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

基本信息

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
项目类别：
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

项目摘要

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 DNA 损伤反应 (DDR) 有缺陷，癌细胞仍具有修复 DNA 并继续生存的独特能力他们的DNA复制。 DNA 复制率更高，DNA 修复活性增强（尽管容易出错）虽然确保不受控制的增殖，但也会在癌细胞中产生高频率的基因突变。细胞 DNA 的这种改变以及癌细胞对不断复制的依赖最初成为了以 DNA 为靶点进行癌症治疗的理由。尽管在一定程度上取得了成功，但其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区别地与细胞 DNA 或其他非 DNA 大分子结合，导致 DNA 损伤。我们推理新的 DNA 相互作用药物 (1) 显示出高序列/区域特异性 (2) 不会直接损伤 DNA (3) 靶向肿瘤细胞使用但正常细胞不使用的 DNA 相关过程可能具有有利的作用治疗结果。在本提案中，我们提供了令人信服的证据，证明咔唑蓝 (CB) 可能是其中之一我们最近开发的这种药物。我们从煤的活性成分咔唑中合成了CB 焦油用于治疗牛皮癣。使用公正的全基因组方法，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)、患者来源的类器官（PDO）和异种移植物（PDX）以及原位异种移植模型，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，因为 CB 可以全身给药抑制 TNBC 和 ER+ 乳腺癌 (BC) 的生长和进展，且不会引起任何毒性。我们发现 CB 抑制富含 A/T 的结合蛋白 HMGA1 的活性，从而抑制多种蛋白的表达包括 CDK4、MCM、GINS 和 CDC6 在内的基因在这些 BC 中高度表达并发挥着关键作用在复制和 DNA 修复中发挥作用。重要的是，据报道 HMGA1 及其靶蛋白可以调节 PARP 抑制剂 (PARPi) 和 CDK4/6 抑制剂 (CDK4/6i) 分别在 TNBC 和转移性 ER+BC 中产生反应。提出了三个具体目标：在目标 1 中，我们将检验 CB 优先针对特定目标的假设 DNA 中对癌细胞增殖/进展至关重要的结构域，可选择性诱导癌细胞死亡。在目标 2 中，我们将阐明 CB 利用 HMGA1 等靶基因致敏的机制 PARPi 和 CDK4/6i 反应分别导致 TNBC 和 ER+BC 的生长/转移抑制。在目标 3，我们将检验 CB 作为一种新型、安全且有效的抗肿瘤剂和治疗剂的假设使用 PDX、PDO 和 PDEx 模型治疗 BC 的佐剂。我们还将建立所需的 PK/PD 参数为CB未来的临床开发提供帮助。这项研究的成功完成将为新范式奠定基础使用 CB 作为治疗剂来治疗 BC。