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CCR5 inhibitors to enhance therapeutic response of breast cancer to DNA damaging agents

CCR5 抑制剂可增强乳腺癌对 DNA 损伤剂的治疗反应

基本信息

批准号：
10057534
负责人：
RICHARD G PESTELL
金额：
$ 38.28万
依托单位：
BARUCH S. BLUMBERG INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057534
关键词：
Adriamycin PFS Anthracycline Attenuated Biological Models Biology Blood Vessels Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment CCR5 gene Cancer Patient Cardiac Cardiac Death Cardiac Myocytes Cardiotoxicity Cell Death Cell Death Induction Cell Death Signaling Process Cell Survival Cells Cessation of life Chemotherapy and/or radiation Clinical Trials Combination Drug Therapy Cytoprotection DNA Damage DNA Repair Development Diagnosis Dose Doxorubicin EFRAC FDA approved G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Gamma Rays Genetic Transcription Goals HIV Heart Heart Neoplasms Heart failure Human Iatrogenic Disease Immunocompetent In Vitro Inflammation Inflammatory Ischemia Liposomes Macaca Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of urinary bladder Mediating Messenger RNA MicroRNAs Modeling Morbidity - disease rate Mus Myocardial dysfunction Myocardium Myopathy Neoplasm Metastasis Oncology Patients Penetration Pre-Clinical Model Proteins Quality of life Radiation Rattus Receptor Signaling Regimen Resistance Role Signal Pathway Signal Transduction T-Lymphocyte Testing Therapeutic Time Tissues Toxic effect Up-Regulation Uterine Cancer base beta-Chemokines cancer cell cancer stem cell cancer survival cancer therapy cardioprotection cell killing chemokine receptor chemotherapy heart damage in vivo induced pluripotent stem cell inhibitor/antagonist leukemia/lymphoma malignant breast neoplasm malignant stomach neoplasm mortality mouse model novel novel strategies paracrine prevent progenitor promoter response side effect stem cells synergism therapeutic effectiveness tissue injury transcriptome treatment response triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

PROJECT SUMMARY/ABSTRACT The current studies propose a fundamental change in approach to treating cancer in order to reduce cardiac toxicity. Anthracyclines, such as Doxorubicin, are currently used to treat many cancers including leukemia, lymphoma, and cancers of the breast, stomach, uterus, ovary, bladder, and lung. Cardiotoxicity from Anthracyclines limits therapeutic effectiveness and compromises patient’s quality of life. Anthracycline induced cardiotoxicity is cumulative and dose-dependent. In order to reduce cardiac toxicity, the DNA damaging agents have been formulated into liposomes to enhance penetration into leaking microvasculature found in tumors. Despite this, 9% of patients present with diminished ejection fraction within 1 year of anthracycline therapy, increasing to >25% of patients over 5 years. DNA damage and inflammation contribute to cardiac toxicity of Anthracyclines. There is an urgent need to reduce this iatrogenic disease. Our approach is novel. We have found that the G-protein coupled receptor CCR5 is expressed in ~50% of human breast cancers (BCa) and >95% of triple negative BCa, wherein CCR5 activates DNA repair and promotes metastasis. CCR5 inhibitors enhance BCa cell killing by DNA damaging cancer therapies (anthracyclines, γ-radiation and PARP inhibitors). CCR5+ BCa stem cells are less prone to cell death. CCR5 is not normally expressed in the heart. In preliminary studies, we show anthracycline treatment increases CCR5 in the murine and human myocardium. We show CCR5+ cardiac progenitor cells are more prone to cell death than their CCR5- counterparts. We hypothesize that CCR5 antagonists (Maraviroc, Vicriviroc), will enhance BCa cell killing. CCR5 antagonists are cardioprotective in several models of cardiac damage. We hypothesize that CCR5 inhibitors will provide both direct cardiac cytoprotection and indirect cardioprotection, through increasing the efficacy of anthracyclines to kill BCa cells allowing for a reduction in total dose. We will determine the cardioprotective effect of CCR5 inhibitors in preclinical models of anthracycline induced toxicity. Moreover, we will examine the differential effects of CCR5 in doxorubicin-induced tissue injury in vitro. These studies bring together an expert in oncology (Dr. Pestell), cardiac death (Dr. Kitsis), G-protein receptor signaling and vascular biology (Dr. Ashton) in order to define a novel approach to reducing anthracycline cardiotoxicity. Initial studies will be conducted using BCa cells. The approach is paradigmatic of the approach for a broad array of cancers in which DNA damage inducing chemotherapy or radiation is used. These studies are likely to impact BCa treatment by simultaneously enhancing efficacy of currently available therapies and reducing cardiac side effects.

项目摘要/摘要目前的研究建议从根本上改变癌症的治疗方法，以减少心脏毒性。目前，多柔比星等蒽环类药物被用于治疗多种癌症，包括白血病、淋巴瘤和乳腺癌、胃癌、子宫癌、卵巢癌、膀胱癌和肺癌。心脏毒性来自蒽环类药物限制了治疗效果，并损害了患者的生活质量。蒽环类药物诱导的心脏毒性具有累积性和剂量依赖性。为了减少心脏毒性，DNA 损伤剂已被配制成脂质体，以增强对渗漏的微血管的渗透在肿瘤中发现。尽管如此，9%的患者在一年内出现射血分数降低。蒽环类药物治疗，5年内增加到25%的患者。DNA损伤和炎症是导致对蒽环类药物的心脏毒性的影响。迫切需要减少这种医源性疾病。我们的方法很新颖。我们发现G蛋白偶联受体CCR5的表达在~50% 人类乳腺癌(BCA)和95%的三阴性BCA，其中CCR5激活DNA修复和促进肿瘤转移。CCR5抑制剂通过DNA损伤癌症治疗增强BCA细胞杀伤力 (蒽环类、γ辐射和PARP抑制剂)。CCR5+BCA干细胞不太容易细胞死亡。CCR5是通常不会在心脏表达。在初步研究中，我们发现，使用蒽环类药物可以增加CCR5 在小鼠和人的心肌中。我们发现CCR5+的心脏祖细胞更容易细胞死亡而不是CCR5的对应者。我们推测CCR5拮抗剂(马拉韦罗、维拉韦罗)会增强BCA细胞的杀伤作用。CCR5 在几种心脏损伤模型中，拮抗剂具有心脏保护作用。我们假设CCR5抑制剂将提供直接的心肌细胞保护和间接的心脏保护，通过增加用来杀死BCA细胞的蒽环类药物，可以减少总剂量。我们将确定对心脏的保护 CCR5抑制剂在蒽环类药物毒性临床前模型中的作用。此外，我们还将审查 CCR5在阿霉素诱导的组织损伤中的差异性作用这些研究汇集了一个肿瘤学(Pestell博士)、心源性死亡(Kitsis博士)、G蛋白受体信号和血管生物学方面的专家 (阿什顿博士)，以确定一种新的方法来减少蒽环类药物的心脏毒性。初步研究将是使用BCA细胞进行。该方法是对多种癌症的方法的典范，在这些癌症中 DNA损伤可导致化疗或放射治疗。这些研究可能会通过以下方式影响BCA的治疗同时提高现有治疗方法的疗效，减少心脏副作用。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Role and Therapeutic Targeting of CCR5 in Breast Cancer.

DOI：
10.3390/cells12182237
发表时间：
2023-09-08
期刊：
CELLS
影响因子：
6
作者：
Hamid, Rasha;Alaziz, Mustafa;Mahal, Amanpreet S.;Ashton, Anthony W.;Halama, Niels;Jaeger, Dirk;Jiao, Xuanmao;Pestell, Richard G.
通讯作者：
Pestell, Richard G.

Assays for the Spectrum of Circulating Tumor Cells.

循环肿瘤细胞谱的测定。

DOI：
10.1007/978-1-0716-1979-7_37
发表时间：
2022
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Jiao,Xuanmao;Upadhyaya,Chandan;Zhang,Zhao;Zhao,Jun;Li,Zhiping;Patel,VivekI;Pestell,RichardG
通讯作者：
Pestell,RichardG

Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990-2019: a systematic analysis from the Global Burden of Disease Study 2019.

DOI：
10.1016/s0140-6736(21)01169-7
发表时间：
2021-06-19
期刊：
Lancet (London, England)
影响因子：
0
作者：
GBD 2019 Tobacco Collaborators
通讯作者：
GBD 2019 Tobacco Collaborators

The global burden of cancer attributable to risk factors, 2010-19: a systematic analysis for the Global Burden of Disease Study 2019.

DOI：
10.1016/s0140-6736(22)01438-6
发表时间：
2022-08-20
期刊：
Lancet (London, England)
影响因子：
0
作者：
通讯作者：

The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance.

DOI：
10.3390/cancers14215388
发表时间：
2022-11-01
期刊：
CANCERS
影响因子：
5.2
作者：
Abdelmalak, Mary;Singh, Rajanbir;Anwer, Mohammed;Ivanchenko, Pavel;Randhawa, Amritdeep;Ahmed, Myra;Ashton, Anthony W.;Du, Yanming;Jiao, Xuanmao;Pestell, Richard
通讯作者：
Pestell, Richard