陳景虹 主持 南加大「蔡明忠轉譯醫學研究實驗室」

中研院士施陳景虹開發新藥有效抑制腫瘤 發稿時間：2015/04/10 07:38 最新更新：2015/04/10 10:39 （中央社記者吳協昌洛杉磯9日專電）南加州大學藥學院教授，同時也是中央研究院院士的施陳景虹帶領的團隊，創造出新的「共軛」分子，能抑制小鼠的前列腺癌，也獲選為美國化學學會期刊的封面文章。目前在南加大藥學院任教的施陳景虹是腦神經化學家，以對人類腦神經的研究而聞名，對於MAO-A的研究已有30年，也被尊稱為「MAO基因研究之母」。這次能夠找出方法，有效抑制腫廇，對於醫學上是一大突破。施陳景虹與其團隊將抗抑鬱藥加染料，完成不可能的配對，創造出結合兩個單獨分子的「共軛」分子NMI，產生腫廇靶向性的工具。研究結果顯示，NMI分子結合標靶癌細胞的近紅外染料以及常用的抗抑鬱藥MAO-A（單胺氧化酶A）抑制劑，能有效的減少、甚至消除小鼠前列腺腫瘤的生長。施陳景虹說，對於這個MAO-A共軛分子的染料，專門針對癌細胞，比任何已知的MAO-A本身更有效，希望可以用於治療前列腺與其他癌症。同樣參與這項研究的南加大藥理學教授歐連育克（Bogdan Olenyuk）也強調，初步結果令人鼓舞，這也是南加大台灣轉譯醫學研究中心團隊合作下的代表作，未來將在這個基礎上，開發更有效的疾病治療。1040410

Rationale for Phase 2 Trial of Phenelzine (a Monoamine Oxidase Inhibitor) for Nonmetastatic Recurrent Prostate Cancer

Background: Monoamine oxidase A (MAOA) is an androgen regulated gene [1] which is highly expressed in the basal cell layer of normal prostate glands [2] and in high grade prostate cancer [3]. Clorgyline, an irreversible MAOA inhibitor, decreases expression of PSA and other androgenresponsive target genes and decreases prostate cancer cell growth in vitro [2, 4]. More recently, MAOA has been shown to exert effects on prostate tumor formation and metastasis through epithelial-mesenchymal transition and angiogenesis [5]. Importantly, MAOA expression was associated with worse outcomes in prostate cancer patients and pharmacologic inhibition of MAOA activity was associated with decreased tumor growth in prostate cancer xenograft models [5]. Thus, we have initiated a clinical trial to explore potential anti-cancer effects of phenelzine (Nardil, an irreversible MAOA/B inhibitor) in patients with recurrent prostate cancer. Methods: A non-randomized phase II trial will explore efficacy of phenelzine 30 mg orally twice daily in 46 subjects (23 in each group with non-castrate or castrate circulating androgen levels). Main eligibility criteria include: recurrent prostate cancer defined by PSA ≥ 0.4 ng/ml (post-prostatectomy) or PSA ≥ 2 ng/ml above a post-therapy nadir (postradiation therapy or primary androgen deprivation therapy). No evidence of metastatic cancer on imaging studies. No history of mania or concurrent use of food or medicines with potential interactions with MAO inhibitors. Patients may have castrate or non-castrate circulating androgen levels but no androgen-directed therapies may be initiated during the study treatment. Primary endpoint: To assess the proportion of patients who achieve a PSA decline of ≥50% from baseline. Statistical methodology: A Simon minimax two-stage design will be used to test the hypothesis that probability of response to phenelzine (P1) is ≥20% and reject the drug if the response probability (P0) is ≤ 5% for each group of patients [3]. An interim analysis will be undertaken when 12 patients have been treated with phenelzine and are evaluable for a PSA response. With this design there is 0.8 probability (power) that we will conclude that phenelzine warrants further study when the true response rate is 20% or greater, and there is only a 0.08 probability (alpha) that we will conclude that this regimen warrants further study when the response rate is 5% or less. The trial is currently active and seeking to enroll 23 subjects into each group to obtain at least 21 evaluable patients.

ClinicalTrials.gov Identifier: NCT02217709

Funding: USC- Taiwan Center for Translational Research supported by Tsai Family Fund to Jean C. Shih

1. Ou, X.M., K. Chen, and J.C. Shih, Glucocorticoid and androgen activation of monoamine oxidase A is regulated differently by R1 and Sp1. J Biol Chem, 2006. 281(30): p. 21512-25.

2. Zhao, H., et al., Inhibition of monoamine oxidase A promotes secretory differentiation in basal prostatic epithelial cells. Differentiation, 2008. 76(7): p. 820-30.

3. True, L., et al., A molecular correlate to the Gleason grading system for prostate adenocarcinoma. Proc Natl Acad Sci U S A, 2006. 103(29): p. 10991-6.

4. Flamand, V., H. Zhao, and D.M. Peehl, Targeting monoamine oxidase A in advanced prostate cancer. J Cancer Res Clin Oncol, 2010. 136(11): p. 1761-71.

5. Wu, J.B., et al., Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. J Clin Invest, 2014. 124(7): p. 2891-908.

Center for USC-Taiwan Translational Research  The Center for USC-Taiwan Translational Research focuses on promising new work in the fight against cancer. USC Trustee Daniel M. Tsai made a gift to the USC School of Pharmacy to establish the USC Daniel Tsai Fund for Translational Research which supports center activities. Currently, center scientists are exploring new cancer therapies that target monoamine oxidase (MAO). Dr. Jean Chen Shih, internationally known for her decades-long, foundational exploration on MAO, directs the center. Central to the activities of the center are the awarding of fellowships to promising graduate students and postdoctoral trainees from Taiwan and USC to allow them to work together side-by-side on translational research endeavors. These "Tsai Scholars" will spend one to two years in USC School of Pharmacy laboratories, learning cutting-edge techniques as they work on novel research programs that aim to develop the next generation of therapeutics. Tsai Scholars will be integral members of these translational research teams. These teams are investigating the use of MAO inhibitors in the treatment of cancer. Recent work from the lab of Dr. Shih has shown that elimination of the gene that encodes monoamine oxidase (MAO) prevents the growth of prostate cancer in mice. As MAO is an important regulator of mood and motivation in the brain, there are already a number of drugs that effectively inhibit its function, called MAOI (MAO inhibitors), which are used clinically as antidepressants. Given the urgent and unmet need for more effective target-based therapies to significantly reduce the lethal outcome of prostate cancer, the repurposing of these drugs may represent a rapid and cost-effective solution. This presents an extraordinary opportunity to translate scientific discovery to patient therapies on an accelerated timeframe. Dr. Shih, a University Professor and the Boyd P. and Elsie D. Welin Professor in Pharmaceutical Sciences, is a globally recognized expert on the MAO genes. Her expertise will be complemented by a group of colleague scientists from USC and in Taiwan. The center will provide a unique international collaboration for students and their mentors.