Novel approach of targeting AT-rich S/MAR regions for treating therapy resistant breast cancers

靶向富含 AT 的 S/MAR 区域治疗耐药性乳腺癌的新方法

• 批准号: 10744563
• 负责人: Manjeet Kumar Rao
• 金额: $ 48.42万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744563
• 关键词: Adjuvant; Affinity; Apoptosis; Binding; Binding Proteins; Binding Sites; Biochemical; Biological Assay; Biophysics; Breast Cancer Patient; CDC6 gene; CDK4 gene; Cancer Center; Carbazoles; Cell Cycle; Cell Death; Cell Line; Cell Proliferation; Cell Survival; Cell model; Cells; Characteristics; Chemicals; Clinic; Clinical Research; Coal Tar; DNA; DNA Binding; DNA Damage; DNA Repair; DNA Repair Pathway; DNA Sequence Alteration; DNA biosynthesis; DNA sequencing; Data; Dependence; Development; Doxorubicin; Drug Targeting; Drug usage; Ensure; Estrogen receptor positive; Frequencies; Funding; Future; Genes; Goals; Growth; HMGA1 gene; Human Genome; Island; Legal patent; Life; Ligands; Malignant Neoplasms; Matrix Attachment Regions; Modeling; Neoplasm Metastasis; Normal Cell; Organoids; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Poly(ADP-ribose) Polymerase Inhibitor; Positioning Attribute; Pre-Clinical Model; Proliferating; Proteins; Psoriasis; Regimen; Reporting; Resistance; Role; Second Primary Cancers; Specificity; Structure; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tumor-Associated Process; Xenograft Model; Xenograft procedure; anti-cancer; antitumor agent; breast cancer survival; cancer cell; cancer therapy; carcinogenesis; chemotherapy; clinical development; drug development; genome-wide; improved; in silico; inhibitor; knock-down; macromolecule; malignant breast neoplasm; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; pharmacokinetics and pharmacodynamics; pre-clinical; preservation; repaired; response; scaffold; stem; targeted treatment; therapeutic evaluation; therapy outcome; therapy resistant; translational potential; triple-negative invasive breast carcinoma; tumor growth

Cancer cells despite defective DNA damage response (DDR) have unique ability to repair their DNA and continue their DNA replication. The higher rate of DNA replication and heightened DNA repair activity (albeit error-prone) though ensure uncontrolled proliferation but also produce genetic mutations at high frequencies in cancer cells. This alteration of cellular DNA and dependency of cancer cells to incessant replication initially became the justification for targeting DNA as a cancer therapy. Though successful to some extent, the major limitations of DNA targeting drugs that are used in clinics today include life threatening toxicity, acquired resistance and occurrence of secondary cancers. These problems mostly stem from the ability of DNA targeting drugs to indiscriminately bind to cellular DNA or other non-DNA macromolecules resulting in DNA damage. We reason new DNA interacting drugs that (1) display high sequence/region specificity (2) do not directly damage the DNA and (3) target DNA-related processes that tumor cells use but not the normal cells could have favorable therapeutic outcomes. In this proposal, we provide compelling evidence that Carbazole Blue (CB) may be one such drug that we recently developed. We synthesized CB from carbazole, which is an active ingredient of coal tar that is used for the treatment of Psoriasis. Using an unbiased genome-wide approach, we discovered that CB interacts with A/T rich DNA regions. Importantly, using cell lines, patient-derived ex-vivo explants (PDEx), patient-derived organoids (PDO) and xenografts (PDX) as well as orthotopic xenograft models, we found that in contrast to chemotherapy drugs, CB is a potent and safe anti-cancer compound as systemic delivery of CB inhibits growth and progression of TNBC and ER+ breast cancers (BCs) without inducing any toxicity. We discovered that CB inhibits the activity of A/T rich binding protein HMGA1 and consequently expression of several genes including CDK4, MCMs, GINS and CDC6 and that are highly expressed in these BCs and play critical roles in replication and DNA repair. Importantly, HMGA1 and its target proteins are reported to regulate PARP inhibitor (PARPi) and CDK4/6 inhibitor (CDK4/6i) responses in TNBC and metastatic ER+BCs, respectively. Three Specific Aims are proposed: In Aim1, we will test the hypothesis that CB preferentially targets specific domains in the DNA that are critical for cancer cell proliferation/progression to selectively induce cancer cell death. In Aim 2, we will elucidate the mechanisms by which CB utilizes target genes such as HMGA1 to sensitize PARPi and CDK4/6i responses leading to growth/metastasis inhibition of TNBC and ER+BCs, respectively. In Aim 3, we will test the hypothesis that CB serves as a novel, safe and potent anti-tumor agent and therapeutic adjuvant for treating BCs using PDX, PDO and PDEx models. We will also establish PK/PD parameters required for future clinical development of CB. Successful completion of this study will set the stage for a new paradigm of treating BCs using CB as a therapeutic.

尽管有缺陷的DNA损伤反应（DDR），但癌细胞具有独特的修复其DNA并继续生长的能力。 DNA复制。更高的DNA复制率和更高的DNA修复活性（尽管容易出错） 虽然确保不受控制的增殖，但也在癌细胞中以高频率产生基因突变。 这种细胞DNA的改变和癌细胞对不断复制的依赖最初成为了癌细胞的一个重要特征。 靶向DNA作为癌症治疗的合理性。虽然在某种程度上是成功的，但它的主要局限性 目前临床上使用的DNA靶向药物包括危及生命的毒性、获得性耐药性和耐药性。 继发性癌症的发生。这些问题主要源于DNA靶向药物的能力， 不加选择地结合细胞DNA或其它非DNA大分子，导致DNA损伤。我们推理 新的DNA相互作用药物，（1）显示高序列/区域特异性（2）不直接损伤DNA （3）肿瘤细胞利用而非正常细胞利用的靶DNA相关过程可能具有有利的 治疗结果。在这项提案中，我们提供了令人信服的证据，咔唑蓝（CB）可能是一个 我们最近开发的药物。以煤的活性成分咔唑为原料合成炭黑 用于治疗牛皮癣的焦油。使用无偏的全基因组方法，我们发现CB 与富含A/T的DNA区域相互作用。重要的是，使用细胞系，患者来源的离体外植体（PDEx）， 患者源性类器官（PDO）和异种移植物（PDX）以及原位异种移植物模型，我们发现， 与化疗药物相比，CB是一种有效且安全的抗癌化合物， 抑制TNBC和ER+乳腺癌（BC）的生长和进展，而不诱导任何毒性。我们 发现CB抑制富含A/T的结合蛋白HMGA1的活性，并因此抑制几种 包括CDK4、MCMs、GINS和CDC6在内的基因，在这些BC中高度表达， 在复制和DNA修复中的作用。重要的是，据报道HMGA1及其靶蛋白调节PARP 抑制剂（PARPi）和CDK 4/6抑制剂（CDK 4/6 i）分别在TNBC和转移性ER + BC中产生反应。 提出了三个具体的目标：在目标1中，我们将测试CB优先靶向特定的假设， DNA中对癌细胞增殖/进展至关重要的结构域，以选择性地诱导癌细胞增殖/进展。 死亡在目标2中，我们将阐明CB利用靶基因如HMGA 1致敏的机制。 PARPi和CDK4/6i应答分别导致TNBC和ER + BC的生长/转移抑制。在 目的3，我们将验证CB作为一种新型，安全，有效的抗肿瘤药物和治疗药物的假设 使用PDX、PDO和PDEx模型治疗BC的佐剂。我们还将确定所需的PK/PD参数 用于CB的未来临床开发。这项研究的成功完成将为一个新的范例奠定基础 使用CB作为治疗剂治疗BC。