________________________________________________________________________ July 2004 A phase II trial of Tetrathiomolybdate [TM] after cytoreductive surgery for malignant pleural mesothelioma (MPM). Abstract No: 7051 Citation: Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 7051 Author(s): H. I. Pass, G. Brewer, T. Stevens, S. Sharma, D. Smith, A. Wali, S. Merajver; Karmanos Cancer Institute/Wayne State University, Detroit, MI; University of Michigan, Ann Arbor, MI Abstract: Background: Resection and adjuvant therapy for MPM results in a 2-year survival of 60% for Stages I/II, and 25% for Stage III (Rusch et al; Proc ASCO 2000). Median time to progression is 7-12 months after resection. Angiogenesis is a predictor of poor prognosis in MPM; TM is an oral copper (Cu)-depleting agent that inhibits angiogenesis and decreases levels of VEGF when ceruloplasmin (Cp) is reduced to 5-15 mg/dl. We hypothesize that cytoreduction of MPM followed by continuous TM can increase survival and delay progression by keeping residual disease in a dormant state. Methods: 34 cytoreduced MPM patients were registered for postoperative TM beginning 4-6 weeks after surgery at 180 mg/day with the dose adjusted to maintain Cp between 5-15 mg/dl. TM was continued until progression; chest/abdominal CTs were performed every 4 months. Results: 4 patients progressed prior to reaching target Cp. The remaining 25 men and 5 women, median age 67 (range 49-81yrs.) remained on TM a median of 10 months (range 4 to>36 mos.). The most common Grade (Gr) 3 toxicity was anemia: 27 episodes (15 patients), requiring transfusion in 7, or TM dose reduction alone (8). One patient had asymptomatic Gr 3 SGPT/SGOT rise which reversed with TM dose modification. All patients reached target Cp levels within 34+2 days (95% CI 30-39 days), and VEGF levels at baseline Cp (Cp=45.2+2 mg/dl) decreased from 2086+390 pg/ml to 1250+712 pg/ml (p<0.002) at target Cp [13+2 mg/dl (p<0.0001 from baseline)]. Survival /progression data are seen shown below. 24 month Overall Survival 24 month Progression Free Survival Stage I/II (n=13) 60% 69% Stage III (n=17) 23% 0% Conclusions: TM has antiangiogenic effects in postoperative MPM patients and the VEGF serum level is a robust biomarker in this therapy. TM has minimal toxicity and is at least comparable in efficacy to previous multimodality trials of cytotoxic agents for MPM. TM should be evaluated for use with standard MPM regimens, as well as for postsurgical maintenance monotherapy. Associated Presentation(s): 1. A phase II trial of Tetrathiomolybdate [TM] after cytoreductive surgery for malignant pleural mesothelioma (MPM). Event: 2004 ASCO Annual Meeting Presenter: Harvey I. Pass, MD Session: Lung Cancer II ________________________________________________________________________ Spetember 2004 Exp Biol Med (Maywood). 2004 Sep;229(8):857-63. Related Articles, Links Tetrathiomolybdate therapy protects against concanavalin a and carbon tetrachloride hepatic damage in mice. Askari FK, Dick R, Mao M, Brewer GJ. Department of Human Genetics, University of Michigan Medical School, 5024 Kresge Building II, Ann Arbor, MI 48109-0534. brewergj@umich.edu Tetrathiomolybdate, an anticopper drug, has been shown to protect mice against pulmonary fibrosis from bleomycin. Our hypothesis is that it does so by inhibiting fibrosis-inducing cytokines. Indeed, we have good evidence, not yet published, that tetrathiomolybdate inhibits pulmonary levels of transforming growth factor-beta and tumor necrosis factor-alpha expression in these bleomycin experiments. Herein, we evaluate tetrathiomolybdate's effectiveness in mitigating hepatitis and fibrosis in mice from the hepatotoxins, concanavalin A and carbon tetrachloride, and its inhibition of cytokines as a possible mechanism. In short-term experiments, concanavalin A elevated serum amino leucine transferase levels several fold, and tetrathiomolybdate completely prevented this increase. In additional experiments, tetrathiomolybdate therapy reversed the elevated serum transaminase levels despite continued concanavalin A injections, with nearly significant serum interleukin- 1beta inhibition. Concanavalin A given for 12 weeks produced mild fibrosis, whereas concomitant tetrathiomolybdate treatment resulted in normal histology. Carbon tetrachloride given for 12 weeks resulted in very high serum amino leucine transferase levels, high serum transforming growth factor-beta levels, cirrhosis as seen histologically, and increase in liver hydroxyproline, a measure of fibrosis. Concomitant tetrathiomolybdate partially and significantly protected against increases in amino leucine transferase and transforming growth factor-beta, fully protected against the increase in hydroxyproline, and resulted in normal histology. In conclusion, tetrathiomolybdate protects against the hepatitis and fibrosis produced by these hepatotoxins, probably by inhibiting the excessive increase in inflammatory and fibrotic cytokines. PMID: 15337842 [PubMed - in process] ________________________________________________________________________ February 2004 Antiangiogenic tetrathiomolybdate protects against Her2/neu-induced breast carcinoma by hypoplastic remodeling of the mammary gland. Q Pan PhD, CG Kleer MD, LW Bao MD, SD Merajver MD PhD Department of Internal Medicine, Division of Hematology and Oncology, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, United States Antiangiogenics have proven to be effective and safe anticancer agents in preclinical animal tumor models but have had mixed results in clinical trials. One possible explanation for the differential efficacy between clinical trials and preclinical models could be the large size of tumors in patients with advanced disease. In theory, antiangiogenics would be most effective in preventing small avascular tumors from activating the angiogenic switch and thus an ideal class of compounds for use in a chemopreventative setting. Tetrathiomolybdate (TM) is a novel anticancer agent that has exhibited antiangiogenic properties in preclinical and clinical studies with minimal adverse events. To determine the efficacy of TM as a chemopreventive agent, nulliparous 100-day old Her2/neu transgenic mice were treated with water (control) or 0.75 mg/day TM for 180 days and observed for tumor development during treatment and 180 days post-treatment. At the 1-year follow-up, 86.7% of control and 40% of TM-treated Her2/neu mice developed palpable mammary tumors with a median time to tumor development of 234 (202-279; 95% confidence interval) days for control mice and greater than 460 days for TM-treated mice (p<0.0005, n=15). Mammary glands from TM-treated Her2/neu mice showed a dramatic decrease in the complexity of the epithelial ductal branching system due to a lower number of secondary branches and terminal end-buds. Histologic analyses revealed that TM- treated Her2/neu mammary glands had a significant decrease in the total number of mammary epithelial cells. Consistent with TM's antiangiogenic effect, microvessel density in Her2/neu mammary glands was lowered by 65.6% (p<0.005, n=3) following TM therapy. Taken together, these results strongly indicate that TM is a potent chemopreventive agent as a consequence of drastic hypoplastic remodeling of the mammary gland. Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 894 (Angiogenesis).