Synergize a novel homologous recombination inhibitor with DNA damagingagents in TNBC

在 TNBC 中协同新型同源重组抑制剂与 DNA 损伤剂

• 批准号: 10760604
• 负责人: CAROLA ANKE NEUMANN
• 金额: $ 39.87万
• 依托单位: CREEGH PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10760604
• 关键词: Adverse effects; Affect; Affinity; African; Alkenes; Attention; Award; BRCA1 gene; BRCA2 gene; Blood; Bone Marrow Cells; Brain; Cell Line; Cells; Chemicals; Chemistry; Cisplatin; Classification; Collaborations; Computer software; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; Data; Defect; Development; Docking; Dose; Doxorubicin; Drug Kinetics; Drug Synergism; Drug Targeting; ERBB2 gene; Embryo; Estrogen Receptors; Evaluation; FDA approved; Fatty Acids; Formulation; Future; Genes; Goals; High Pressure Liquid Chromatography; In Vitro; Ionizing radiation; Kinetics; Laboratories; Lead; Libraries; Longevity; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metastatic malignant neoplasm to brain; Modality; Molecular; Mus; Nitrogen Dioxide; Nuclear; Operative Surgical Procedures; Oral; PARP inhibition; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Photometry; Poly(ADP-ribose) Polymerase Inhibitor; Productivity; Progesterone Receptors; Program Development; Rad51 recombinase; Radiation therapy; Rattus; Recovery; Resistance; Safety; Single-Stranded DNA; Small Business Technology Transfer Research; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Validation; adduct; analytical method; brca gene; cancer cell; chemotherapeutic agent; chemotherapy; design; drug development; drug efficacy; experience; experimental study; gene function; homologous recombination; improved; in vivo; inhibitor; inhibitor therapy; lead candidate; loss of function; malignant breast neoplasm; method development; mouse model; nitroalkene; novel; patient derived xenograft model; patient population; pre-clinical; preclinical evaluation; programs; receptor; recombinase; repaired; resistance mechanism; response; restoration; scale up; side effect; small molecule inhibitor; standard care; standard of care; synergism; targeted treatment; treatment strategy; triple negative cancer; triple-negative invasive breast carcinoma; tumor growth; young woman

15-20% of all breast cancers are triple negative, being devoid of the three receptors that classify and define treatment strategies for most mammary cancers: estrogen receptor (ER), progesterone receptor (PR) and ERB2 (also known as HER2). Because of this, no targeted therapies are available for TNBC patients. This poses a destitute situation, as TNBC is an aggressive cancer that disproportionally affects younger women and those having African origins. Currently, standard care for TNBC patients includes surgery, radiation treatment and chemotherapy, where the two latter have toxic side effects. Poly-ADP-ribose polymerase inhibitor (PARPi) monotherapy is FDA approved in BRCA1/2-deficient TNBC patients as they present with deficiencies in DNA repair which are exacerbated by PARPi and thus lead to killing of cancer cells. However, about 80% of all TNBC patients are wild type for BRCA1/2 genes and thus not eligible for PARPi therapies or stop responding to PARPi as restoration of DNA repair is one of the frequent PARPi resistance mechanism. We tested a library of novel compounds (nitro fatty acids) that inhibit homologous recombination (HR)-mediated DNA DSB repair through specifically and reversibly adducting to the recombinase RAD51 thus inhibiting its activity. A lead candidate (CP- 8) was identified that induces chemically an HR-defect (HRD) DNA repair in TNBC cells proficient in HR- mediated DNA repair and synergizes with DNA damaging treatments such PARPi and ionizing radiation (IR). Preliminary toxicity studies in mice showed no adverse effects by CP-8 which not only diminishes TNBC tumor growth when combined with PARP inhibitors in vitro and in vivo, but also alleviates toxic side effects of PARP inhibitors on bone marrow cells. Our overarching working hypothesis is that CP-8 is a safe, reversible and potent sensitizer of HR-proficient (naïve or PARPi resistant) primary and brain metastatic TNBC tissues to DNA damaging therapies by reducing RAD51 functionality. Moreover, we expect that co-treatment of CP-8 would allow dose reduction of DNA damaging agent thus reducing toxic side effects in patients. Aim 1 will examine a TNBC cell line panel, TNBC PDX explants and in vivo mouse models for drug synergism of CP-8 with DNA damaging agents varying in mechanism. Three PARPi (ola, tala and nir) resistant TNBC cell lines have been already generated in the laboratory to assess re-sensitization to PARPi by CP-8. PDX models were chosen from a recent study considering their relative low response to DNA damaging agents. Target engagement of RAD51 by CP-8 as well as DNA DSB will be assessed in cell lines, TNBC PDX explants and in vivo tissues and correlated with drug efficacies. Cell lines and tissues will be analyzed by already established click chemistry-assisted affinity capture and HPLC-MS/MS for possible additional CP-8 targets and metabolite content. Aim 2 will perform IND enabling studies of the in vitro and in vivo CP-8 pharmacology in collaboration with PharmaDirections with the short-term goal to prepare CP-8 for a Phase 2 (R42) evaluation.

15-20％的所有乳腺癌都是三重阴性的，没有分类和定义的三个受体 大多数乳腺癌的治疗策略：雌激素受体（ER），孕酮受体（PR）和ERB2 （也称为HER2）。因此，没有针对TNBC患者的靶向疗法。这定位a 贫穷情况，因为TNBC是一种侵略性癌症，对年轻妇女和那些 具有非洲起源。目前，针对TNBC患者的标准护理包括手术，放射治疗和 化学疗法，两个拉特具有毒性副作用。多-ADP-核糖聚合酶抑制剂（PARPI） 单药治疗在BRCA1/2缺陷TNBC患者中批准了FDA，因为他们出现DNA缺陷 修复受PARPI加剧，从而导致癌细胞杀死。但是，大约有80％的TNBC 患者是BRCA1/2基因的野生类型，因此没有资格接受PARPI疗法或停止对PARPI做出反应 由于DNA修复的恢复是经常的抗抗性机制之一。我们测试了一个小说的库 通过抑制同源重组（HR）介导的DNA DSB修复的化合物（硝基脂肪酸） 牵头候选人（CP- 8）鉴定出在TNBC细胞中诱导化学诱导HR-FEFECT（HRD）DNA修复 介导的DNA修复并通过DNA损伤处理协同作用，例如PARPI和电离辐射（IR）。 小鼠的初步毒性研究表明，CP-8没有不利影响，这不仅会减少TNBC肿瘤 当与PARP抑制剂在体外和体内结合时生长，但也可以减轻PARP的毒性副作用 骨髓细胞上的抑制剂。我们的总体工作假设是CP-8是一种安全，可逆和有效的 HR-Proficy（幼稚或PARPI抗性）原发性和脑转移性TNBC组织的敏化剂对DNA 通过降低RAD51功能来破坏疗法。而且，我们希望CP-8的共同治疗将 允许减少DNA损伤剂的剂量，从而减少患者的毒性副作用。 AIM 1将检查 TNBC细胞管线面板，TNBC PDX外植体和用于DNA的CP-8药物协同作用的体内小鼠模型 机制的破坏药物各不相同。三个PARPI（OLA，TALA和NIR）耐药TNBC细胞系已是 已经在实验室中生成，以评估CP-8对PARPI的重新敏感性。从中选择了PDX模型 最近的一项研究考虑了它们对DNA损伤剂的相对低反应。 RAD51的目标参与 通过CP-8以及DNA DSB将在细胞系，TNBC PDX外植体和体内组织中进行评估以及相关 具有药物效率。细胞系和组织将通过已经建立的点击化学辅助亲和力分析 捕获和HPLC-MS/MS，以获取可能的其他CP-8靶标和代谢物含量。 AIM 2将执行IND 促进与药物合作的体外和体内CP-8药理学的研究 为第2阶段（R42）评估准备CP-8的短期目标。