Elucidating and Targeting tumor dependencies and drug resistance determinants at the single cell level

在单细胞水平上阐明和靶向肿瘤依赖性和耐药性决定因素

• 批准号: 10709574
• 负责人: ANDREA CALIFANO
• 金额: $ 95.62万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709574
• 关键词: Acute; Address; Adult; Biological Assay; Biological Markers; Breast Adenocarcinoma; CLIA certified; Cancer Patient; Categories; Cells; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Data Set; Dependence; Desmoplastic Small Round Cell Tumor; Development; Dissection; Drug Controls; Drug Targeting; Drug resistance; Genetic; Genetic Transcription; Glioblastoma; Goals; Health; Immunotherapy; Individual; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Methodology; Molecular; Mutate; Mutation; Network-based; Neuroblastoma; Neuroendocrine Tumors; Oncogenes; Oncoproteins; Pathway interactions; Patients; Pediatric Neoplasm; Pharmaceutical Preparations; Population; Progression-Free Survivals; Prostate; Prostate Adenocarcinoma; Proteins; Relapse; Reporter Genes; Research Personnel; Reverse engineering; Role; Signal Transduction; Slice; Testing; The Cancer Genome Atlas; Tissues; Tumor Subtype; Validation; biomarker development; cancer cell; cancer genetics; cohort; design; drug sensitivity; falls; follow-up; improved; neoplastic cell; novel; patient derived xenograft model; pharmacologic; resistance mechanism; response; sarcoma; single-cell RNA sequencing; success; targeted treatment; therapeutic target; therapeutically effective; transcription factor; tumor; tumorigenesis

Cancer targets fall into two major categories: oncoproteins that elicit tumor essentiality due to their direct role in tumorigenesis or tumor maintenance (oncogene dependencies) and proteins that elicit synthetic lethality with oncogene mutations but are not themselves mutated (non-oncogene dependencies). Unfortunately, clonal selection and inherent cancer cell plasticity—as well as the ability of cancer cells to undergo adaptation and reprogramming to drug resistant states, following treatment—are currently challenging the concept of individual proteins as effective therapeutic targets for an entire tumor mass—especially if identified from bulk tissue analyses. Indeed, despite several successes, only 5% – 11% of cancer patients benefit from targeted therapy, based on progression free survival, often with no substantial overall survival differences; while promising, immune therapy is also subject to selective response and relapse. To address these challenges, our proposal will study a more universal class of mutation-agnostic, non-oncogene dependencies implemented by tightly-autoregulated sets of Master Regulator (MR) proteins that we have called Tumor Checkpoint (TC) modules. We have shown that MR proteins mechanistically implement a tumor cell’s transcriptional state by canalizing the effect of mutations and aberrant signals in their upstream pathways. As such, within the context of a transcriptionally-distinct tumor subtype, they represent largely mutation-agnostic dependencies. Our proposal will thus focus on the elucidation and pharmacological targeting of MRs and TC-modules at the single cell level, within molecularly distinct, yet co-existing tumor subpopulations. This will lead to design of successful combination therapy approaches and will help elucidate and pharmacologically target mechanisms of drug resistance and cell adaptation. To accomplish these goals, we will extend a highly successful, network- based framework developed by our CTD2 Center, for the elucidation, validation, and pharmacological targeting of MR proteins and TC-modules. Indeed, we have shown that genetic or pharmacological targeting of this new class of tumor dependencies can induce collapse of TC-module activity and induce loss of tumor viability in a wide range of malignancies, ranging from glioblastoma, neuroblastoma, and neuroendocrine tumors, to prostate and breast adenocarcinoma, among many others. In particular, analysis of 25 TCGA cohorts has identified 112 transcriptionally distinct tumor subtypes, each one regulated by a distinct subtype-specific TC-module, which was independent of patient-specific mutations. These methodologies are especially relevant in rare, aggressive tumors—including several pediatric malignancies—where cohort size may be too small to support correlative analyses. Critically, these studies have led to the development of two NY/CA Dpt. of Health approved, CLIA- compliant tests, OncoTarget and OncoTreat, whose predictions have spurred several clinical trials. These approaches will be extended to elucidate TC-module dependencies and to develop drug sensitivity biomarkers at the single cell level.

癌症靶标分为两个主要类别：由于其在 肿瘤发生或肿瘤维持（癌基因依赖性）和引起合成致死性的蛋白质 致癌基因突变，但本身并非突变（非癌基因依赖性）。不幸的是，克隆人 选择和继承癌细胞的可塑性 - 以及癌细胞进行适应和 对抗药性状态进行重新编程，在治疗后 - 目前挑战 单个蛋白质作为整个肿瘤质量的有效治疗靶标，尤其是从 散装组织分析。确实，几个成功，只有5％ - 11％的癌症患者受益于 基于无进展生存的有针对性治疗，通常没有实质性的总体生存差异；尽管 有希望的免疫治疗也需要选择性反应和缓解。为了应对这些挑战，我们的 提案将研究实施的更为普遍的突变敏捷性，非co依依赖性 通过我们称为肿瘤检查点（TC）的紧密自动调节的主调节剂（MR）蛋白 模块。我们已经表明，MR蛋白质通过 在其上游途径中引导突变和异常信号的效果。因此，在上下文中 在具有转录赋予的肿瘤亚型中，它们主要代表突变 - 敏捷依赖性。我们的 因此，建议将集中于MRS和TC模块在该地区的阐明和药物靶向 单细胞水平，内部分子不同但共存的肿瘤亚群。这将导致设计 成功的组合疗法方法，将有助于阐明和药物针对机制 耐药性和细胞适应性。为了实现这些目标，我们将扩展一个非常成功的网络 - 由我们的CTD2中心开发的基于基于的框架，用于阐明，验证和药物靶向 MR蛋白质和TC模型的。实际上，我们已经表明了这种新的遗传或药物靶向 肿瘤依赖性类别可以诱导TC模块活性的崩溃并诱导A中的肿瘤生存力丧失 广泛的恶性肿瘤，范围从胶质母细胞瘤，神经母细胞瘤和神经内分泌肿瘤到前列腺 和乳腺腺癌，等等。特别是，对25个TCGA队列的分析已确定112 转录不同的肿瘤亚型，每种由独特的亚型特异性TC模块调节的肿瘤亚型 独立于患者特异性突变。这些方法在罕见，侵略性方面特别相关 肿瘤 - 包括几种儿科恶性肿瘤 - 同类群体可能太小而无法支持相关性 分析。至关重要的是，这些研究导致了两个NY/CA DPT的发展。健康批准，Clia- 合规测试，Oncotarget和Oncotreat，其预测刺激了几项临床试验。这些 方法将扩展以阐明TC模块依赖性并发展药物敏感性生物标志物 在单细胞水平。