Share This Article:

Preliminary Findings on the Use of Targeted Therapy in Combination with Sodium Phenylbutyrate in Colorectal Cancer after Failure of Second-Line Therapy—A Potential Strategy for Improved Survival

Full-Text HTML XML Download Download as PDF (Size:3899KB) PP. 1270-1288
DOI: 10.4236/jct.2014.513128    2,690 Downloads   3,246 Views   Citations

ABSTRACT

Colorectal cancer (CRC) is the second leading cause of cancer death related mortality with 1.2 million new cases diagnosed annually worldwide. Despite remarkable advances in the treatment of resectable CRC, advanced disease that recurs following initial two lines of chemotherapy, remains incurable. Targeted therapies using a single agent or in combination with other drugs have been tested in a number of clinical trials, with only moderate improvement. Here we present preliminary findings of improved overall survival (OS) using a combination of sodium phenylbutyrate with various targeted and chemotherapeutic agents in stage IV CRC patients who had failed at least two lines of chemotherapy. Results suggest a strategy of simultaneous interruption of signal transduction involving EGFR (VEGF) KRAS-ERK and PI3K-AKT pathways and interference with cell cycle, cancer cell metabolism, maintenance of cancerous stem cells, and promotion of apoptosis. In a group of 15 patients, median OS was higher compared to other third-line therapies (14.7 months compared to between 4.8 and 9.5 months in other studies). Given the understanding that our findings are preliminary, we propose the validation of our initial results using a well-designed phase I/II trial in recurrent advanced colorectal cancer.

Cite this paper

Burzynski, S. , Janicki, T. , Burzynski, G. and Brookman, S. (2014) Preliminary Findings on the Use of Targeted Therapy in Combination with Sodium Phenylbutyrate in Colorectal Cancer after Failure of Second-Line Therapy—A Potential Strategy for Improved Survival. Journal of Cancer Therapy, 5, 1270-1288. doi: 10.4236/jct.2014.513128.

References

[1] Siegel, R., Ma, J., Zou, Z. and Jemal, A. (2014) Cancer Statistics, 2014. CA: A Cancer Journal for Clinicians, 64, 9-29. http://dx.doi.org/10.3322/caac.21208
[2] Jemal, A., Center, M.M., DeSantis, C. and Ward, E.M. (2010) Global Patterns of Cancer Incidence and Mortality Rates and Trends. Cancer Epidemiology, Biomarkers & Prevention, 19, 1893-1907. http://dx.doi.org/10.1158/1055-9965.EPI-10-0437
[3] Recondo Jr., G., Diaz-Canton, E., De La Vega, M., Greco, M., Recondo Sr., G. and Valsecchi, M.E. (2014) Advances and New Perspectives in the Treatment of Metastatic Colon Cancer. World Journal of Gastrointestinal Oncology, 6, 211-224. http://dx.doi.org/10.4251/wjgo.v6.i7.211
[4] 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
[5] 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.
[6] Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Marszalek, A. (2013) Long-Term Survival (>13 Years) in a Child with Recurrent Diffuse Pontine Gliosarcoma: A Case Report. Journal of Pediatric Hematology/Oncology, 36, e433-e439. http://dx.doi.org/10.1097/MPH.0000000000000020
[7] 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
[8] 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
[9] 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 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
[10] 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
[11] 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 of Cancer Therapy, 5, 1127-1144. http://dx.doi.org/10.4236/jct.2014.512113
[12] 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 Advanced Malignant Mesothelioma, the Strategy for Improved Survival. Journal of Cancer Therapy, 5, 1072-1091.
http://dx.doi.org/10.4236/jct.2014.512116
[13] Burzynski, S.R. (1976) Antineoplastons: Biochemical Defense against Cancer. Physiological Chemistry and Physics, 8, 275-279.
[14] Burzynski, S.R. (1986) Antineoplastons—History of the Research (I). Drugs under Experimental and Clinical Research, 12, 1-9.
[15] Burzynski, S.R. (1986) Synthetic Antineoplastons and Analogs. Drugs of the Future, 11, 679-688.
[16] Burzynski, S.R. (2004) The Present State of Antineoplaston Research (1). Integrative Cancer Therapies, 3, 47-58. http://dx.doi.org/10.1177/1534735403261964
[17] 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
[18] 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
[19] 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
[20] 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
[21] Karapetis, C.S., Khambata-Ford, S., Jonker, D.J., O’Callaghan, C.J., Tu, D., Tebbutt, N.C., et al. (2008) K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer. New England Journal of Medicine, 359, 1757-1765. http://dx.doi.org/10.1056/NEJMoa0804385
[22] Amado, R.G., Wolf, M., Peeters, M., Van Cutsem, E., Siena, S., Freeman, D.J., et al. (2008) Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients with Metastatic Colorectal Cancer. Journal of Clinical Oncology, 26, 1626-1634. http://dx.doi.org/10.1200/JCO.2007.14.7116
[23] Grothey, A., Van Cutsem, E., Sobrero, A., Siena, S., Falcone, A., Ychou, M., et al. (2013) Regorafenib Monotherapy for Previously Treated Metastatic Colorectal Cancer (CORRECT): An International, Multicentre, Randomized, Placebo-Controlled, Phase 3 Trial. The Lancet, 381, 303-312.
http://dx.doi.org/10.1016/S0140-6736(12)61900-X
[24] Vogelstein, B., Fearon, E.R., Hamilton, S.R., Kern, S.E., Preisinger, A.C., Leppert, M., et al. (1988) Genetic Alterations during Colorectal Tumor Development. New England Journal of Medicine, 319, 525-532. http://dx.doi.org/10.1056/NEJM198809013190901
[25] Efferth, T. (2012) Signal Transduction Pathways of the Epidermal Growth Factor Receptor in Colorectal Cancer and Their Inhibition by Small Molecules. Current Medicinal Chemistry, 19, 5735-5744. http://dx.doi.org/10.2174/092986712803988884
[26] Vivanco, I. and Mellinghoff, I.K. (2010) Epidermal Growth Factor Receptor Inhibitors in Oncology. Current Opinion in Oncology, 22, 573-578. http://dx.doi.org/10.1097/CCO.0b013e32833edbdf
[27] Hu-Lieskovan, S., Vallbohmer, D., Zhang, W., Yang, D., Pohl, A., Labonte, M.J., et al. (2011) EGF61 Polymorphism Predicts Complete Pathologic Response to Cetuximab-Based Chemotherapy Independent of KRAS Status in Locally Advanced Rectal Cancer Patients. Clinical Cancer Research, 17, 5161-5169. http://dx.doi.org/10.1158/1078-0432.CCR-10-2666
[28] Laurent-Puig, P., Cayre, A., Manceau, G., Buc, E., Bachet, J.B., Lecomte, T., et al. (2009) Analysis of PTEN, BRAF, and EGFR Status in Determining Benefit from Cetuximab Therapy in Wild-Type KRAS Metastatic Colon Cancer. Journal of Clinical Oncology, 27, 5924-5930.
http://dx.doi.org/10.1200/JCO.2008.21.6796
[29] Sartore-Bianchi, A., Bencardino, K., Cassingena, A., Venturini, F., Funaioli, C., Cipani, T., et al. (2010) Therapeutic Implications of Resistance to Molecular Therapies in Metastatic Colorectal Cancer. Cancer Treatment Reviews, 36, S1-S5. http://dx.doi.org/10.1016/S0305-7372(10)70012-8
[30] Park, J.H., Han, S.W., Oh, D.Y., Im, S.A., Jeong, S.Y., Park, K.J., et al. (2011) Analysis of KRAS, BRAF, PTEN, IGF1R, EGFR Intron 1 CA Status in Both Primary Tumors and Paired Metastases in Determining Benefit from Cetuximab Therapy in Colon Cancer. Cancer Chemotherapy and Pharmacology, 68, 1045-1055. http://dx.doi.org/10.1007/s00280-011-1586-z
[31] Parsons, B.L. and Myers, M.B. (2013) Personalized Cancer Treatment and the Myth of KRAS Wild-Type Colon Tumors. Discovery Medicine, 15, 259-267.
[32] Baldus, S.E., Schaefer, K.L., Engers, R., Hartleb, D., Stoecklein, N.H. and Gabbert, H.E. (2010) Prevalence and Heterogeneity of KRAS, BRAF, and PIK3CA Mutations in Primary Colorectal Adenocarcinomas and Their Corresponding Metastases. Clinical Cancer Research, 16, 790-799. http://dx.doi.org/10.1158/1078-0432.CCR-09-2446
[33] Bando, H., Yoshino, T., Tsuchihara, K., Ogasawara, N., Fuse, N., Kojima, T., et al. (2011) KRAS Mutations Detected by the Amplification Refractory Mutation System-Scorpion Assays Strongly Correlate with Therapeutic Effect of Cetuximab. British Journal of Cancer, 105, 403-406. http://dx.doi.org/10.1038/bjc.2011.247
[34] Molinari, F., Felicioni, L., Buscarino, M., De Dosso, S., Buttitta, F., Malatesta, S., et al. (2011) Increased Detection Sensitivity for KRAS Mutations Enhances the Prediction of Anti-EGFR Monoclonal Antibody Resistance in Metastatic Colorectal Cancer. Clinical Cancer Research, 17, 4901-4914. http://dx.doi.org/10.1158/1078-0432.CCR-10-3137
[35] Townsley, C.A., Major, P., Siu, L.L., Dancey, J., Chen, E., Pond, G.R., et al. (2006) Phase II Study of Erlotinib (OSI-774) in Patients with Metastatic Colorectal Cancer. British Journal of Cancer, 94, 1136-1143. http://dx.doi.org/10.1038/sj.bjc.6603055
[36] Santoro, A., Comandone, A., Rimassa, L., Granetti, C., Lorusso, V., Oliva, C., et al. (2008) A Phase II Randomized Multicenter Trial of Gefitinib plus FOLFIRI and FOLFIRI Alone in Patients with Metastatic Colorectal Cancer. Annals of Oncology, 19, 1888-1893. http://dx.doi.org/10.1093/annonc/mdn401
[37] Tournigand, C., Samson, B., Scheithauer, W., Lledo, G., Viret, F., Andre, T., et al. (2012) Bevacizumab (Bev) with or without Erlotinib as Maintenance Therapy, Following Induction First-Line Chemotherapy plus Bev, in Patients (pts) with Metastatic Colorectal Cancer (mCRC): Efficacy and Safety Results of the International GERCOR DREAM Phase III Trial. Journal of Clinical Oncology, 30, Article ID: LBA3500.
[38] Caponigro, F., Casale, M. and Bryce, J. (2003) Farnesyl Transferase Inhibitors in Clinical Development. Expert Opinion on Investigational Drugs, 12, 943-954.
http://dx.doi.org/10.1517/13543784.12.6.943
[39] Wilhelm, S.M., Dumas, J., Adnane, L., Lynch, M., Carter, C.A., Schutz, G., et al. (2011) Regorafenib (BAY 73-4506): A New Oral Multikinase Inhibitor of Angiogenic, Stromal and Oncogenic Receptor Tyrosine Kinases with Potent Preclinical Antitumor Activity. International Journal of Cancer, 129, 245-255. http://dx.doi.org/10.1002/ijc.25864
[40] Boisvert-Adamo, K. and Aplin, A.E. (2008) Mutant B-RAF Mediates Resistance to Anoikis via Bad and Bim. Oncogene, 27, 3301-3312. http://dx.doi.org/10.1038/sj.onc.1211003
[41] Corcoran, R.B., Dias-Santagata, D., Bergethon, K., Iafrate, A.J., Settleman, J. and Engelman, J.A. (2010) BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation. Science Signaling, 3, ra84.
http://dx.doi.org/10.1126/scisignal.2001148
[42] Poulikakos, P.I., Zhang, C., Bollag, G., Shokat, K.M. and Rosen, N. (2010) RAF Inhibitors Transactivate RAF Dimers and ERK Signaling in Cells with Wild-Type BRAF. Nature, 464, 427-430.
http://dx.doi.org/10.1038/nature08902
[43] Yeh, J.J., Routh, E.D., Rubinas, T., Peacock, J., Martin, T.D., Shen, X.J., et al. (2009) KRAS/BRAF Mutation Status and ERK1/2 Activation as Biomarkers for MEK1/2 Inhibitor Therapy in Colorectal Cancer. Molecular Cancer Therapeutics, 8, 834-843. http://dx.doi.org/10.1158/1535-7163.MCT-08-0972
[44] Tentler, J.J., Nallapareddy, S., Tan, A.C., Spreafico, A., Pitts, T.M., Morelli, M.P., et al. (2014) Identification of Predictive Markers of Response to the MEK1/2 Inhibitor Selumetinib (AZD6244) in K-ras-Mutated Colorectal Cancer. Molecular Cancer Therapeutics, 9, 3351-3362.
http://dx.doi.org/10.1158/1535-7163.MCT-10-0376
[45] Abraham, R.T. and Gibbons, J.J. (2007) The Mammalian Target of Rapamycin Signaling Pathway: Twists and Turns in the Road to Cancer Therapy. Clinical Cancer Research, 13, 3109-3114. http://dx.doi.org/10.1158/1078-0432.CCR-06-2798
[46] Meric-Bernstam, F. and Gonzalez-Angulo, A.M. (2009) Targeting the mTOR Signaling Network for Cancer Therapy. Journal of Clinical Oncology, 27, 2278-2287.
http://dx.doi.org/10.1200/JCO.2008.20.0766
[47] Liu, Q., Thoreen, C., Wang, J., Sabatini, D. and Gray, N.S. (2009) mTOR Mediated Anti-Cancer Drug Discovery. Drug Discovery Today: Therapeutic Strategies, 6, 47-55.
http://dx.doi.org/10.1016/j.ddstr.2009.12.001
[48] Fan, Q.W., Cheng, C.K., Nicolaides, T.P., Hackett, C.S., Knight, Z.A., Shokat, K.M., et al. (2007) A Dual Phosphoinositide-3-Kinase Alpha/mTOR Inhibitor Cooperates with Blockade of Epidermal Growth Factor Receptor in PTEN-Mutant Glioma. Cancer Research, 67, 7960-7965.
http://dx.doi.org/10.1158/0008-5472.CAN-07-2154
[49] Khare, S. and Verma, M. (2012) Epigenetics of Colon Cancer. Methods in Molecular Biology, 863, 177-185. http://dx.doi.org/10.1007/978-1-61779-612-8_10
[50] Schaefer, M., Hagemann, S., Hanna, K. and Lyko, F. (2009) Azacytidine Inhibits RNA Methylation at DNMT2 Target Sites in Human Cancer Cell Lines. Cancer Research, 69, 8127-8132.
http://dx.doi.org/10.1158/0008-5472.CAN-09-0458
[51] Susman, S., Tomuleasa, C., Soritau, O., Mihu, C., Rus-Ciuca, D., Sabourin, J.C., et al. (2012) The Colorectal Cancer Stem-Like Cell Hypothesis: A Pathologist’s Point of View. Journal of B.U.ON, 17, 230-236.
[52] Vermeulen, L. and Snippert, J. (2014) Stem Cell Dynamics in Homeostasis and Cancer of the Intestine. Nature Reviews Cancer, 14, 468-480. http://dx.doi.org/10.1038/nrc3744
[53] Bertrand, F.E., Angus, C.W., Partis, W.J. and Sigounas, G. (2012) Developmental Pathways in Colon Cancer: Crosstalk between WNT, BMP, Hedgehog and Notch. Cell Cycle, 11, 4344-4351.
http://dx.doi.org/10.4161/cc.22134
[54] Steinbach, G., Lynch, P.M., Phillips, R.K., Wallace, M.H., Hawk, E., Gordon, G.B., et al. (2000) The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor, in Familial Adenomatous Polyposis. New England Journal of Medicine, 342, 1946-1952. http://dx.doi.org/10.1056/NEJM200006293422603
[55] Dihlmann, S., Siermann, A. and von Knebel Doeberits, M. (2001) The Nonsteroidal Anti-Inflammatory Drugs Aspirin and Indomethacin Attenuate β-Catenin/TCF-4 Signaling. Oncogene, 20, 645-653. http://dx.doi.org/10.1038/sj.onc.1204123
[56] Sikandar, S., Dizon, D., Shen, X., Li, Z., Besterman, J. and Lipkin, S.M. (2010) The Class I HDAC Inhibitor MGCD0103 Induces Cell Cycle Arrest and Apoptosis in Colon Cancer Initiating Cells by Upregulating Dickkopf-1 and Non-Canonical Wnt Signaling. Oncotarget, 1, 596-605.
[57] Asklund, T., Kvarnbrink, S., Holmlund, C., Wibom, C., Bergenheim, T., Henriksson, R., et al. (2012) Synergistic Killing of Glioblastoma Stem-Like Cells by Bortezomib and HDAC Inhibitors. Anticancer Research, 32, 2407-2413.
[58] Fujishita, T., Aoki, K., Lane, H.A., Aoki, M. and Taketo, M.M. (2008) Inhibition of the mTORC1 Pathway Suppresses Intestinal Polyp Formation and Reduces Mortality in ApcDelta716 Mice. Proceedings of the National Academy of Sciences of the United States of America, 105, 13544-13549.
http://dx.doi.org/10.1073/pnas.0800041105
[59] Fre, S., Bardin, A., Robine, S. and Louvard, D. (2011) Notch Signaling in Intestinal Homeostasis Across Species: The Cases of Drosophila, Zebrafish and the Mouse. Experimental Cell Research, 317, 2740-2747. http://dx.doi.org/10.1016/j.yexcr.2011.06.012
[60] Voojis, M., Liu, Z. and Kopan, R. (2011) Notch: Architect, Landscaper, and Guardian of the Intestine. Gastroenterology, 141, 448-459. http://dx.doi.org/10.1053/j.gastro.2011.06.003
[61] Miyamoto, S. and Rosenberg, D.W. (2011) Role of the Notch Signaling in Colon Homeostasis and Carcinogenesis. Cancer Science, 102, 1938-1942.
http://dx.doi.org/10.1111/j.1349-7006.2011.02049.x
[62] Meng, R.D., Shelton, C.C., Li, Y.M., Qin, L.X., Notterman, D., Paty, P.B., et al. (2009) Gamma-Secretase Inhibitors Abrogate Oxaliplatin-Induced Activation of the Notch-1 Signaling Pathway in Colon Cancer Cells Resulting in Enhanced Chemosensitivity. Cancer Research, 69, 573-582.
http://dx.doi.org/10.1158/0008-5472.CAN-08-2088
[63] Strosberg, J.R., Yeatman, T., Weber, J., Coppola, D., Schell, M.J., Han, G., et al. (2012) A Phase II Study of RO4929097 in Metastatic Colorectal Cancer. European Journal of Cancer, 48, 997-1003. http://dx.doi.org/10.1016/j.ejca.2012.02.056

  
comments powered by Disqus

Copyright © 2017 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.