Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies.
Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies.
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DOI：
10.3390/cancers12092392
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发表时间：
2020-08-24
期刊：
影响因子：
5.2
通讯作者：
Tang AH
中科院分区：
文献类型：
--
作者：
Gupta GK;Collier AL;Lee D;Hoefer RA;Zheleva V;Siewertsz van Reesema LL;Tang-Tan AM;Guye ML;Chang DZ;Winston JS;Samli B;Jansen RJ;Petricoin EF;Goetz MP;Bear HD;Tang AH
三阴性乳腺癌（TNBC）的特征在于雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体（HER 2）的缺失或低表达，是乳腺癌的最具侵袭性的亚型。TNBC占美国乳腺癌病例的15%，并且以高复发率和差的总存活率（OS）而闻名。化疗耐药TNBC是一种遗传多样性，高度异质性和快速演变的疾病，挑战了我们对不完全应答者和复发患者进行个性化治疗的能力。目前，由蒽环类、烷化剂和紫杉烷类组成的一线标准化疗通常用于治疗高危和局部晚期TNBC。几种FDA批准的靶向程序性细胞死亡蛋白-1（Keytruda）和程序性死亡配体-1（Tecentriq）、聚ADP-核糖聚合酶（PARP）和/或抗体药物偶联物（Trodelvy）的药物已显示出改善TNBC子集临床结局的前景。这些针对关键基因突变和驱动恶性肿瘤生长的特定分子信号传导途径的抑制剂已被用作单药和/或与标准化疗方案联合使用。在这里，我们回顾了目前TNBC的治疗选择，未满足的临床需求和可行的药物靶点，包括表皮生长因子（EGFR），血管内皮生长因子（VEGF），雄激素受体（AR），雌激素受体β（ERβ），磷酸肌醇-3激酶（PI 3 K），哺乳动物雷帕霉素靶蛋白（mTOR）和蛋白激酶B（PKB或AKT）在TNBC中的激活。在发育、进化和癌症生物学的强有力证据的支持下，我们提出K-RAS/SIAH通路激活是一个主要的肿瘤驱动因素，SIAH是一个新的药物靶点，一个治疗反应性预后生物标志物，也是TNBC的一个主要肿瘤易感性。由于持续的K-RAS/SIAH/EGFR通路激活赋予TNBC肿瘤细胞化疗耐药性、侵袭性扩散和早期复发，我们希望设计以抗SIAH为中心的抗K-RAS/EGFR靶向治疗作为未来控制和根除不可治愈的TNBC的新治疗策略。
Triple-negative breast cancer (TNBC), characterized by the absence or low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive subtype of breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S., and is known for high relapse rates and poor overall survival (OS). Chemo-resistant TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize treatment for incomplete responders and relapsed patients. Currently, the frontline standard chemotherapy, composed of anthracyclines, alkylating agents, and taxanes, is commonly used to treat high-risk and locally advanced TNBC. Several FDA-approved drugs that target programmed cell death protein-1 (Keytruda) and programmed death ligand-1 (Tecentriq), poly ADP-ribose polymerase (PARP), and/or antibody drug conjugates (Trodelvy) have shown promise in improving clinical outcomes for a subset of TNBC. These inhibitors that target key genetic mutations and specific molecular signaling pathways that drive malignant tumor growth have been used as single agents and/or in combination with standard chemotherapy regimens. Here, we review the current TNBC treatment options, unmet clinical needs, and actionable drug targets, including epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), androgen receptor (AR), estrogen receptor beta (ERβ), phosphoinositide-3 kinase (PI3K), mammalian target of rapamycin (mTOR), and protein kinase B (PKB or AKT) activation in TNBC. Supported by strong evidence in developmental, evolutionary, and cancer biology, we propose that the K-RAS/SIAH pathway activation is a major tumor driver, and SIAH is a new drug target, a therapy-responsive prognostic biomarker, and a major tumor vulnerability in TNBC. Since persistent K-RAS/SIAH/EGFR pathway activation endows TNBC tumor cells with chemo-resistance, aggressive dissemination, and early relapse, we hope to design an anti-SIAH-centered anti-K-RAS/EGFR targeted therapy as a novel therapeutic strategy to control and eradicate incurable TNBC in the future.
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影响因子：
7.4
作者：
Asano Y;Kashiwagi S;Goto W;Takada K;Takahashi K;Morisaki T;Fujita H;Takashima T;Tomita S;Ohsawa M;Hirakawa K;Ohira M
通讯作者：
Ohira M
影响因子：
45.3
作者：
Bardia, Aditya;Mayer, Ingrid A.;Vahdat, Linda T.
通讯作者：
Vahdat, Linda T.
DOI：
10.1056/nejmoa1111097
发表时间：
2012-01-26
期刊：
The New England journal of medicine
影响因子：
--
作者：
Bear HD;Tang G;Rastogi P;Geyer CE Jr;Robidoux A;Atkins JN;Baez-Diaz L;Brufsky AM;Mehta RS;Fehrenbacher L;Young JA;Senecal FM;Gaur R;Margolese RG;Adams PT;Gross HM;Costantino JP;Swain SM;Mamounas EP;Wolmark N
通讯作者：
Wolmark N
影响因子：
6.4
作者：
Beckers, Rhiannon K.;Selinger, Christina I.;O'Toole, Sandra A.
通讯作者：
O'Toole, Sandra A.
影响因子：
--
作者：
Austin D;Hamilton N;Elshimali Y;Pietras R;Wu Y;Vadgama J
通讯作者：
Vadgama J