Genomic and Microenvironmental Determinants, Temporal Dynamics, and Treatment Efficacy of Radiation-Based Combination Therapies
基因组和微环境决定因素、时间动态以及基于放射的联合疗法的治疗效果
基本信息
- 批准号:10704661
- 负责人:
- 金额:$ 147.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-14 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:Antibody-drug conjugatesAutomobile DrivingBiographyBiological MarkersBiological ProductsBladderBreast Cancer PatientCancer PatientChemotherapy and/or radiationCisplatinClinicClinicalCombined Modality TherapyDNA DamageDataDiseaseEventFoundationsGene ExpressionGeneticGenetic TranscriptionGenomicsGoalsHead and Neck CancerHead and Neck Squamous Cell CarcinomaHead and neck structureImmuneImmune checkpoint inhibitorImmune systemImmunologic FactorsImmunologicsImmunotherapyInternationalMalignant neoplasm of urinary bladderModalityMolecularMutationOncologyOutcomePathogenesisPatientsRadiationRadiation ToleranceRadiation therapyRadiobiologyResearchResearch PersonnelResistanceRobin birdRoentgen RaysTestingTherapeuticTreatment EfficacyWorkantitumor effectcancer therapycancer typecheckpoint therapychemotherapyimmune checkpoint blockadeimprovedimproved outcomeinnovationinsightmultidisciplinarymultimodalitynext generationpreservationprogramsradiation effectradiation resistanceradiation responseradiomicsresponsestandard of caretreatment strategytumor
项目摘要
PROJECT SUMMARY
Overall Section
Our ROBIN center focuses on elucidating the genomic and microenvironmental determinants, and
temporal dynamics underlying efficacy of radiation-based combination therapies. Radiotherapy (RT), alone or
in combination with other treatments, is used to treat about two-thirds of all cancer patients. Despite the
widespread use of radiation therapy in oncology, our understanding of the mechanisms driving response and
resistance remains poor. Our long-term goal is to understand the mechanisms that underlie efficacy and
resistance of radiation-based therapies. New efforts to improve treatment for many cancer types now focus on
using combination therapies in which radiation is used with systemic agents, highlighting the urgent need to
understand the drivers of efficacy. Among the most promising new biologics being studied for use with
radiation are antibody-drug conjugates (ADC) and immune checkpoint inhibitors (ICI). We will use an
innovative molecular characterization trial testing radiation plus ADC in bladder cancer and radiation plus ICI in
head and neck cancer to characterize the mechanistic drivers underlying these next generation RT-based
combinations. The central hypothesis of this U54 application is that specific genetic and immunologic
mechanisms underlie sensitivity and resistance to radiation-based combination therapies. We will address
these questions through 3 specific aims. In Aim 1, we will work to understand the molecular mechanisms that
underlie efficacy of treatment with radiation plus ADC. Here, our working hypothesis is that specific genetic and
immunologic events underlie response to RT plus sacituzumab govitecan (SG) treatment. We will leverage our
molecular characterization trial (Part A) investigating the use of RT and sacituzumab for bladder preservation
therapy. We will determine the differential molecular effects with standard-of-care RT + cisplatin versus RT +
SG. In Aim 2, we will improve identification of patients who are sensitive or resistant to RT-based therapies
based on new insights into transcriptional dynamics and temporal reprogramming during treatment with
radiation-based therapies. Here, we will leverage our molecular characterization trial treating head and neck
squamous cell carcinoma (HNSCC) or bladder cancer patients with RT + chemotherapy versus RT + SG or
ICI. We will build on recent experimental and clinical breakthroughs led by our research groups, which have
identified highly refined gene expression programs associated with RT sensitivity and delta radiomics. In Aim
3, we will identify the differential mechanisms underlying the anti-tumor activities of RT + cisplatin versus RT +
immune checkpoint blockade. Here, using our head and neck trial (Part B), we will uncover the unique genetic
and immunologic factors that govern response to RT when combined with these two classes of agents. We
will elucidate the differential molecular effects of the two approaches, immune reprogramming, and
mechanisms of acquired resistance. Our studies will help build a foundation to optimize multimodal, radiation-
based definitive treatment strategies.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Timothy An-thy Chan其他文献
Timothy An-thy Chan的其他文献
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{{ truncateString('Timothy An-thy Chan', 18)}}的其他基金
Genomic and Microenvironmental Determinants, Temporal Dynamics, and Treatment Efficacy of Radiation-Based Combination Therapies
基因组和微环境决定因素、时间动态以及基于放射的联合疗法的治疗效果
- 批准号:
10746700 - 财政年份:2023
- 资助金额:
$ 147.36万 - 项目类别:
Project 3 Molecular Mechanisms Underlying Therapy Response to Radiation and Immune Checkpoint Blockade
项目 3 辐射和免疫检查点封锁治疗反应的分子机制
- 批准号:
10818969 - 财政年份:2022
- 资助金额:
$ 147.36万 - 项目类别:
Genomic and Microenvironmental Determinants, Temporal Dynamics, and Treatment Efficacy of Radiation-Based Combination Therapies
基因组和微环境决定因素、时间动态以及基于放射的联合疗法的治疗效果
- 批准号:
10875876 - 财政年份:2022
- 资助金额:
$ 147.36万 - 项目类别:
Genomic and Microenvironmental Determinants, Temporal Dynamics, and Treatment Efficacy of Radiation-Based Combination Therapies
基因组和微环境决定因素、时间动态以及基于放射的联合疗法的治疗效果
- 批准号:
10526300 - 财政年份:2022
- 资助金额:
$ 147.36万 - 项目类别:
Project 1 Genetic and Immunologic Mechanisms Underlying Combination Sacituzumab plus Radiation Therapy for Bladder Cancer
项目 1 Sacituzumab 联合放射治疗膀胱癌的遗传和免疫机制
- 批准号:
10704713 - 财政年份:2022
- 资助金额:
$ 147.36万 - 项目类别:
Project 1 Genetic and Immunologic Mechanisms Underlying Combination Sacituzumab plus Radiation Therapy for Bladder Cancer
项目 1 Sacituzumab 联合放射治疗膀胱癌的遗传和免疫机制
- 批准号:
10526303 - 财政年份:2022
- 资助金额:
$ 147.36万 - 项目类别:
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