia Group B (CALGB 30307) (Abstract 7707). Journal of Clinical Oncology, 25.
[37] Kelly, W.K., O’Connor, O.A., Krug, L.M., Chiao, J.H., Heaney, M., Curley, T., et al. (2005) Phase I Study of an Oral Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid, in Patients with Advanced Cancer. Journal of Clinical Oncology, 23, 3923-3931. http://dx.doi.org/10.1200/JCO.2005.14.167
[38] Burzynski, S.R., Burzynski, M.D. 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
[39] Brevet, M., Shimizu, S., Bott, M.J., Shukla, N., Zhou, Q., Olshen, A.B., et al. (2011) Coactivation of Receptor Tyrosine Kinases in Malignant Mesothelioma as a Rationale for Combination Targeted Therapy. Journal of Thoracic Oncology, 6, 864-874.
http://dx.doi.org/10.1097/JTO.0b013e318215a07d
[40] Varghese, S., Chen, Z., Bartlett, D.L., Pingpank, J.F., Libutti, S.K., Steinberg, S.M., et al. (2011) Activation of the Phosphoinositide-3-Kinase and Mammalian Target of Rapamycin Signaling Pathways Are Associated with Shortened Survival in Patients with Malignant Peritoneal Mesothelioma. Cancer, 117, 361-371. http://dx.doi.org/10.1002/cncr.25555
[41] Menges, C.W., Chen, Y., Mossman, B.T., Chernoff, J., Yeung, A.T. and Testa, J.R. (2010) A Phosphotyrosine Proteomic Screen Identifies Multiple Tyrosine Kinase Signaling Pathways Aberrantly Activated in Malignant Mesothelioma. Genes and Cancer, 1, 493-505.
http://dx.doi.org/10.1177/1947601910375273
[42] Thurneysen, C., Opitz, I., Kurtz, S., Weder, W., Stahel, R.A. and Felley-Bosco, E. (2009) Functional Inactivation of NF2/Merlin in Human Mesothelioma. Lung Cancer, 64, 140-147.
http://dx.doi.org/10.1016/j.lungcan.2008.08.014
[43] Stamenkovic, I. and Yu, Q. (2010) Merlin, a “Magic” Linker between the Extracellular Cues and Intracellular Signaling Pathways That Regulate Cell Motility, Proliferation and Survival. Current Protein and Peptide Science, 11, 471-484. http://dx.doi.org/10.2174/138920310791824011
[44] Lopez-Lago, M.A., Okada, T., Murillo, M.M., Socci, N. and Giancotti, F.G. (2009) Loss of the Tumor Suppressor Gene NF2, Encoding Merlin, Constitutively Activates Integrin-Dependent mTORC1 Signaling. Molecular and Cellular Biology, 29, 4235-4249. http://dx.doi.org/10.1128/MCB.01578-08
[45] James, M.F., Han, S., Polizzano, C., Plotkin, S.R., Manning, B.D., Stemmer-Rachamimov, A.O., et al. (2009) NF2/Merlin Is a Novel Negative Regulator of mTOR Complex 1 and Activation of mTORC1 Is Associated with Meningioma and Schwannoma Growth. Molecular and Cellular Biology, 29, 4250-4261. http://dx.doi.org/10.1128/MCB.01581-08
[46] Christensen, B.C., Houseman, E.A., Godleski, J.J., Marsit, C.J., Longacker, J.L., Roelofs, C.R., et al. (2009) Epigenetic Profiles Distinguish Pleural Mesothelioma from Normal Pleura and Predict Lung Asbestos Burden and Clinical Outcome. Cancer Research, 69, 227-234.
http://dx.doi.org/10.1158/0008-5472.CAN-08-2586
[47] Goto, Y., Shinjo, K., Kondo, Y., Shen, L., Toyota, M., Suzuki, H., et al. (2009) Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma. Cancer Research, 69, 9073-9082. http://dx.doi.org/10.1158/0008-5472.CAN-09-1595

  
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