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.

所有乳腺癌中有15-20%是三阴性的，缺乏分类和定义乳腺癌的三种受体。 大多数乳腺癌的治疗策略：雌激素受体（ER）、孕激素受体（PR）和ERB 2 (also称为HER 2）。因此，TNBC患者没有靶向治疗。这会带来一定的 贫困状况，因为TNBC是一种侵袭性癌症，对年轻女性和 有非洲血统的。目前，TNBC患者的标准护理包括手术、放射治疗和放射治疗。 化疗，其中后两者具有毒副作用。聚ADP-核糖聚合酶抑制剂 FDA批准单药治疗BRCA 1/2缺陷型TNBC患者，因为他们存在DNA缺陷， PARPi会加剧修复，从而杀死癌细胞。然而，大约80%的TNBC 患者是BRCA 1/2基因野生型，因此不适合PARPi治疗或停止对PARPi的应答 因为DNA修复的恢复是PARPi抗性的常见机制之一。我们测试了一个小说库 化合物（硝基脂肪酸），通过抑制同源重组（HR）介导的DNA DSB修复， 特异性地和可逆地加合到重组酶RAD 51上，从而抑制其活性。一个领先的候选人（CP- 8)在精通HR的TNBC细胞中化学诱导HR缺陷（HRD）DNA修复。 介导的DNA修复并与DNA损伤治疗如PARPi和电离辐射（IR）协同作用。 在小鼠中的初步毒性研究显示CP-8没有副作用，其不仅减少TNBC肿瘤， 当与PARP抑制剂在体外和体内组合时， 抑制剂对骨髓细胞的作用我们的总体工作假设是CP-8是一种安全，可逆和有效的 HR有效（未经治疗或PARPi耐药）原发性和脑转移性TNBC组织对DNA的敏化剂 通过降低RAD 51功能来破坏治疗。此外，我们预计CP-8的共治疗将 允许减少DNA损伤剂的剂量，从而减少对患者的毒副作用。目标1将检查 用于CP-8与DNA的药物协同作用的TNBC细胞系组、TNBC PDX外植体和体内小鼠模型 破坏剂在机理上各不相同。三种PARPi（奥拉、tala和nir）抗性TNBC细胞系已被鉴定。 已经在实验室中产生，以评估CP-8对PARPi的再致敏性。PDX型号选自 最近的一项研究考虑到它们对DNA损伤剂的反应相对较低。RAD 51的目标接合 将在细胞系、TNBC PDX外植体和体内组织中评估CP-8以及DNA DSB的作用，并将其相关性 药物功效。细胞系和组织将通过已经建立的点击化学辅助亲和力进行分析 捕获和HPLC-MS/MS用于可能的额外CP-8靶标和代谢物含量。目标2将执行IND 与PharmaDirections合作，使体外和体内CP-8药理学研究成为可能， 短期目标是为CP-8的第2阶段（R42）评估做好准备。