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.

癌细胞尽管DNA损伤反应不良（DDR）具有独特的修复DNA的能力并继续他们的DNA复制。 DNA复制率较高和DNA修复活性增强（尽管容易出错）尽管确保不受控制的增殖，但在癌细胞的高频处也会产生遗传突变。细胞DNA的这种改变以及癌细胞对不间断复制的依赖性最初成为靶向DNA作为癌症疗法的理由。尽管在某种程度上成功，但主要局限性当今诊所中使用的DNA靶向药物包括威胁生命的毒性，获得的抗药性和次要癌症的发生。这些问题主要源于DNA靶向药物的能力与细胞DNA或其他非DNA大分子相结合，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）不会直接损害DNA （3）肿瘤细胞使用但不具有正常细胞的目标DNA相关过程可能具有有利治疗结果。在此提案中，我们提供了令人信服的证据，表明甲壳虫蓝（CB）可能是一个我们最近开发的这种药物。我们从煤炭中合成了Carbazole的CB 用于治疗牛皮癣的焦油。使用公正的全基因组方法，我们发现CB 与A/T富的DNA区域相互作用。重要的是，使用细胞系，患者衍生的前体外植体（PDEX），患者衍生的类器官（PDO）和异种移植物（PDX）以及原位异种移植模型，我们发现在与化学疗法药物形成鲜明对比的是，CB是一种有效且安全的抗癌化合物，作为CB的全身递送抑制TNBC和ER+乳腺癌（BC）的生长和进展，而无需诱导任何毒性。我们发现CB抑制A/T富含结合蛋白HMGA1的活性，因此表达了几种包括CDK4，MCMS，GINS和CDC6在内的基因，并且在这些BC中高度表达并发挥关键在复制和DNA修复中的作用。重要的是，据报道HMGA1及其靶蛋白调节PARP TNBC和转移性ER+BC中的抑制剂（PARPI）和CDK4/6抑制剂（CDK4/6I）反应。提出了三个具体目标：在AIM1中，我们将测试CB优先针对特定目标的假设 DNA中的结构域对于癌细胞增殖/进展至关重要，以选择性诱导癌细胞死亡。在AIM 2中，我们将阐明CB利用靶基因（例如HMGA1）敏化的机制 PARPI和CDK4/6I的反应分别导致TNBC和ER+BC的生长/转移抑制。在 AIM 3，我们将测试CB作为一种新颖，安全且有效的抗肿瘤剂和治疗的假设使用PDX，PDO和PDEX模型处理BCS的辅助。我们还将建立所需的PK/PD参数用于CB的未来临床发展。这项研究的成功完成将为新的范式奠定基础使用CB作为治疗性治疗BC。