maytansine and Pancreatic-Neoplasms

The antibody-drug conjugate trastuzumab emtansine (T-DM1) is approved for human epidermal growth factor receptor 2 (HER2/ERBB2)-positive breast cancer. We aimed to study tumor HER2 expression and its effects on T-DM1 responses in patients with HER2-positive urothelial bladder cancer (UBC) or pancreatic cancer (PC)/cholangiocarcinoma (CC). In the phase II KAMELEON study (NCT02999672), HER2 status was centrally assessed by immunohistochemistry, with positivity defined as non-focal homogeneous or heterogeneous overexpression of HER2 in ≥30% of stained cells. We also performed exploratory biomarker analyses (e.g., gene-protein assay) on tissue samples collected from study participants and consenting patients who failed screening. Of the 284 patients successfully screened for HER2 status (UBC, n = 69; PC/CC, n = 215), 13 with UBC, four with PC, and three with CC fulfilled eligibility criteria. Due to recruitment difficulty, the sponsor terminated KAMELEON prematurely. Of the five responders in the UBC cohort (overall response rate, 38.5%), HER2 expression was heterogeneous in two and homogeneous in three. The one responder in the PC/CC cohort had PC, and the tumor displayed homogeneous expression. In the biomarker-evaluable population, composed of screen-failed and enrolled patients, 24.3% (9/37), 1.5% (1/66), and 8.2% (4/49) of those with UBC, PC, or CC, respectively, had HER2-positive tumors. In a gene-protein assay combining in situ hybridization with immunohistochemistry, greater HER2 homogeneity was associated with increased ERBB2 amplification ratio. In conclusion, KAMELEON showed that some patients with HER2-positive UBC or PC can respond to T-DM1 and provided insight into the prevalence of HER2 positivity and expression patterns in three non-breast tumor types.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Breast Neoplasms; Carcinoma, Transitional Cell; Cholangiocarcinoma; Female; Humans; Maytansine; Pancreatic Neoplasms; Receptor, ErbB-2; Trastuzumab; Urinary Bladder Neoplasms

One hundred and five patients with advanced measurable pancreatic carcinoma were randomized to receive therapy with maytansine, low-dose chlorozotocin (120 mg/m2), or high-dose chlorozotocin (175 mg/m2). Objective response rates were as follows: maytansine, no responses among 48 patients; low-dose chlorozotocin, none among 27; and high-dose chlorozotocin, three among 30 (10%). Among patients with excellent performance status (Eastern Cooperative Oncology Group grade of 0-1) and no prior chemotherapy, response rates were as follows: maytansine, no responses among 17 patients; low-dose chlorozotocin, none among 14; and high-dose chlorozotocin, three among 28 (11%). The responses observed with high-dose chlorozotocin were transient (5-8 weeks) and were of no benefit to the patients. None of these agents given by the methods of this study can be recommended for patients with advanced pancreatic cancer.

Topics: Adenocarcinoma; Dose-Response Relationship, Drug; Drug Evaluation; Humans; Injections, Intravenous; Leukocyte Count; Maytansine; Oxazines; Pancreatic Neoplasms; Platelet Count; Prognosis; Streptozocin

Topics: Antibodies, Monoclonal; Breast Neoplasms; Cell Line, Tumor; ErbB Receptors; Female; Humans; Immunoconjugates; Maytansine; Pancreatic Neoplasms; Receptor, ErbB-2; Trastuzumab

An anti-HER2 antibody-drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed.. In vitro and in vivo pharmacologic activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models. The mechanism of action for the efficacy was also evaluated. Pharmacokinetics in cynomolgus monkeys and the safety profiles in rats and cynomolgus monkeys were assessed.. DS-8201a exhibited a HER2 expression-dependent cell growth-inhibitory activity and induced tumor regression with a single dosing at more than 1 mg/kg in a HER2-positive gastric cancer NCI-N87 model. Binding activity to HER2 and ADCC activity of DS-8201a were comparable with unconjugated anti-HER2 antibody. DS-8201a also showed an inhibitory activity to Akt phosphorylation. DS-8201a induced phosphorylation of Chk1 and Histone H2A.X, the markers of DNA damage. Pharmacokinetics and safety profiles of DS-8201a were favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys, supporting DS-8201a as being well tolerated in humans. DS-8201a was effective in a T-DM1-insensitive PDX model with high HER2 expression. DS-8201a, but not T-DM1, demonstrated antitumor efficacy against several breast cancer PDX models with low HER2 expression.. DS-8201a exhibited a potent antitumor activity in a broad selection of HER2-positive models and favorable pharmacokinetics and safety profiles. The results demonstrate that DS-8201a will be a valuable therapy with a great potential to respond to T-DM1-insensitive HER2-positive cancers and low HER2-expressing cancers. Clin Cancer Res; 22(20); 5097-108. ©2016 AACR.

Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Agents; Breast Neoplasms; Camptothecin; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 1; Female; Histones; Humans; Immunoconjugates; Macaca fascicularis; Maytansine; Mice; Mice, Nude; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Receptor, ErbB-2; Topoisomerase I Inhibitors; Trastuzumab

Although pancreatic ductal adenocarcinomas (PDAs) widely express HER2, the expression level is generally low. If HER2 expression in PDA cells could be enhanced by treatment with a given agent, then combination therapy with that agent and trastuzumab emtansine (T-DM1), a chemotherapeutic agent that is a conjugate of trastuzumab, might lead to significant antitumor effects against PDA.. Cell proliferation was examined by spectrophotometry. HER2 expression was examined by flow cytometry, immunoblot and quantitative reverse transcription polymerase chain reaction. T-DM1 binding to cells was examined by flow cytometry and enzyme-linked immunosorbent assay.. Out of 5 tested human PDA cell lines, including MIA PaCa-2, three showed increases in HER2 expression after gemcitabine (GEM) treatment. The binding of T-DM1 to GEM-treated MIA PaCa-2 cells was higher than to untreated MIA PaCa-2 cells. Treatment with GEM and T-DM1 showed synergic cytotoxic effects on MIA PaCa-2 cells in vitro. Cells in the G2M phase of the cell cycle were retained after GEM treatment and showed higher levels of HER2 expression, possibly contributing to the synergic effect of GEM and T-DM1.. Combined treatment with GEM and T-DM1 might confer a potent therapeutic modality against PDA as a result of GEM-mediated HER2 up-regulation.

Topics: Adenocarcinoma; Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Maytansine; Mice; Pancreatic Neoplasms; Receptor, ErbB-2; Trastuzumab; Xenograft Model Antitumor Assays

The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. By screening tropical plant extracts by using our screening system, Zizyphus cambodiana was found to include Hh/GLI signaling inhibitors. Bioassay-guided fractionation of this plant extract led to the isolation of three active pentacyclic triterpenes, colubrinic acid (1), betulinic acid (2) and alphitolic acid (3), as potent inhibitors. The inhibition of GLI-related protein expression with 1 or 2 was observed in HaCaT cells with exogenous GLI1, or human pancreatic cancer cells (PANC1), which express Hh/GLI components aberrantly. The expressions of GLI-related proteins PTCH and BCL2 were clearly inhibited by 1 or 2. We also examined the cytotoxicity of these active compounds against PANC1, human prostate cancer cells (DU145) and mouse embryo fibroblast cells (C3H10T1/2). The cytotoxicity against cancer cells (PANC1 and DU145) by 1 or 2 would be caused by inhibition of the expression of the anti-apoptosis protein BCL2. These pentacyclic triterpene inhibitors showed an important relationship between Hh/GLI signaling inhibition, the decrease of BCL2, and cytotoxicity against cancer cells.

Topics: Animals; Betulinic Acid; Blotting, Western; Cell Survival; Cells, Cultured; Fibroblasts; Humans; Male; Maytansine; Mice; Oncogene Proteins; Pancreatic Neoplasms; Patched Receptors; Patched-1 Receptor; Pentacyclic Triterpenes; Phenols; Phenylethyl Alcohol; Plant Extracts; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Receptors, Cell Surface; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Trans-Activators; Transcription, Genetic; Triterpenes; Zinc Finger Protein GLI1; Zinc Fingers; Ziziphus