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Preclinical-Clinical Trials Collaboration to effectively advance new combination therapies for malignant peripheral nerve sheath tumors

临床前-临床试验合作有效推进恶性周围神经鞘瘤的新联合疗法

基本信息

批准号：
10393313
负责人：
KAREN M CICHOWSKI
金额：
$ 48.07万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2022-07-08 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10393313
关键词：
Affect Animal Model Applications Grants Back Basic Science Biological Biological Markers Biology Biopsy Boston Bromodomain Cancer Biology Cells Chemotherapy and/or radiation Child Clinic Clinical Clinical Investigator Clinical Research Clinical Trials Collaborations Combined Modality Therapy Complement Correlative Study DNA Sequence Alteration Data Development Developmental Therapeutics Program Disease District of Columbia Dose Enrollment Epigenetic Process Evaluation Extramural Activities Foundations Future Gene Expression Profile Genomics Goals Grant Hereditary Malignant Neoplasm Hospitals Human Immune checkpoint inhibitor Immunologics Immunology Immunotherapy In Vitro Individual Industry Infrastructure Lead MEKs Malignant Neoplasms Medical center Modeling Mus Nature Neoplasm Metastasis Neurofibromatoses Neurofibromatosis 1 Neurofibrosarcoma Patient Outcomes Assessments Patients Pediatric Oncology Phase I/II Clinical Trial Phase I/II Trial Phosphotransferases Refractory Refractory Disease Relapse Research Personnel Research Project Grants Resistance Resources Sampling Schedule Scientist Series Signal Transduction Soft tissue sarcoma Syndrome Testing Therapeutic Time Translating Translational Research Translations United States National Institutes of Health Unresectable Woman Work anti-PD-L1 antibodies base bench to bedside clinical application clinical center clinical translation crizotinib design effective therapy immunoreactivity improved in vivo inhibitor insight mouse model multidisciplinary neoplasm immunotherapy neoplasm resource new combination therapies novel novel drug class novel therapeutic intervention novel therapeutics open label pharmacodynamic biomarker phase 1 study phase 2 study pre-clinical preclinical study predicting response prototype resistance mechanism response response biomarker sarcoma small molecule inhibitor standard of care targeted treatment therapeutic development therapeutic target therapy development transcriptomics translational scientist tumor tumor DNA tumor microenvironment tumorigenesis

项目摘要

ABSTRACT Neurofibromatosis type 1 (NF1) is a prevalent familial cancer syndrome affecting 1 in 3500 individuals worldwide. The most commonly lethal feature associated with NF1 is malignant peripheral nerve sheath tumors (MPNST). These soft tissue sarcomas are highly aggressive and frequently metastasize. Despite radiation and chemotherapy, inoperable tumors rapidly progress and are universally lethal. As such, identifying effective treatments for MPNST is critical. The primary goal of this application is to establish a robust preclinical/clinical pipeline (bench-to-bedside and back) to rapidly develop and test new (combination) therapies for this deadly malignancy. This effort will harness the specialized expertise of clinical investigators at the NCI and Children’s National Medical Center, extramural experts in NF1 biology and therapeutic development, and will leverage the unique resources of the NIH Clinical Center. Specifically, new discoveries of mechanisms that drive NF1-related tumorigenesis together with recent insights into the immunoreactivity of MPNST will be used to develop rational combination therapies and will be tested in a robust preclinical MPNST mouse model (Karen Cichowski, BWH, extramural preclinical center). These insights will then be used to perform clinical trials in MPNST patients with an emphasis on evaluating more than one combination therapy within the same trial (Brigitte Widemann, NCI, Intramural NIH Clinical Center, AeRang Kim, Children’s National Medical Center). This will allow for more timely identification of active agents and will allow patients with this highly refractory disease to have more treatment options available to them. Furthermore, the preclinical to clinical translation will be complemented by comprehensive genomic and immunological analyses of tumor samples obtained prior to treatment and on treatment with novel agents in order to identify mechanisms of response and resistance and to identify additional potential targets for therapy (Jack Shern, NCI, Intramural NIH). As such, insight and samples from the clinic will serve as the foundation to develop new or improve existing therapies, thus highlighting the iterative and collaborative nature of this pipeline. Taken together, we have assembled a multi-disciplinary team of basic and clinical scientists from different fields to develop and translate promising therapies for individuals with MPNST. This effort includes experts in NF1 biology and therapeutic development, a diverse set of clinicians with expertise in MPNST and immunotherapy, and genomicists. Importantly, a subset of these investigators already have a track record of working together to develop new trials for MPNST patients. This grant will allow more effective and rapid translation of promising new therapies for MPNST and will expand the type of (combination) therapies that are developed, by bringing in additional expertise and leveraging the unique resources of the NIH Clinical Center. Ultimately, these studies have the potential to change the standard of care for the currently treatment refractory tumors associated with the common familial cancer syndrome NF1.

摘要