Novel Drug Discovery

 

NOVEL DRUG DEVELOPMENT AT ANTICANCER IN SOI (MetaMouse ®) MODELS

LICENSING AND CONTRACT RESEARCH

 

Novel Pancreatic Cancer Drugs Developed Using MetaMouse  Models with RFP Imaging [PPT]

 

1. The metalloproteinase inhibitor Batimastat: Active against a SOI human-patient colon tumor model 1 including:
    a. Inhibition of primary tumor growth
    b. Inhibition of metastatic events
    c. Extension of survival.

2. The metalloproteinase inhibitor CT1746: Active against a SOI human colon tumor xenograft model 2 :
    a. Arrest of primary tumor growth
    b. Inhibition of metastatic events, and
    c. A large increase in survival.

3. IFN-?: Active against a patient pleural cancer SOI model 3:
    a. Elimination of metastatic events
    b. Decrease in cachexia, and
    c. Extension of survival.

4. Angiogenesis inhibitor TNP-470: Active in patient colon and stomach tumor SOI models 4,5,6,7,8:
   a. Inhibition of liver metastasis in colon cancer
   b. Minimal or no effect on primary tumor.

5. Anti-VEGF antibody: Active in SOI model of colon and stomach cancer 7, 9, 10:
    a. Inhibition of liver metastasis in colon cancer
    b. Minimal or no effect on primary tumor.

6. Antisense phosporothionate oligionucleotide specific for VEGF-receptor active in SOI model of stomach cancer 11:
    a. Inhibition of peritoneal tumor dissemination
    b. Increased tumor cell apoptosis
    c. Microvessel density (MVD) in tumor nodules.

7. New platinum analogs {Pt(cis-dach)(DPPE)?2NO3} and {Pt(trans-dach)(DPPE)?2NO3} active in SOI model of bladder and stomach cancer 12, 13:
    a. No metastases in either of the high- or low-dose platinum-analog-treated groups in SOI model of bladder cancer.
    b. No mesenteric lymph node metastases in the groups treated with the high or low doses of both new platinum analogs with SOI model of colon cancer.

8. Liposomal doxorubicin (Doxil) 14.
    a. Inhibition of MDA-MB-231 human breast tumor xenografts, which were resistant to free doxorubicin.

9. Camptothecin analog DX-8951f: Active in SOI models of pancreatic cancer 15.
    a. DX-8951f showed efficacy against two human pancreatic tumor cell lines in the SOI-GFP model. DX-8951f was highly effective against primary and metastatic growth in the two models and showed significantly higher efficacy than gemcitabine, the standard treatment of pancreatic cancer.

10. Cytosine analog, CS-682: Active in SOI model of pancreatic cancer 16, 17.
      a.CS-682 showed efficacy on inhibiting pancreatic cancer growth and metastasis in a RFP orthotopic nude mouse model of human pancreatic model.
      b.CS-682 showed efficacy in an adjuvant treatment orthotopic model of human pancreatic cancer suggesting possibility of chronic use of CS-682 to control pancreatic cancer.

11. Estrogen analog 2-methoxyoestradiol-bis-sulphamate: active in MDA-MB-435 SOI model of breast cancer 18.

12. Truncated galectin-3 (galectin-3C) was found active in an orthotopic breast cancer xenograft nude mouse model imaged with green fluorescent protein 19.

13. The agonistic anti-LTBR monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents 34.

14. Additive effects of glufosfamide and gemcitabine in fluorescent orthotopic mouse models of human pancreatic cancer 35, 36.

 

15. A monoclonal antibody to the chemokine receptor CXCR2 was effective against pancreatic cancer in the SOI model37.

 

16. TSU68 prevents liver metastasis of colon cancer xenografts by modulating the premetastatic niche38.

 

17. Type II PDGFRβ/B-RAF inhibitor disrupts angiogenesis and tumor growth39.

 

18. A small molecule inhibitor of SDF-1/CXCR4 inhibits vasculogenesis, but not angiogenesis, and prevents the recurrence of glioblastoma following irradiation in mice 40.

 

19. HER-2 therapy inhibits metastasis of esophageal cancer41.

 

20. Metronomic gemcitabine therapy greatly inhibits metastasis of pancreatic cancer42.

 

21. Bisphosphonate olpadronate inhibits bone metastasis in prostate cancer43

 

22. Knockdown of the β1 integrin subunit reduces primary tumor growth and inhibits pancreatic cancer metastasis44.

 

23. High antimetastatic efficacy of MEN4901/T-0128, a novel camptothecin carboxymethyldextran conjugate45.

 

24. Imaging the inhibition by anti-β1 integrin antibody on lung seeding of single cells in live mice46.

 

25. Traditional Medicinal Herb Celastrus orbiculatus Thunb on human hepatocellular carcinoma in an orthotopic fluorescent nude mouse model47.

 

26. Real-time imaging of induction of apoptosis of human breast cancer cells by the traditional Chinese medicine herb Tubeimu48.

Feasibility for the drug discovery in the SOI models has been demonstrated with colon, pancreatic, stomach, bladder, and lung cancer where chemotherapy has resulted in dose-response, differential sensitivity of primary and metastatic tumors, reproducibility, and correlation to historical clinical activity of the drugs including 5-FU, CDDP, mitomycin-C as well as the new agents listed above 1, 4-8, 11-13, 20-33, 45

References
  1. Wang X, Fu X, Brown PD, Crimmin MJ, Hoffman RM. Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. Cancer Res. 54, 4726-4728, 1994.[PDF]

  2. An Z, Wang X, Willmott N, Chander SK, Tickle S, Docherty AJ, Mountain A, Millican AT, Morphy R, Porter JR, Epemolu RO, Kubota T, Moossa AR, Hoffman RM. Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor. Clin. Exp. Metastasis 15, 184-195, 1997.[PDF]

  3. An Z, Wang X, Astoul P, Danays T, Moossa AR, Hoffman RM. Interferon gamma is highly effective against orthotopically-implanted human pleural adenocarcinoma in nude mice. Anticancer Res. 16, 2545-2551, 1996. [PDF]

  4. Kanai T, Konno H, Tanaka T, Matsumoto K, Baba M, Nakamura S, Baba S. Effect of angiogenesis inhibitor TNP-470 on the progression of human gastric cancer xenotransplanted into nude mice. Int. J. Cancer 71, 838-841, 1997.[PDF]

  5. Konno H, Tanaka T, Kanai T, Maruyama K, Nakamura S, Baba S. Efficacy of an angiogenesis inhibitor, TNP-470, in xenotransplanted human colorectal cancer with high metastatic potential. Cancer 77, 1736-1740, 1996.[PDF]

  6. Konno H, Tanaka T, Matsuda I, Kanai T, Maruo Y, Nishino N, Nakamura S, Baba S. Comparison of the inhibitory effect of the angiogenesis inhibitor, TNP-470, and mitomycin C on the growth and liver metastasis of human colon cancer. Int. J. Cancer 61, 268-271, 1995.[PDF]

  7. Konno H, Tanaka T, Baba M, Matsumoto K, Kamiya K, Nakamura S, Baba S, Arai T, Asano M, Suzuki H. Antitumor effect of angiogenesis inhibitors on colon cancer. Biotherapy 11, 993-996, 1997.

  8. Tanaka T, Konno H, Matsuda I, Nakamura S, Baba S. Prevention of hepatic metastasis of human colon cancer by angiogenesis inhibitor TNP-470. Cancer Res. 55, 836-839, 1995.[PDF]

  9. Konno H, Arai T, Tanaka T, Baba M, Matsumoto K, Kanai T, Nakamura S, Baba S, Naito Y, Sugimura H, Yukita A, Asano M, Suzuki H. Antitumor effect of a neutralizing antibody to vascular endothelial growth factor on liver metastasis of endocrine neoplasm. Jpn. J. Cancer Res. 89, 933-939, 1998.[PDF]

  10. Matsumoto K, Konno H, Tanaka T, Baba M, Kanai T, Kamiya K, Ohba K, Nakamura S. Combination therapy with vascular endothelial growth factor neutralizing antibody and mitomycin C on human gastric cancer xenograft. Jpn. J. Cancer Res. 91, 748-752, 2000.[PDF]

  11. Kamiyama M, Ichikawa Y, Ishikawa T, Chishima T, Hasegawa S, Hamaguchi Y, Nagashima Y, Miyagi Y, Mitsuhashi M, Hyndman D, Hoffman RM, Ohki S, Shimada H. VEGF receptor antisense therapy inhibits angiogenesis and peritoneal dissemination of human gastric cancer in nude mice. Cancer Gene Therapy 9, 197-201, 2002.[PDF]

  12. Chang S-G, Kim JI, Jung J-C, Rho Y-S, Lee K-T, An Z, Wang X, Hoffman RM. Antimetastatic activity of the new platinum analog {Pt(cis-dach)(DPPE)×(2NO3} in a metastatic model of human bladder cancer. Anticancer Res. 17, 3239-3242, 1997.[PDF]

  13. Rho Y-S, Lee K-T, Jung J-C, Yoon C, An Z, Hoffman RM, Chang S-G. Efficacy of new platinum analog DPPE in an orthotopic nude mouse model of human colon cancer. Anticancer Res. 19, 157-161, 1999.[PDF]

  14. Woessner R, An Z, Li X, Hoffman RM, Dix R, Bitonti A. Comparison of three approaches to doxorubicin therapy: free doxorubicin, liposomal doxorubicin, and b-glucuronidase-activated prodrug (HMR 1826). Anticancer Res. 20, 2289-2296, 2000. [PDF]

  15. Sun F-X, Tohgo A, Bouvet M, Yagi S, Nassirpour R, Moossa AR, Hoffman RM. Efficacy of camptothecin analog DX-8951f (Exatecan Mesylate) on human pancreatic cancer in an orthotopic metastatic model. Cancer Res. 63, 80-85, 2003.[PDF]

  16. Katz MH, Bouvet M, Takimoto S, Spivac D, Moossa AR, Hoffman RM. Selective antimetastatic activity of cytosine analog CS-682 in a red fluorescent protein orthotopic model of pancreatic cancer. Cancer Res. 63, 5521-5525, 2003.[PDF]

  17. Wu M, Mazurchuk R, Chaudhary ND, Spernyak J, Veith J, Pera P, Greco W, Hoffman RM, Kobayashi T, Bernacki RJ. High-resolution magnetic resonance imaging of the efficacy of the cytosine analog 1-[2-C-Cyano-2-deoxy-b-d-arabino-pentofuranosyl]-N4-palmitoyl cytosine (CS-682) in a liver-metastasis athymic nude mouse model. Cancer Res. 63, 2477-2482, 2003.[PDF]

  18. Ireson CR, Chander SK, Purohit A, Perera S, Newman SP, Parish D, Leese MP, Smith AC, Potter BV and Reed MJ. Pharmacokinetics and efficacy of 2-methoxyoestradiol and 2-methoxyoestradiol-bis-sulphamate in vivo in rodents. Br. J. Cancer 90, 932–937, 2004.[PDF]

  19. John CM, Leffler H, Kahl-Knutsson B, Svensson I, Jarvis GA. Truncated galectin-3 inhibits tumor growth and metastasis in orthotopic nude mouse model of human breast cancer. Clin. Cancer Res. 9, 2374-2383, 2003.[PDF]

  20. Rashidi B, An Z, Sun F-X, Li X, Tang ZY, Moossa AR, Hoffman RM. Efficacy of intra-hepatectomy 5-FU on recurrence and metastasis of human hepatocellular carcinoma in nude mice. Int. J. Cancer 91, 231-235, 2001.[PDF]

  21. Lee NC, Bouvet M, Nardin S, Jiang P, Baranov E, Rashidi B, Yang M, Wang X, Moossa AR, Hoffman RM. Antimetastatic efficacy of adjuvant gemcitabine in a pancreatic cancer orthotopic model. Clin. Exp. Metastasis 18, 379-384, 2000.[PDF]

  22. Furukawa T, Kubota T, Watanabe M, Kuo TH, Kase S, Saikawa Y, Tanino H, Teramoto T, Ishibiki K, Kitajima M, Hoffman RM. Immunochemotherapy prevents human colon cancer metastasis after orthotopic onplantation of histologically-intact tumor tissue in nude mice. Anticancer Res. 13, 287-291, 1993.[PDF]

  23. Furukawa T, Kubota T, Watanabe M, Kuo TH, Kitajima M, Hoffman RM. Differential chemosensitivity of local and metastatic human gastric cancer after orthotopic transplantation of histologically intact tumor tissue in nude mice. Int. J. Cancer 54, 397-401, 1993.

  24. Furukawa T, Kubota T, Watanabe M, Kitajima M, Hoffman RM. A novel "patient-like" treatment model of human pancreatic cancer constructed using orthotopic transplantation of histologically intact human tumor tissue in nude mice. Cancer Res. 53, 3070-3072, 1993. [PDF]

  25. Kuo TH, Kubota T, Watanabe M, Furukawa T, Kase S, Tanino H, Saikawa Y, Ishibiki K, Kitajima M, Hoffman RM. Site-specific chemosensitivity of human small-cell lung carcinoma growing orthotopically compared to subcutaneously in SCID mice: The importance of orthotopic models to obtain relevant drug evaluation data. Anticancer Res. 13, 627-630, 1993.[PDF]

  26. Fu X, Le P, Hoffman RM. A metastatic orthotopic-transplant nude-mouse model of human patient breast cancer. Anticancer Res. 13, 901-904, 1993.[PDF]

  27. Astoul P, Colt HG, Wang X, Hoffman RM. Metastatic human pleural ovarian cancer model constructed by orthotopic implantation of fresh histologically-intact patient carcinoma in nude mice. Anticancer Res. 13, 1999-2002, 1993.[PDF]

  28. Astoul P, Wang X, Hoffman RM. ‘Patient-like’ nude- and SCID-mouse models of human lung and pleural cancer (Review). Int. J. Oncology 3, 713-718, 1993.[PDF]

  29. Kubota T, Inoue S, Furukawa T, Ishibiki K, Kitajima M, Kawamura E, Hoffman RM. Similarity of serum – Tumor pharmacokinetics of antitumor agents in man and nude mice. Anticancer Res. 13, 1481-1484, 1993.[PDF]

  30. Astoul P, Colt HG, Wang X, Hoffman RM. A “patient-like” nude mouse model of parietal pleural human lung adenocarcinoma. Anticancer Res. 14, 85-91, 1994.

  31. Olbina G, Cieslak D, Ruzdijic S, Esler C, An Z, Wang X, Hoffman R, Seifert W, Pietrzkowski Z. Reversible inhibition of IL-8 receptor B mRNA expression and proliferation in non-small cell lung cancer by antisense oligonucleotides. Anticancer Res. 16, 3525-3530, 1996.[PDF]

  32. Rashidi B, An Z, Sun F-X, Moossa AR, Hoffman RM. Antimetastatic intraoperative chemotherapy of human colon tumors in the livers of nude mice. Clin. Cancer Res. 6, 2464-2468, 2000.[PDF]

  33. Katz MH, Bouvet M, Takimoto S, Spivack D, Moossa AR, Hoffman RM. Survival efficacy of adjuvant cytosine-analogue CS-682 in a fluorescent orthotopic model of human pancreatic cancer. Cancer Res. 64, 1828-1833, 2004.[PDF]

  34. Lukashev M, LePage D, Wilson C, Bailly V, Garber E, Lukashin A, Ngam-ek A, Zeng W, Allaire N, Perrin S, Xu X, Szeliga K, Wortham K, Kelly R, Bottiglio C, Ding J, Griffith L, Heaney G, Silverio E, Yang W, Jarpe M, Fawell S, Reff M, Carmillo A, Miatkowski K, Amatucci J, Crowell T, Prentice H, Meier W, Violette SM, Mackay F, Yang D, Hoffman RM, Browning JL. Targeting the lymphotoxin-β receptor with agonist antibodies as a potential cancer therapy. Cancer Res. 66, 9617-9624, 2006.[PDF]

  35. Ammons, W.S., Wang, J.W., Yang, Z., Tidmarsh, G.F., and Hoffman, R.M. A novel alkylating agent, glufosfamide, enhances the activity of gemcitabine in vitro and in vivo. Neoplasia 9, 625-633, 2007.[PDF]

  36. Duan, J.X., Jiao, H., Kaizerman, J., Stanton, T., Evans, J.W., Lan, L., Lorente, G., Banica, M., Jung, D., Wang, J., Ma, H., Li, X., Yang, Z., Hoffman, R.M., Ammons, W.S., Hart, C.P., and Matteucci, M. Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs. Journal of Medicinal Chemistry 51, 2412-2420, 2008.[PDF]

  37. Yamamoto, M., Kikuchi, H., Ohta, M., Kawabata, T., Hiramatsu, Y., Kondo, K., Baba, M., Kamiya, K., Tanaka, T., Kitagawa, M., Konno, H. TSU68 prevents liver metastasis of colon cancer xenografts by modulating the premetastatic niche. Cancer Res. 68, 9754-9762, 2008.[PDF]

  38. Matsuo, Y., Raimondo, M., Woodward, T.A., Wallace, M.B., Gill, K.R., Tong, Z., Burdick, M.D., Yang, Z., Strieter, R.M., Hoffman, R.M., Guha, S. CXC-chemokine/CXCR2 biological axis promotes angiogenesis in vitro and in vivo in pancreatic cancer. Int. J. Cancer 125, 1027-1037, 2009.[PDF]

  39. Murphy, E.A., Shields, D.J., Stoletov, K., Dneprovskaia, E., McElroy, M., Greenberg, J.I., Lindquist, J., Acevedo, L.M., Anand, S., Majeti, B.K., Tsigelny, I., Saldanha, A., Walsh, B., Hoffman, R.M., Bouvet, M., Klemke, R.L., Vogt, P.K., Arnold, L., Wrasidlo, W., and Cheresh, D.A. Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRb/B-RAF. Proc. Natl. Acad. Sci. USA 107, 4299-4304, 2010. [PDF]

  40. Kioi, M., Vogel, H., Schultz, G., Hoffman, R.M., Harsh, G.R., and Brown, J.M. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma following irradiation in mice. Journal of Clinical Investigation 120, 694-705, 2010. [PDF]

  41. Gros, S., Kurschat, N., Dohrmann, T., Reichelt, U., Dancau, A-M., Peldschus, K., Adam, G., Hoffman, R.M., Izbicki, J.R., Kaifi, J.T. Therapeutic targeting of the HER-2 receptor in a highly metastatic orthotopic model of esophageal carcinoma. Molecular Cancer Therapeutics 9, 2037-2045, 2010.[PDF]

  42. Tran Cao, H.S., Bouvet, M., Kaushal, S., Keleman, A., Romney, E., Kim, G., Fruehauf, J., Imagawa, D.K., Hoffman, R.M., Katz, M. Low-dose metronomic gemcitabine in combination with Sunitinib inhibits multi-site metastasis and increases survival in an orthotopic model of pancreatic cancer. Molecular Cancer Therapeutics 9, 2068-2078, 2010. [PDF] (Highlights Section. Molecular Cancer Therapeutics 9, 1929, 2010 [PDF]).

  43. Yang, M., Burton, D.W., Geller, J., Hillegonds, D., Hastings, R.H., Deftos, L.J., and Hoffman, R.M.  The bisphosphonate olpadronate inhibits skeletal prostate cancer progression in a green fluorescent protein nude mouse model.  Clinical Cancer Research 12, 2602-2606, 2006. [PDF]

  44. Grzesiak, J.J., Tran Cao, H.S., Burton, D.W., Kaushal, S., Vargas, F., Clopton, P., Snyder, C.S., Deftos, L.J., Hoffman, R.M., and Bouvet, M.  Knockdown of the β1 integrin subunit reduces primary tumor growth and inhibits pancreatic cancer metastasis.  International Journal of Cancer 129, 2905-2915, 2011.

  45. Ma, H., Li, X., Yang, Z., Okuno, S., Kawaguchi, T., Yagi, S., Bouvet, M, and Hoffman, R.M.  High antimetastatic efficacy of MEN4901/T-0128, a novel camptothecin carboxymethyldextran conjugate.  J. Surg. Res. 171, 684-690, 2011. 

  46. Kimura, H., Tome, Y., Momiyama, M., Hayashi, K., Tsuchiya, H., Bouvet, M., Hoffman, R.M.  Imaging the inhibition by anti-β1 integrin antibody on lung seeding of single cells in live mice.  Int. J. Cancer 131, 2027-2033, 2012.

  47. Wang, M., Zhang, X., Xiong, X., Yang, Z., Sun, Y., Yang, Z., Hoffman, R.M., and Liu, Y.  Efficacy of the Chinese Traditional Medicinal Herb Celastrus orbiculatus Thunb on human hepatocellular carcinoma in an orthotopic fluorescent nude mouse model.  Anticancer Res. 32, 1213-1220, 2012.[PDF]

  48. Hu, M., Zhao, M., An, C., Yang, M., Zhang, Y., Suetsugu, A., Tome, Y., Yano, S., Fu, Y., Hoffman, R.M., and Hu, K.  Real-time imaging of induction of apoptosis of human breast cancer cells by the traditional Chinese medicine herb Tubeimu.  Anticancer Res. 32, 2509-2514, 2012 [PDF]

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