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10-15-04 AACR Article: 2C3+Rapamycin in Pancreatic
Found by Terry on RB, who suggests possible connection to Merck.

A Phase2 study at John Hopkins, by Dr. Manuel Hidalgo, was designed “To determine how and for how long patients with previously treated advanced pancreatic cancer respond to Rapamycin. Rapamycin, a macrocyclic lactone which has antitumor properties, is an oral medication given on an outpatient basis once everyday.”

Nature.com says, “According to scientists at the University of Regensburg, Germany, the newer immunosuppressive drug, Rapamycin may reduce the risk of subsequent tumor development, whereas older drugs such as cycosporine could facilitate cancer growth.”

Now, Thorpe and 2C3 co-inventor Rolf Brekken (a PPHM SAB’er) join up with friends at Harvard Medical School and Mayo Clinic to study 2C3 + Rapamycin in Pacreatic Cancer, and conclude “A Rapamycin + 2C3 combo inhibit both primary and metastatic tumor growth in pancreatic cancer, and is a significant advantage compared with single treatment with Rapamycin.” Now, WHO’s going to take it and RUN? BTW, Terry, a quick Google told me that Rapamycin’s manufacturer is WYETH. Merck? Wyeth? – either one will do!

“Effect of Rapamycin Alone and in Combination with Antiangiogenesis Therapy in an Orthotopic Model of Human Pancreatic Cancer”
Clinical Cancer Research Vol. 10, 6993-7000, Oct. 15, 2004
American Association for Cancer Research
Experimental Therapeutics, Preclinical Pharmacology
http://clincancerres.aacrjournals.org/cgi/content/abstract/10/20/6993
Susann Stephan1, Kaustubh Datta 1,5,6, Enfeng Wang 1,5,6, Jinping Li1 5,6, Rolf A. Brekken 3, Sareh Parangi 2, Philip E. Thorpe 4 and Debabrata Mukhopadhyay 1,5,6
Depts of 1 Pathology and 2 Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Depts of 3 Surgery and 4 Pharmacology, UT-SW Medical Center, Dallas, Texas; and 5 Mayo Clinic Cancer Center and 6 Dept of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN

Purpose: The overall 5-year survival of patients with pancreatic cancer remains <5%. Novel therapeutic strategies are needed. We examined the effect of Rapamycin, alone and in combination with antiangiogenesis therapy, on pancreatic cancer in vivo.

Experimental Design: Human pancreatic cancer AsPC-1 cells were orthotopically injected into severe combined immunodeficient/beige mice to evaluate primary tumor growth and liver metastasis after treatment with Rapamycin alone or in combination with anti-vascular endothelial growth factor antibody 2C3. Tumor cell proliferation was determined by bromodeoxyuridine incorporation. To detect tumor cell apoptosis, the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used. Tumor angiogenesis was investigated by using a monoclonal anti-CD31 antibody. All statistical tests were two-sided.

Results: Rapamycin, alone and in combination with 2C3, strongly inhibited primary and metastatic tumor growth in an orthotopic pancreatic cancer animal model. Furthermore, the combination therapy significantly improved the effect on liver metastasis compared with single treatment with either rapamycin (P = 0.0128) or 2C3 (P = 0.0099). Rapamycin alone inhibited pancreatic tumor cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Nevertheless, the combination therapy showed a significant, stronger inhibition of tumor cell proliferation (P = 0.0002 versus Rapamycin alone and P < 0.0001 versus 2C3 alone). The induction of apoptosis was significantly higher than in the rapamycin-treated group (P = 0.0039). Additionally, the combination therapy further improved suppression of tumor cell angiogenesis compared with rapamycin treatment (P = 0.029)

Conclusions: Our studies propose new therapeutic strategies to inhibit both primary and metastatic tumor growth in pancreatic cancer. Considering the fact that liver metastasis is a crucial problem in advanced stages of pancreatic cancer, the combination therapy of Rapamycin plus anti-vascular endothelial growth factor antibody 2C3 is a significant advantage compared with single treatment with Rapamycin.