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。

基本信息

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
项目类别：
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

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

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项目摘要

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。在此阶段I STTR项目中，Light Switch Bio将与弗吉尼亚合作英联邦大学和宾夕法尼亚大学IR-Platin的早期发展，治疗头颈鳞状细胞癌（HNSCC）的第一类光活化化疗，全球第六个领先的癌症。大多数HNSCC患者患有晚期疾病，需要掺入顺铂的多模式疗法，该疗法已证明有效控制局部疾病。但是，顺铂的使用受到剂量限制毒性的问题的困扰，这些毒性可能是致命的，有助于长期残疾。对于许多患者，这些毒性意味着它们无法延长顺铂的治疗和结果的结果较差。当与辐射结合时，顺铂也是已知会加剧辐射诱导的粘膜炎，会导致长期吞咽疾病。这些挑战为可以在本地提供顺铂提供的策略提供了机会，避免了残疾系统活性顺铂的病态和潜在的致命副作用。我们解决这种需求的策略是IR-Platin：一种非活性的顺铂前药，可在存在近红外（NIR）光。双重激活模式有望导致有效治疗大型和低氧肿瘤，这是光动力疗法的两个主要局限性。而且，因为发行活化的铂种是用光引导的，该系统与铂化学疗法相关在HNSCC中，应大大减少。此外，光疗诱导光疗的趋势抗肿瘤免疫反应，结合活性铂（II）物种的可调节能力，授予IR- Platin提供控制远处疾病和复发性疾病的潜力。我们的出版物和初步数据已经建立了IR-铂，其体外稳定性，小鼠中的低毒性的双重作用机理，并且与顺铂相比，用IR-Platin和NIR光治疗的HNSCC肿瘤的小鼠改善了肿瘤控制。该提案的目的是确定IR-Platin对治疗的可行性和治疗潜力原位小鼠模型中的HNSCC。预计拟议的调查结果将有助于获得关键的初步数据，以支持更大的辅助研究和我们的II期STTR应用。具体目标 1专注于IR-Platin的肿瘤摄取，毒性，效率和作用机理的原位治疗机理 HNSCC的鼠标模型。具体目标2研究了IR-Platin的药代动力学。这些研究会提供关键数据来评估IR-铂对HNSCC治疗的治疗潜力，并将放置基础用于其他轻便可及癌症的靶向治疗（例如，不可切除的鳞状皮肤和食道的癌；肺癌；膀胱癌）。作为第一类治疗策略， Platin还将为Light Switch Bio开发的其他轻靶药物铺平道路，这些药物可以减轻 - 通过物理靶向其活性来靶向毒性。