ROS Targeted Therapy for Lethal Prostate Cancer

ROS 靶向治疗致命性前列腺癌

• 批准号: 10112557
• 负责人: RUOXIANG WANG
• 金额: $ 19.52万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112557
• 关键词: Address; American; Androgen Antagonists; Antimalarials; Antineoplastic Agents; Apoptosis; Apoptotic; Artemisinins; Biological; Biological Availability; Biological Process; Blood; Cancer Etiology; Carbocyanines; Carrier Proteins; Castration; Cause of Death; Cell Death; Cell model; Cessation of life; Chemicals; Chemoresistance; Collaborations; Conjugating Agent; Detection; Development; Disease; Drug Delivery Systems; Drug Kinetics; Drug Sensitization; Drug resistance; Dyes; Family; Foundations; Future; Goals; Growth; Homeostasis; Hour; Hydroxyl Radical; Hypoxia Inducible Factor; In Vitro; Isotopes; Knowledge; Label; Lead; Ligand Binding; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Mitochondria; Modeling; Mus; Near-infrared optical imaging; Neoplasm Metastasis; Normal tissue morphology; OATP Transporters; Organ; Organelles; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Primary Neoplasm; Production; Property; Prostate Cancer therapy; Radio; Reactive Oxygen Species; Regulation; Reporting; Resistance; Scientist; Singlet Oxygen; Solid; Specific qualifier value; Specificity; Structure-Activity Relationship; Superoxides; Surface; Testing; Therapeutic; Therapeutic Intervention; Tissues; Treatment Efficacy; Up-Regulation; advanced prostate cancer; anti-cancer therapeutic; bioluminescence imaging; cancer cell; cancer diagnosis; cancer drug resistance; cancer therapy; castration resistant prostate cancer; chemical property; chemotherapy; comparative; design; differential expression; drug-sensitive; effective therapy; effectiveness evaluation; effectiveness study; hormone therapy; image guided; imaging modality; improved; in vitro testing; in vivo; innovation; men; molecular imaging; mortality; mouse model; neoplastic cell; novel; prostate cancer cell; prostate cancer cell line; prostate cancer metastasis; prostate cancer prevention; prostate cancer progression; receptor binding; refractory cancer; side effect; small molecule; targeted delivery; targeted treatment; tool; transcription factor; tumor; tumor growth; tumor hypoxia; uptake

PROJECT SUMMARY Prostate cancer (PC) is the second leading cause of cancer mortality in American men. Current therapeutics only show marginal efficacy and are often associated with serious side effects and drug resistance that contribute to patient mortality. Cancer drug resistance is one of the most challenging difficulties that needs to be addressed with innovative mechanistic knowledge and tactical application. Reactive oxygen species (ROS), such as superoxide anion (O2−), singlet oxygen (1O2) and hydroxyl radical (·OH), are highly active metabolic by-products, whose homeostasis is maintained by redox regulation. High levels of ROS can cause tissue damages and even cell death. Though small molecule reactive oxygen generating agents (ROSG) that enhance intracellular ROS levels may thus serve as anti-tumor therapeutics, the in vivo efficacy of these compounds in cancer therapy is severely impeded by their unfavorable pharmacokinetic properties, low bioavailability, and their poor targeting property specifically to tumor cells. In this regard, we have discovered that certain some specified near infrared (NIR) heptamethine carbocyanine dye (HMCD) can enter cancer cells with high selectivity via organic anion transporting polypeptide (OATP) family of carrier proteins, which are differentially expressed in cancer cells while the expression can be further enhanced by intra-tumoral hypoxia through upregulation of transcription factor of the hypoxia inducible factor (HIF-1α). To improve the efficacy of ROS-mediated cancer therapy, we sought to conjugate small molecule ROSG with cancer-specific HMCD for cancer cell targeting and delivery. This innovative project will allow us to test the potential impact of delivering small molecule ROSG directly to cancer cells to induce apoptosis. We hypothesize that HMCD-ROSG kills cancer cells in vitro; and will also be effective in vivo for targeted treatment of lethal PCs. The unique mechanism of action is mediated by ROS production in cancer cell subcellular organelles, disrupting vital biologic function to elicit apoptosis. Our preliminary results indicated that, compared with hormonal therapy and chemotherapy, PC cells could be killed more effectively by HMCD-ROSG. The synthesis and characterization of HMCD-ROSG conjugates will be performed and the biological activities of these new chemical entities will be tested in vitro with drug-sensitive and drug-resistant PC cells lines and in vivo with mouse models. We will employ NIR and bioluminescence imaging modalities as detection tools to assess specificity of the HMCD-ROSG conjugates into tumors and to study the effectiveness of these novel compounds as anti-cancer therapeutic and sensitizing agents for high efficacy on prevention of PC progression and metastasis. The proposed project will be performed by a scientific collaboration between a chemist and cancer scientist. The proposal will provide a solid foundation and new aspect to the ROS-mediated therapy as a potent therapeutic intervention for advanced and castration-resistant PC and metastasis.

项目摘要 前列腺癌（PC）是美国男性癌症死亡率的第二大原因。当前的疗法 仅显示边际效果，通常与严重的副作用和耐药性有关 致患者死亡率。癌症耐药性是需要解决的最挑战的困难之一 具有创新的机械知识和战术应用。活性氧（ROS），例如 超氧化阴离子（O2-），单氧（1O2）和羟基自由基（·OH）是高度活跃的代谢副产物， 氧化还原调节维持其稳态。高水平的ROS会导致组织损伤，甚至 细胞死亡。尽管小分子活性氧产生剂（ROSG）增强了细胞内ROS 因此，水平可以用作抗肿瘤疗法，这些化合物在癌症治疗中的体内效率是 由于其不利的药代动力学特性，低生物利用度及其靶向较差而极大地阻碍了 专门针对肿瘤细胞的特性。在这方面，我们发现某些人在保险附近指定 （NIR）己氨酸碳环氨酸染料（HMCD）可以通过有机阴离子以高选择性进入癌细胞 运输多肽（OATP）载体蛋白家族，在癌细胞中以不同的表达 通过上调的转录因子的上调 缺氧诱导因子（HIF-1α）。为了提高ROS介导的癌症疗法的效率，我们试图 与癌细胞靶向和递送的癌症特异性HMCD共轭小分子ROSG。这 创新的项目将使我们能够测试将小分子ROSG直接传递到癌症的潜在影响 细胞诱导凋亡。我们假设HMCD-ROSG在体外杀死了癌细胞。并且也将有效 体内用于致命PC的靶向治疗。独特的作用机理是由ROS的产生介导的 癌细胞亚细胞细胞器，破坏了重要的生物学功能引起凋亡。我们的初步结果 表明，与马疗治疗和化学疗法相比，PC细胞可以通过 HMCD-ROSG。将执行HMCD-ROSG结合物的合成和表征 这些新化学实体的生物活性将在体外用药物敏感和耐药性测试 PC细胞线和带有小鼠模型的体内。我们将采用NIR和生物发光成像作为 检测工具以评估HMCD-ROSG结合物成肿瘤的特异性并研究有效性 在这些新型化合物中，作为抗癌的热和敏化剂，以高效预防 PC进展和转移。拟议的项目将由科学合作进行 化学家和癌症科学家。该提案将为ROS介导的稳固的基础和新方面 治疗是对晚期和cast割PC和转移的潜在治疗干预措施。