Light-directed therapy of squamous cell head and neck cancer with a novel dual-acting chemotherapeutic.

使用新型双作用化疗药物对鳞状细胞头颈癌进行光定向治疗。

• 批准号: 10761072
• 负责人: Hisashi Harada
• 金额: $ 40.62万
• 依托单位: LIGHT SWITCH BIO, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-03 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10761072
• 关键词: Address; Adjuvant; Animals; Biodistribution; Biological Assay; Biotechnology; Cause of Death; Cell Death; Characteristics; Cisplatin; Clinical; Collaborations; Combined Modality Therapy; Cytotoxic agent; Darkness; Data; Deglutition; Development; Disease; Disease model; Distant; Dose; Dose Limiting; Drug Kinetics; Drug Targeting; Economic Burden; Effectiveness; Esophageal carcinoma; Fluorescence; Foundations; Generations; Goals; Grant; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Histologic; Human Papillomavirus; In Vitro; Incidence; Investigation; Kidney; Kinetics; Lasers; Legal patent; Licensing; Light; Lighting; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Maximum Tolerated Dose; Measures; Medical Technology; Morbidity - disease rate; Mouth Neoplasms; Mucositis; Mus; Outcome; Oxygen; PUVA Photochemotherapy; Patients; Penetration; Pennsylvania; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phototherapy; Platinum; Prodrugs; Publications; Radiation; Recurrent disease; Regimen; Research; Safety; Singlet Oxygen; Site; Skin Carcinoma; Small Business Technology Transfer Research; Solid Neoplasm; Squamous cell carcinoma; Survivors; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Treatment Protocols; Tumor Volume; Universities; Virginia; Work; advanced disease; analog; animal imaging; anti-tumor immune response; chemotherapy; commercialization; compare effectiveness; cytotoxic; disability; dosage; drug candidate; effective therapy; efficacy evaluation; improved; in vivo; mouse model; novel; novel therapeutic intervention; novel therapeutics; preclinical development; side effect; skin squamous cell carcinoma; systemic toxicity; targeted treatment; time interval; treatment strategy; tumor; tumor hypoxia; uptake

PROJECT SUMMARY. In this Phase I STTR project, Light Switch Bio will collaborate with Virginia Commonwealth University and the University of Pennsylvania for the early-stage development of IR-Platin, a first-in-class photoactivated chemotherapy for treatment of head and neck squamous cell carcinoma (HNSCC), the sixth leading cancer worldwide. Most patients with HNSCC present with advanced disease and need multimodal therapy incorporating cisplatin, which has shown to be effective in controlling locoregional disease. However, the use of cisplatin is plagued by issues with dose-limiting toxicities that are potentially lethal and contribute to long-term disability. For many patients, these toxicities mean that they cannot receive prolonged treatment of cisplatin and as a result suffer worse outcomes. When combined with radiation, cisplatin is also known to exacerbate radiation-induced mucositis that creates a spectrum of long-term swallowing disabilities. These challenges present an opportunity for strategies that can deliver cisplatin locally, avoiding the disabling morbidities and potentially lethal side effects of systemically active cisplatin. Our strategy to address this need is IR-Platin: an inactive prodrug of cisplatin that releases activated platinum(II) species and singlet oxygen in the presence of near-infrared (nIR) light. The dual mode of activation is expected to lead to effective treatment of large and hypoxic tumors, two of the main limitations of photodynamic therapy. Moreover, because the release of activated platinum species is directed with light, the systemic toxicity associated with platinum chemotherapy in HNSCC should be strongly diminished. Further, the demonstrated tendency for phototherapies to induce an antitumor immune response, in combination with the adjuvant capacity of active platinum(II) species, grants IR- Platin the potential to provide control of distant disease and recurrent disease. Our publications and preliminary data have established the dual mechanisms of action of IR-Platin, its in vitro stability, its low toxicity in mice, and improved tumor control in mice bearing HNSCC tumors treated with IR-Platin plus nIR light compared to cisplatin. The goal of this proposal is to establish the feasibility and therapeutic potential of IR-Platin for the treatment of HNSCC in orthotopic mouse models. The results of the proposed investigation are anticipated to help obtain critical preliminary data to support larger IND-enabling studies and our Phase II STTR application. Specific Aim 1 focuses on IR-Platin’s tumor uptake, toxicity, efficacy, and mechanism of action for treatment in orthotopic mouse models of HNSCC. Specific Aim 2 investigates the pharmacokinetics of IR-Platin. These studies will provide critical data to evaluate the therapeutic potential of IR-Platin for the treatment of HNSCC and will lay the foundation for its use in the targeted treatment of other light accessible cancers (e.g. non-resectable squamous carcinomas of the skin and esophagus; lung cancer; bladder cancer). As a first-in-class treatment strategy, IR- Platin will also pave the way for Light Switch Bio’s development of other light-targeted drugs that mitigate off- target toxicities by physically targeting their activity.

项目摘要。在这个第一阶段的STTR项目中，Light Switch Bio将与弗吉尼亚州合作， 英联邦大学和宾夕法尼亚大学为IR-Platin的早期开发， 用于治疗头颈部鳞状细胞癌（HNSCC）的一流光活化化疗， 全球第六大癌症大多数HNSCC患者存在晚期疾病，需要 联合顺铂的多模式疗法，其已显示在控制局部疾病中有效。 然而，顺铂的使用受到剂量限制性毒性问题的困扰，这些毒性可能是致命的， 造成长期残疾。对于许多患者来说，这些毒性意味着他们不能接受长期的治疗。 顺铂的治疗，并因此遭受更差的结果。当与放疗结合时，顺铂也 已知会加剧辐射引起的粘膜炎，从而造成一系列长期吞咽障碍。 这些挑战为可以局部递送顺铂的策略提供了机会，从而避免了致残性的化疗。 全身活性顺铂的发病率和潜在致命的副作用。我们应对这一需求的战略 是IR-铂：顺铂的非活性前药，其在细胞内释放活化的铂（II）物质和单线态氧。 近红外（NIR）光的存在。双重激活模式有望导致有效治疗 大的和缺氧的肿瘤，光动力疗法的两个主要限制。此外，由于释放 光直接照射活化的铂类物质，与铂化疗相关的全身毒性 HNSCC的发病率应该大大降低。此外，已证实的光疗诱导肿瘤细胞凋亡的趋势， 抗肿瘤免疫应答，与活性铂（II）物质的佐剂能力结合，赠款IR- 铂类药物具有控制远端疾病和复发疾病的潜力。我们的出版物和初步 数据已经确定了IR-铂的双重作用机制，其体外稳定性，其在小鼠中的低毒性， 与顺铂相比，用IR-铂加nIR光处理的携带HNSCC肿瘤的小鼠中的肿瘤控制得到改善。 本提案的目的是确定IR-铂治疗以下疾病的可行性和治疗潜力： 原位小鼠模型中的HNSCC。预计拟议调查的结果将有助于获得 关键的初步数据，以支持更大的IND使能研究和我们的II期STTR应用。具体目标 1侧重于IR-铂的肿瘤摄取，毒性，疗效和原位治疗的作用机制。 HNSCC小鼠模型。具体目标2研究了IR-铂的药代动力学。这些研究将 为评估IR-Platin治疗HNSCC的治疗潜力提供了关键数据，并将奠定 为其用于靶向治疗其他光可及癌症（如不可切除的鳞状细胞癌）奠定了基础。 皮肤癌和食道癌;肺癌;膀胱癌）。作为一流的治疗策略，IR- 铂还将为Light Switch Bio开发其他光靶向药物铺平道路， 通过物理靶向它们的活性来靶向毒性。