Development of Tumor and Immuno-Metabolism Based Small Molecule Therapeutics for Refractory Breast Cancer

基于肿瘤和免疫代谢的难治性乳腺癌小分子疗法的发展

• 批准号: 10266156
• 负责人: Vincent Sandanayaka
• 金额: $ 85.45万
• 依托单位: NIROGYONE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266156
• 关键词: 4T1; Accounting; Achievement; Acute; Advanced Development; Applications Grants; Back; Biological; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer cell line; CD8B1 gene; Cancer Cell Growth; Canis familiaris; Cell Survival; Cell membrane; Cells; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Complement; Data; Development; Development Plans; Diagnosis; Dose; Dose-Limiting; Drug Interactions; Drug Kinetics; Epigenetic Process; Estrogens; Evaluation; Event; Excretory function; Extracellular Matrix; Glycolysis; Goals; Growth; Immune; Immunity; Immunosuppression; Inflammatory; Interferon Type II; Interleukin-1 beta; Interleukin-10; Lactate Transporter; MDA MB 231; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Metabolic Pathway; Metabolism; Methods; Modeling; Molecular; Monkeys; Mus; Mutation; Organ; Outcome; Patients; Pharmaceutical Preparations; Phase; Population; Positioning Attribute; Process; Progesterone; Prognostic Marker; Protein Family; Rattus; Refractory; Regimen; Relapse; Reporting; Resistance; Safety; Schedule; Signal Pathway; Small Business Innovation Research Grant; TNF gene; Testing; Toxic effect; Toxicology; Transforming Growth Factor beta; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Validation; Woman; Xenograft Model; Xenograft procedure; antitumor effect; base; breast cancer diagnosis; cancer biomarkers; cancer cell; cancer immunotherapy; cell killing; chemotherapy; cytokine; cytotoxicity; design; effective therapy; experimental study; first-in-human; immune activation; immune checkpoint blockade; immune function; immunoregulation; in vivo; inhibitor/antagonist; insight; macrophage; malignant breast neoplasm; meetings; melanoma; mouse model; novel; novel drug class; novel therapeutic intervention; novel therapeutics; overexpression; patient derived xenograft model; pharmacodynamic biomarker; pre-clinical; preclinical development; predictive marker; programs; receptor; safety study; scale up; small molecule; small molecule therapeutics; standard of care; success; synergism; targeted agent; targeted treatment; transport inhibitor; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor progression; tumor xenograft

Development of Tumor and Immuno-Metabolism Based Small Molecule Therapeutics for Refractory Breast Cancer Abstract Worldwide, approximately 1 million women are diagnosed with breast cancer each year. Triple Negative Breast Cancer (TNBC) is defined as that which does not express estrogen, progesterone, or Her-2 receptors. TNBC is the most deadly sub-type of breast cancer, accounting for ~15% of the breast cancer diagnoses and ~25% of breast cancer-related deaths. Median survival for 30% of the patients with TNBC is one year. TNBC has poor clinical outcomes due to its high metastatic rate, resistance to chemotherapy, and lack of effective treatment options. Although immunotherapy for cancers is rapidly expanding with the discovery of new targets and methods to activate immune function within tumors, it has only shown success in a limited subset of metastatic TNBC patients. The lactate-rich TNBC tumor microenvironment (TME) has been shown to be highly immunosuppressive, promoting tumor growth and progression. Cancer cells transport lactate across the cell membrane to the extracellular matrix via monocarboxylate transporters, MCT1 and MCT4. We have developed dual MCT1/4 inhibitors (dMCTi) to block lactate excretion to the TME thereby directly killing cancer cells and simultaneously activating local immunity in the TME. In our preliminary studies, we have shown that dMCTi are potent compounds against multiple TNBC cell lines. Also, we have shown that in in vivo experiments with both mouse xenograft models (MDA-MB-231, breast cancer) and syngeneic mouse models of melanoma and TNBC; SM1 (melanoma, BRAFV600E), and 4T1 (TNBC), dMCTi exert significant anti-tumor efficacy. Anti-tumor efficacy in MDA-MB-231 immune-deficient xenograft model shows inhibitors’ direct cell killing effect. In the 4T1 and SM1 syngeneic models, we observed a decrease in expression of multiple immunosuppressive molecules such as B7 family proteins, macrophage polarization to M1, MDSCs, and increase in CD8+ population in treated tumors compared to the control tumors. Furthermore, profiling of cytokines indicated an increase in pro-inflammatory IFNγ, TNFα, IL-1β and decrease in tumor promoting TGFβ, IL-10 in treated tumors compared to the control tumors confirming that the anti-tumor effect of dMCTis is in part due to enhanced immune function. Supported by these preliminary data, we selected a dMCTi, NGY-B, as a pre-clinical development candidate. In this Direct Phase-II application, we propose to (1) conduct preclinical pharmacokinetic and safety studies of NGY-B, (2) Establish an effective dose regimen of NGY-B, investigate the efficacy of NGY-B in several mouse tumor models, and study the immune suppressive mechanisms in vivo, (3) establish NGY-B scalability for manufacturing, and request a pre-IND Type B meeting with FDA. Upon completion of these Aims, Nirogyone will have established NGY-B’s scalability, broader efficacy, and potential dose-limiting toxicities. We will then submit a SBIR Phase IIb grant application to evaluate non-GLP and GLP toxicology studies and assemble the IND package for first- in-human clinical trials.

基于肿瘤和免疫代谢的小分子疗法的难治性的开发 乳腺癌 抽象的 在全球范围内，每年约有100万妇女被诊断出患有乳腺癌。三重负乳房 癌症（TNBC）定义为不表达雌激素，孕激素或HER-2受体的癌症。 TNBC是 乳腺癌最致命的亚型，占乳腺癌诊断的约15％，约25％ 与乳腺癌有关的死亡。 30％的TNBC患者的中位生存期为一年。 TNBC差 由于其高转移率，对化学疗法的耐药性以及缺乏有效治疗而导致的临床结果 尽管随着新目标和方法的发现，癌症的免疫疗法正在迅速扩大 为了激活肿瘤中的免疫功能，它仅显示在有限的转移性TNBC中成功 患者。富含鞋底的TNBC肿瘤微环境（TME）已显示为高度 免疫抑制，促进肿瘤的生长和进展。癌细胞在细胞上运输乳酸 通过单羧酸盐转运蛋白MCT1和MCT4到细胞外基质的膜。我们已经发展了 双MCT1/4抑制剂（DMCTI）以阻止鞋底排泄到TME，从而直接杀死癌细胞和 类似地激活TME中的局部免疫力。在我们的初步研究中，我们表明DMCTI是 潜在化合物针对多个TNBC细胞系。另外，我们已经表明，在体内实验中 小鼠定征模型（MDA-MB-231，乳腺癌）和黑色素瘤和TNBC的同性小鼠模型； SM1（黑色素瘤，BRAFV600E）和4T1（TNBC），DMCTI具有明显的抗肿瘤效率。抗肿瘤效率 在MDA-MB-231中，免疫缺陷型Xenogroticon模型显示了抑制剂的直接细胞杀死效果。在4T1和SM1中 合成模型，我们观察到多种免疫抑制分子（例如 B7家族蛋白，对M1的巨噬细胞极化，MDSC和CD8+种群的增加。 与对照肿瘤相比。此外，细胞因子的分析表明促炎的增加 与对照相比 肿瘤证实了DMCTI的抗肿瘤作用部分是由于免疫功能增强所致。支持 通过这些初步数据，我们选择了DMCTI，NGY-B作为临床前开发候选者。在这个直接 II期应用，我们建议（1）进行NGY-B的临床前药代动力学和安全性研究，（2） 建立NGY-B的有效剂量方案，研究NGY-B在几种小鼠肿瘤模型中的有效性， 并研究体内的免疫抑制机制，（3）建立制造的NGY-B可伸缩性，并 请求与FDA进行预先启动B类型。完成这些目标后，Nirogyone将建立 NGY-B的可伸缩性，更广泛的效率和潜在的剂量限制战术。然后，我们将提交SBIR阶段 IIB授予应用于评估非GLP和GLP毒理学研究的应用，并组装IND包装 人类临床试验。