Share This Article:

Preliminary Findings on the Use of Targeted Therapy in Combination with Sodium Phenylbutyrate in Recurrent Advanced Pancreatic Cancer—A Potential Strategy for Improved Survival

Full-Text HTML Download Download as PDF (Size:2980KB) PP. 1072-1091
DOI: 10.4236/jct.2014.512113    1,983 Downloads   2,501 Views   Citations

ABSTRACT

Metastatic pancreatic cancer carries an estimated five-year survival rate of only 2%. Gemcitabine-based chemotherapy remains a first-line standard-of-care treatment for elderly patients with advanced pancreatic cancer. Combination chemotherapy FOLFIRINOX offers better results, but it is not recommended for the older patient population due to substantial toxicity. Standard-of-care second-line treatment is not yet established and is used in approximately 30% of patients since performance status is too low to consider further therapy. Targeted therapies with a single agent and in combinations have been tested in numerous clinical trials, but except for the combination of gemcitabine and erlotinib, have not yet proven efficacy. Here, we present preliminary findings of improved overall survival (OS) using a combination of sodium phenylbutyrate with various chemotherapeutic and targeted agents in stage IV A and B pancreatic cancer patients who failed at least one line of chemotherapy. The results suggest a strategy of simultaneous interruption of signal transmission involving multiple pathways in the second-line treatment that are believed to interfere with cell cycle, cancer cell metabolism, autophagy and maintenance of cancer stem cells and promote apoptosis. In this group of patients, median OS was higher compared to other second-line therapies (10.5 months compared to between 2.9 and 6.5 months in other studies, and in the best supportive care group, 2.3 months). 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 pancreatic 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 Recurrent Advanced Pancreatic Cancer—A Potential Strategy for Improved Survival. Journal of Cancer Therapy, 5, 1072-1091. doi: 10.4236/jct.2014.512113.

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] Rahib, L., Smith, B.D., Aisenberg, R., Rosenzweig, A.B., Fleshman, J.M. and Matrisian, L.M. (2014) Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver and Pancreas Cancers in the United States. Cancer, 74, 2913-2921.
[3] DeSantis, C.E., Lin, C.C., Mariotto, A.B., Siegel R.L., Stein, K.D., et al. (2014) Cancer Treatment and Survivorship Statistics, 2014. CA: A Cancer Journal for Clinicians, 64, 252-271.
http://dx.doi.org/10.3322/caac.21235
[4] 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
[5] (2013) Cancer Facts and Figures 2013. American Cancer Society, Atlanta.
[6] Burris, H.A., Moore, M.J. andersen, J., Green, M.R., Rothenberg, M.L., et al. (1997) Improvements in Survival and Clinical Benefit with Gemcitabine as First-Line Therapy for Patient with Advanced Pancreas Cancer: A Randomized Trial. Journal of Clinical Oncology, 15, 2403-2413.
[7] Berlin, J.D., Catalano, P., Thomas, J.P., Kugler, J.W., Haller, D.G. and Benson, A.B. (2002) Phase III Study of Gemcitabine in Combination with Fluorouracil versus Gemcitabine Alone in Patients with Advanced Pancreatic Carcinoma: Eastern Cooperative Oncology Group Trial E2297. Journal of Clinical Oncology, 20, 3270-3275. http://dx.doi.org/10.1200/JCO.2002.11.149
[8] Bramhall, S.R., Schulz, J., Nemunaitis, J., Brown, P.D., Baillet, M. and Buckels, J.A. (2002) A Double-Blind Placebo-Controlled, Randomized Study Comparing Gemcitabine and Marimastat with Advanced Pancreatic Cancer. British Journal of Cancer, 87, 161-167. http://dx.doi.org/10.1038/sj.bjc.6600446
[9] Rocha Lima, C.M., Green, M.R., Rotche, R., Miller Jr., W.H., Jeffrey, G.M., et al. (2004) Irinotecan plus Gemcitabine Results in No Survival Advantage Compared with Gemcitabine Monotherapy in Patients with Locally Advanced or Metastatic Pancreatic Cancer Despite Increased Tumor Response Rate. Journal of Clinical Oncology, 22, 3776-3783. http://dx.doi.org/10.1200/JCO.2004.12.082
[10] Van Cutsem, E., van de Velde, H., Karasek, P., Oettle, H., Vervenne, W.L., et al. (2004) Phase III Trial of Gemcitabine plus Tipifarnib Compared with Gemcitabine plus Placebo in Advanced Pancreatic Cancer. Journal of Clinical Oncology, 22, 1430-1438. http://dx.doi.org/10.1200/JCO.2004.10.112
[11] Louvet, C., Labianca, R., Hammel, P., Lledo, G., Zampino, M.G., et al. (2004) GemOx (Gemcitabine + Oxaliplatin) versus Gem (Gemcitabine) in Non Resectable Pancreatic Adenocarcinoma: Final Results of the GERCOR/GISCAD Intergroup Phase III. Journal of Clinical Oncology, 22, 4008.
[12] Oettle, H., Richards, D.A., Ramanathan, R.K., van Laethem, J.L., Peeters, M., et al. (2005) A Randomized Phase III Study Comparing Gemcitabine + Pemetrexed versus Gemcitabine in Patients with Locally Advanced and Metastatic Pancreas Cancer. Annals of Oncology, 16, 1639-1645. http://dx.doi.org/10.1093/annonc/mdi309
[13] Abou Alfa, G.K., Letourneau, R., Harker, G., Modiano, M., Hurwitz, H., et al. (2006) A Randomized Phase III Trial of DX-8951f (Exatecan Mesylate; DX) and Gemcitabine (GEM) vs Gemcitabine Alone in Advanced Pancreatic Cancer (APC). Journal of Clinical Oncology, 24, 4441-4447.
http://dx.doi.org/10.1200/JCO.2006.07.0201
[14] Stathopoulos, G.P., Syrigos, K., Aravantinos, G., Polyzos, A., Papakotoulas, P., et al. (2006) A Multicenter Phase III Trial Comparing Irinotecan-Gemcitabine (IG) with Gemcitabine (G) Monotherapy as First-Line Treatment in Patients with Locally Advanced or Metastatic Pancreatic Cancer. British Journal of Cancer, 95, 587-592. http://dx.doi.org/10.1038/sj.bjc.6603301
[15] Moore, M.J., Goldstein, D., Hamm, J., Figer, A., Hecht, J.R., et al. (2007) Erlotinib plus Gemcitabine Compared with Gemcitabine Alone in Patients with Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology, 25, 1960-1966. http://dx.doi.org/10.1200/JCO.2006.07.9525
[16] Kulke, M.H., Blaszkowsky, L.S., Ryan, D.P., Clark, J.W., Meyerhardt, J.A., et al. (2007) Capecitabine plus Erlotinib in Gemcitabine-Refractory Advanced Pancreatic Cancer. Journal of Clinical Oncology, 25, 4787-4792. http://dx.doi.org/10.1200/JCO.2007.11.8521
[17] Chauffert, B., Mornex, F., Bonnetain, F., Rougier, P., Mariette, C., et al. (2008) Phase III Trial Comparing Intensive Induction Chemoradiotherapy (60 Gy, Infusional 5-FU and Intermittent Cisplatin) Followed by Maintenance Gemcitabine with Gemcitabine Alone for Locally Advanced Unresectable Pancreatic Cancer: Definitive Results of the 2000-2001 FFCD/SFRO Study. Annals of Oncology, 19, 1592-1599. http://dx.doi.org/10.1093/annonc/mdn281
[18] Xiong, H.Q., Varadhachary, G.R., Blais, J.C., Hess, K.R., Abbruzzese, J.L. and Wolf, R.A. (2008) Phase 2 Trial of Oxaliplatin plus Capecitabine (XELOX) as Second-Line Therapy for Patients with Advanced Pancreatic Cancer. Cancer, 113, 2046-2052. http://dx.doi.org/10.1002/cncr.23810
[19] Poplin, E., Feng, Y., Berlin, J., Rothenberg, M.L., Hochster, H., et al. (2009) Phase III, Randomized Study of Gemcitabine and Oxaliplatin versus Gemcitabine (Fixed-Dose Rate Infusion) Compared with Gemcitabine (30-Minute Infusion) in Patients with Pancreatic Carcinoma E6201: A Trial of the Eastern Cooperative Oncology Group. Journal of Clinical Oncology, 27, 3778-3785, Erratum 5859. http://dx.doi.org/10.1200/JCO.2008.20.9007
[20] Heinemann, V., Phillip, P.A. and Pelzer, U. (2009) Accomplishments in 2008 in the Treatment of Metastatic Pancreatic Cancer. Gastrointest Cancer Research, 3, S43-S47.
[21] Cunningham, D., Chau, I., Stocken, D.D., Valle, J.W., Smith, D., et al. (2009) Phase III Randomized Comparison of Gemcitabine versus Gemcitabine plus Capecitabine in Patients with Advanced Pancreatic Cancer. Journal of Clinical Oncology, 27, 5513-5518.
http://dx.doi.org/10.1200/JCO.2009.24.2446
[22] Colucci, G., Labianca, R., Di Costanzo, F., Gebbia, V., Carteni, G., et al. (2010) Randomized Phase III Trial of Gemcitabine Plus Cisplatin Compared with Single-Agent Gemcitabine as First-Line Treatment of Patients with Advanced Pancreatic Cancer: The GIP-1 Study. Journal of Clinical Oncology, 28, 1645-1651. http://dx.doi.org/10.1200/JCO.2009.25.4433
[23] Kindler, H.L., Niedzwiecki, D., Hollis, D., Sutherland, S., Schrag, D., et al. (2010) Gemcitabine Plus Bevacizumab Compared with Gemcitabine Plus Placebo in Patients with Advanced Pancreatic Cancer: Phase III Trial of the Cancer and Leukemia Group B (CALGB 80303). Journal of Clinical Oncology, 28, 3617-3622. http://dx.doi.org/10.1200/JCO.2010.28.1386
[24] Philip, P.A., Benedetti, J., Corless, C.L., Wong, R., O’Reilly, E.M., et al. (2010) Phase III Study Comparing Gemcitabine Plus Cetuximab versus Gemcitabine in Patients with Advanced Pancreatic Adenocarcinoma: Southwest Oncology Group Directed Intergroup Trial S0205. Journal of Clinical Oncology, 28, 3605-3610. http://dx.doi.org/10.1200/JCO.2009.25.7550
[25] Conroy, T., Desseigne, F., Ychou, M., Bouche’, O., Guimbaud, R., et al. (2011) FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. New England Journal of Medicine, 364, 1817-1825. http://dx.doi.org/10.1056/NEJMoa1011923
[26] Goncalves, A., Gilabert, M., Francois, E., Dahan, L., Perrier, H., et al. (2012) BAYPAN Study: A Double-Blind Phase III Randomized Trial Comparing Gemcitabine plus Sorafenib and Gemcitabine plus Placebo in Patients with Advanced Pancreatic Cancer. Annals of Oncology, 23, 2799-2805. http://dx.doi.org/10.1093/annonc/mds135
[27] Von Hoff, D.D., Ervin, T., Arena, F.P., Chiorean, E.G., Infante, J., et al. (2013) Increased Survival in Pancreatic Cancer with Nab-Paclitaxel plus Gemcitabine. New England Journal of Medicine, 369, 1691-1703. http://dx.doi.org/10.1056/NEJMoa1304369
[28] Huang, Z.Q., Saluja, A.K., Dudeja, V., Vickers, S.M. and Buchsbaum, D.J. (2011) Molecular Targeted Approaches for Treatment of Pancreatic Cancer. Current Pharmaceutical Design, 17, 2221-2238. http://dx.doi.org/10.2174/138161211796957427
[29] Wolfgang, C.L., Herman, J.M., Laheru, D.A., Klein, A.P., Erdek, M.A., et al. (2013) Recent Progress in Pancreatic Cancer. CA: A Cancer Journal for Clinicians, 63, 318-348.
http://dx.doi.org/10.3322/caac.21190
[30] Pelzer, U., Schwaner, I., Stieler, J., Adler, M., Seraphin, J., et al. (2011) Best Supportive Care (BSC) versus Oxaliplatin, Folinic Acid and 5-Fluorouracil (OFF) plus BSG in Patients for Second-Line Advanced Pancreatic Cancer: A Phase III-Study from the German CONKO-Study Group. European Journal of Cancer, 47, 1676-1681. http://dx.doi.org/10.1016/j.ejca.2011.04.011
[31] 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
[32] 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
[33] Baker, M.J., Brem, S., Daniels, S., Sherman, B. and Phuphanich, S. (2002) Complete Response of a Recurrent, Multicentric Malignant Glioma in a Patient Treated with Phenylbutyrate. Journal of Neuro-Oncology, 59, 239-242. http://dx.doi.org/10.1023/A:1019905127442
[34] 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
[35] Asklund, T., Kvarnbrink, S., Holmlund, C., Wibom, C., Bergenheim, T., et al. (2012) Synergistic Killing of Glioblastoma Stem-Like Cells by Bortezomib and HDAC Inhibitors. Anticancer Research, 32, 2407-2413.
[36] 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
[37] Milella, M., Gelibter, A., Di Cosimo, S., Bria, E., Ruggeri, E.M., et al. (2004) Pilot Study of Celecoxib and Infusional 5-Fluorouracil as Second-Line Treatment for Advanced Pancreatic Carcinoma. Cancer, 101, 133-138. http://dx.doi.org/10.1002/cncr.20338
[38] Cantore, M., Rabbi, C., Fiorentini, G., Oliani, C., Zamagni, D., et al. (2004) Combined Irinotecan and Oxaliplatin in Patients with Advanced Pre-Treated Pancreatic Cancer. Oncology, 67, 93-97. http://dx.doi.org/10.1159/000080993
[39] Androulakis, N., Syrigos, K., Polyzos, A., Aravantinos, G., Stathopoulos, G.P., et al. (2005) Oxaliplatin for Pretreated Patients with Advanced or Metastatic Pancreatic Cancer: A Multicenter Phase II Study. Cancer Investigation, 23, 9-12. http://dx.doi.org/10.1081/CNV-46502
[40] Demols, A., Peeter, M., Polus, M., Marechal, R., Gay, F., et al. (2006) Gemcitabine and Oxaliplatin (GEMOX) in Gemcitabine Refractory Advanced Pancreatic Adenocarcinoma: A Phase II Study. British Journal of Cancer, 94, 481-485. http://dx.doi.org/10.1038/sj.bjc.6602966
[41] Ignatiadis, M., Polyzos, A., Stathopoulos, G.P., Tselepatiotis, E., Christophylakis, C., et al. (2006) A Multicenter Phase II Study of Docetaxel in Combination with Gefitinib in Gemcitabine-Pretreated Patients with Advanced/Metastatic Pancreatic Cancer. Oncology, 71, 159-163.
http://dx.doi.org/10.1159/000106064
[42] Boeck, S., Weigang-Kohler, K., Fuchs, M., Kettner, E., Quietzsch, D., et al. (2007) Second-Line Chemotherapy with Pemetrexed after Gemcitabine Failure in Patients with Advanced Pancreatic Cancer: A Multicenter Phase II Trial. Annals of Oncology, 18, 745-751.
http://dx.doi.org/10.1093/annonc/mdl463
[43] Wolpin, B.M., Hezel, A.F., Abrams, T., Blaszkowsky, L.S., Meyerhardt, J.A., et al. (2009) Oral mTOR Inhibitor Everolimus in Patients with Gemcitabine-Refractory Metastatic Pancreatic Cancer. Journal of Clinical Oncology, 27, 193- 198. http://dx.doi.org/10.1200/JCO.2008.18.9514
[44] Jones, S., Zhang, X., Parsons, D.W., Lin, J.C., Leary, R.J., et al. (2008) Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses. Science, 321, 1801-1806.
http://dx.doi.org/10.1126/science.1164368
[45] Almoguera, C., Shibata, D., Forrester, K., Martin, J., Arnheim, N. and Perucho, M. (1988) Most Human Carcinomas of the Exocrine Pancreas Contain Mutant c-K-ras Genes. Cell, 53, 549-554.
http://dx.doi.org/10.1016/0092-8674(88)90571-5
[46] Caldas, C., Hahn, S.A., da Costa, L.T., Redston, M.S., Schutte, M., et al. (1994) Frequent Somatic Mutations and Homozygous Deletions of the p16 (MTS1) Gene in Pancreatic Adenocarcinoma. Nature Genetics, 8, 27-32.
http://dx.doi.org/10.1038/ng0994-27
[47] Ruggeri, B., Zhang, S.Y., Caamano, J., DiRado, M., Flynn, S.D. and Klein-Szanto, A.J. (1992) Human Pancreatic Carcinomas and Cell Lines Reveal Frequent and Multiple Alterations in the p53 and Rb-1 Tumor-Suppressor Genes. Oncogene, 7, 1503-1511.
[48] Scarpa, A., Capelli, P., Mukai, K., Zamboni, G., Oda, T., et al. (1993) Pancreatic Adenocarcinomas Frequently Show p53 Gene Mutations. American Journal of Pathology, 142, 1534-1543.
[49] Hahn, S.A., Schutte, M., Hoque, A.T., Moskaluk, C.A., da Costa, L.T., et al. (1996) DPC4, a Candidate Tumor Suppressor Gene at Human Chromosome 18q21.1. Science, 271, 350-353.
http://dx.doi.org/10.1126/science.271.5247.350
[50] Rodriguez-Viciana, P., Tetsu, O., Oda, K., Okada, J., Rauen, K. and McCormick, F. (2005) Cancer Targets in the Ras Pathway. Cold Spring Harbor Symposia on Quantitative Biology, 70, 461-467. http://dx.doi.org/10.1101/sqb.2005.70.044
[51] Navas, C., Hernandez-Porras, I., Schuhmacher, A.J., Sibilia, M., Guerra, C. and Barbacid, M. (2012) EGF Receptor Signaling Is Essential for K-Ras Oncogene-Driven Pancreatic Ductal Adenocarcinoma. Cancer Cell, 22, 318-330. http://dx.doi.org/10.1016/j.ccr.2012.08.001
[52] Komoto, M., Nakata, B., Amano, R., Yamada, N., Yashiro, M., et al. (2009) HER2 Overexpression Correlates with Survival after Curative Resection of Pancreatic Cancer. Cancer Science, 100, 1243-1247. http://dx.doi.org/10.1111/j.1349-7006.2009.01176.x
[53] Mach, J.P., Azria, D., Robert, B. and Pelegrin, A. (2012) In Pancreatic Carcinoma, Dual EGFR/HER2 Targeting with Cetuximab/Trastuzumab Is More Effective than Treatment with Trastuzumab/Erlotinib or Lapatinib Alone: Implication of Receptors’ Down-Regulation and Dimers’ Disruption. Neoplasia, 14, 121-130.
[54] Collisson, E.A., Trejo, C.L., Silva, J.M., Gu, S., Korkola, J.E., et al. (2012) A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma. Cancer Discovery, 2, 685-693. http://dx.doi.org/10.1158/2159-8290.CD-11-0347
[55] Mendoza, M.C., Er, E.E. and Blenis, J. (2011) The Ras-Erk and PI3K-mTOR Pathways: Cross-Talk and Compensation. Trends in Biochemical Sciences, 36, 320-328.
http://dx.doi.org/10.1016/j.tibs.2011.03.006
[56] Nagaraj, N.S., Washington, M.K. and Merchant, N.B. (2011) Combined Blockade of Src Kinase and Epidermal Growth Factor Receptor with Gemcitabine Overcomes STAT3-Mediated Resistance of Inhibition of Pancreatic Tumor Growth. Clinical Cancer Research, 17, 483-493.
http://dx.doi.org/10.1158/1078-0432.CCR-10-1670
[57] Ulivi, P., Arienti, C., Tesei, A., Fabbri, F., Zoli, W., et al. (2008) Different Mechanisms Involved in the Activity of BAY 43-9006 (Sorafenib) in Human Pancreatic Cancer Cell Lines. Proceedings of the American Association of Cancer Research 99th Annual Meeting, San Diego, 12-16 April 2008, Abstract 2809.
[58] Ottenhof, N.A., de Wilde, R.F., Maitra, A., Hruban, R.H. and Offerhaus, G.J. (2011) Molecular Characteristics of Pancreatic Ductal Adenocarcinoma. Pathology Research International, 2011, Article ID: 620601. http://dx.doi.org/10.4061/2011/620601
[59] Venkannagari, S., Fiskus, W., Peth, K., Atadja, P., Hidalgo, M., et al. (2012) Superior Efficacy of Co-treatment with Dual PI3K/mTOR Inhibitor NVP-BEZ235 and Pan-histone Deacetylase Inhibitor against Human Pancreatic Cancer. Oncotarget, 3, 1416-1427.
[60] Seo, Y., Baba, H., Fukuda, T., Takashima, M. and Sugimachi, K. (2000) High Expression of Vascular Endothelial Growth Factor Is Associated with Liver Metastasis and a Poor Prognosis for Patients with Ductal Pancreatic Adenocarcinoma. Cancer, 88, 2239-2245. http://dx.doi.org/10.1002/(SICI)1097-0142(20000515)88:10<2239::AID-CNCR6>3.0.CO;2-V
[61] Morris, J.P., Wang, S.C. and Hebrok, M. (2010) KRAS, Hedgehog, Wnt and the Twisted Developmental Biology of Pancreatic Ductal Adenocarcinoma. Nature Reviews Cancer, 10, 683-695.
http://dx.doi.org/10.1038/nrc2899
[62] Thayer, S.P., di Magliano, M.P., Heiser, P.W., Nielsen, C.M., Roberts, D.J., et al. (2003) Hedgehog Is an Early and Late Mediator of Pancreatic Cancer Tumorigenesis. Nature, 425, 851-856.
http://dx.doi.org/10.1038/nature02009
[63] di Magliano, M.P., Sekine, S., Ermilov, A., Ferris, J., Dlugosz, A.A. and Hebrok, M. (2006) Hedgehog/Ras Interactions Regulate Early Stages of Pancreatic Cancer. Genes and Development, 20, 3161-3173. http://dx.doi.org/10.1101/gad.1470806
[64] Catenacci, D.V.T., Bahary, N., Nattam, S.R., de Wilton Marsh, R., Walace, J.A., et al. (2013) Final Analysis of a Phase IB/Randomized Phase II Study of Gemcitabine (G) plus Placebo (P) or Vismodegib (V), a Hedgehog (Hh) Pathway Inhibitor, in Patients (pts) with Metastatic Pancreatic Cancer (PC): A University of Chicago Phase II Consortium Study. Journal of Clinical Oncology, 31.
[65] Rudin, C.M., Hann, C.L., Laterra, J., Yauch, R.L., Callahan, C.A., et al. (2009) Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449. New England Journal of Medicine, 361, 1173-1178. http://dx.doi.org/10.1056/NEJMoa0902903
[66] De La O, J.P., Emerson, L.L., Goodman, J.L., Froebe, S.C., Illum, B.E., et al. (2008) Notch and Kras Reprogram Pancreatic Acinar Cells to Ductal Intraepithelial Neoplasia. PNAS, Proceedings of the National Academy of Sciences of the United States of America, 105, 18907-18912.
http://dx.doi.org/10.1073/pnas.0810111105
[67] Romero, D., Iglesias, M., Vary, C.P. and Quintanilla, M. (2008) Functional Blockade of Smad4 Leads to a Decrease in β-Catenin Levels and Signaling Activity in Human Pancreatic Carcinoma Cells. Carcinogenesis, 29, 1070-1076. http://dx.doi.org/10.1093/carcin/bgn054
[68] Beck, B., Driessens, G., Goossens, S., Youssef, K.K., Kuchnio, A., et al. (2011) A Vascular Niche and a VEGF-Nrp1 Loop Regular the Initiation and Stemness of Skin Tumours. Nature, 478, 399-403. http://dx.doi.org/10.1038/nature10525
[69] Snuderl, M., Batista, A., Kirkpatrick, N.D., de Almodovar, C.R., Riedemann, L., et al. (2013) Targeting Placental Growth Factor/Neuropilin 1 Pathway Inhibits Growth and Spread of Medulloblastoma. Cell, 152, 1065-1076. http://dx.doi.org/10.1016/j.cell.2013.01.036
[70] De Bacco, F., Casanova, E., Medico, E., Pellegatta, S., Orzan, F., et al. (2012) The MET Oncogene Is a Functional Marker or a Glioblastoma Stem Cell Subtype. Cancer Research, 72, 4537-4550.
http://dx.doi.org/10.1158/0008-5472.CAN-11-3490
[71] Burzynski, S.R. (1976) Antineoplastons: Biochemical Defense against Cancer. Physiological Chemistry and Physics, 8, 275-279.
[72] Burzynski, S.R. (1986) Antineoplastons—History of the Research (I). Drugs under Experimental and Clinical Research, 12, 1-9.
[73] Burzynski, S.R. (2004) The Present State of Antineoplaston Research (1). Integrative Cancer Therapies, 3, 47-58. http://dx.doi.org/10.1177/1534735403261964
[74] 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
[75] 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, Epub Ahead of Print. http://dx.doi.org/10.1007/s00381-014-2401-z
[76] 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
[77] 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

  
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.