心得安与三阴性乳腺癌蒽环类疗效

　　三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对常用的内分泌治疗和HER2靶向治疗无效，因此亟需其他的治疗靶点。三阴性乳腺癌受神经支配，通常表达肾上腺素能受体β2。普萘洛尔旧称心得安，属于肾上腺素能受体β阻滞剂，常用于治疗高血压、心绞痛、心动过速等。既往研究发现，服用与未服用β阻滞剂的三阴性乳腺癌患者相比，无癌生存率显著较高，但是这些影响的具体机制尚不明确。

　　2023年4月26日，美国科学促进会《科学》旗下《科学转化医学》在线发表澳大利亚莫纳什大学、埃普沃斯医院、斯威本科技大学、贝克心脏与糖尿病研究所、澳大利亚神经科学研究所、新南威尔士大学、彼得麦卡伦癌症中心、挪威癌症登记中心、美国英斯特朗、洛杉矶加利福尼亚大学、日本国际医疗福祉大学、群马大学、意大利米兰大学欧洲肿瘤研究院的研究报告，发现β阻滞剂可增强蒽环类化疗药物对三阴性乳腺癌转移的控制。

　　该研究首先通过临床流行病学分析，确定服用β阻滞剂与蒽环类化疗对于防止三阴性乳腺癌进展、复发和致死存在显著相关性。

　　随后，该研究利用三阴性乳腺癌异种移植小鼠模型，分析β阻滞剂对蒽环类疗效的影响。对于小鼠三阴性乳腺癌细胞4T1.2和人类三阴性乳腺癌细胞MDA-MB-231小鼠移植模型，β阻滞剂普萘洛尔（心得安）通过减少转移的发生和发展，可显著提高蒽环类多柔比星的疗效。

　　在没有β阻滞剂的情况下，单用蒽环类化疗可通过肿瘤细胞诱导神经生长因子，提高乳腺肿瘤交感神经纤维活性和去甲肾上腺素浓度。

　　此外，利用临床前模型和临床标本，该研究还发现蒽环类可上调肿瘤细胞肾上腺素能受体β2表达和信号传导。利用6-羟基多巴胺或利用基因技术删除肿瘤细胞的神经生长因子或肾上腺素能受体β2编码基因，可抑制乳腺肿瘤交感神经信号传导的神经毒素，减少异种移植小鼠模型转移，增强蒽环类化疗效果。

　　因此，该研究结果表明，蒽环类化疗的神经调节作用可减低其潜在治疗效果，可以通过抑制肿瘤微环境肾上腺素能受体β2信号传导而克服。用肾上腺素能受体β2阻滞剂辅助蒽环类化疗代表一种潜在的治疗策略，可以加强三阴性乳腺癌的临床管理，故有必要进一步开展临床研究进行验证。

Sci Transl Med. 2023 Apr 26;15(693):eadf1147. IF: 19.319

Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer.

Chang A, Botteri E, Gillis RD, Lofling L, Le CP, Ziegler AI, Chung NC, Rowe MC, Fabb SA, Hartley BJ, Nowell CJ, Kurozumi S, Gandini S, Munzone E, Montagna E, Eikelis N, Phillips SE, Honda C, Masuda K, Katayama A, Oyama T, Cole SW, Lambert GW, Walker AK, Sloan EK.

Monash University, Parkville, VIC, Australia; Epworth HealthCare, Richmond, VIC, Australia; Swinburne University of Technology, Hawthorn, VIC, Australia; Baker Heart & Diabetes Institute, Melbourne, VIC, Australia; Neuroscience Research Australia, Randwick, NSW, Australia; University of New South Wales, Sydney, NSW, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Cancer Registry of Norway, Oslo, Norway; Insitro, San Francisco, CA, USA; University of California Los Angeles, Los Angeles, CA, USA; International University of Health and Welfare, Chiba, Japan; Gunma University Graduate School of Medicine, Gunma, Japan; European Institute of Oncology IRCCS, Milan, Italy.

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated β2-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or β2-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting β2-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive β2-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer in need of additional therapeutic targets. TNBCs are innervated and often express β2-adrenoceptor (β2AR); however, pharmacologic β-adrenoceptor antagonists (beta-blockers) have yet to be explored in conjunction with current standard therapy, anthracycline chemotherapy, for TNBC. Here, Chang et al. evaluate this combination therapy and the role of anthracycline chemotherapy in TNBC innervation. Using preclinical mouse models and clinical samples, the authors saw that beta blockade enhanced efficacy of anthracycline chemotherapy by reducing metastasis and represents a potential therapeutic strategy for TNBC that requires further investigation.

PMID: 37099632

DOI: 10.1126/scitranslmed.adf1147