Uncover the role of H3.3-G343R mutation in shaping the DNA damage response, anti-tumor immunity and mechanisms of resistance in glioma.
Castro M, Lowenstein P
NIH 1R01NS122165-01A1
1/15/2022-12/31/2027
Major Goals: We propose to test the hypothesis that H3.3G34R reshapes the epigenetic landscape, resulting in alterations in chromatin states and transcriptional changes. These alterations cause DDR impairment and induce genomic instability which in turn leads to cGAS-STING-Pathway-mediated activation of the immune system with the H3.3G34R pHGG TME.
Principal Investigator
The role of collagen and its signaling mechanisms in glioma progression and invasion
Castro M, Lowenstein P
NIH R01 NS122234-01A1
9/01/2021–8/31/2026
Major Goals: Gliomas are incurable tumors. We recently discovered that Collagen 1A1 is expressed at high levels in perivascular cells and also in tumor cells themselves. We will now examine the role of Collagen 1A1 in each cell type. To do so we will explore whether cell-type specific depletion of Collagen 1A1 from glioma cells will halt tumor progression. These results will permit to develop therapeutics targeted to collagen expression.
Co-Principal Investigator
The role of collagen receptor LAIR-1 in glioma progression and the tumor immune microenvironment
Lowenstein P
NIH R01 NS127378
4/01/2022–3/31/2027
Major Goals: We have recently discovered that Collagen1A1 has important effects on brain tumor growth, progression and invasion. In this proposal we will test the hypothesis that immune inhibitory collagen receptor LAIR-1 is necessary for collagen toinhibit anti-glioma immune responses. In this application, we will examine the role of LAIR-1 expressed by tumor cells, and infiltrating immune cells, on the capacity of the immune system to modulate glioma growth. The therapeutic potential of these interactions will be tested by using specific decoy receptors for LAIR-1.
Principal Investigator
Novel nano-vaccine technology for inducing immunity against gliomas
Castro M, Moon J
NIH RO1 NS122536
7/15/2021-3/31/2026
Major Goals: The proposed research is relevant to public health because these studies will improve our understanding of the biology-materials interfaces and may lead to new design principles for biomaterials engineered to elicit robust levels of immune responses, thereby addressing current technical limitations in vaccine technologies.
Co-Investigator
Chem-immunotherapy strategy for pediatric high grade glioma
Castro M, Schwendeman S
NIH R21 NS123879-01
7/15/2021-6/30/2022
Major goal: Develop HDL NP for the treatment pf pediatric high grade gliomas harboring H3G34R mutations
Co-Investigator
Castro M, Lowenstein P
NIH R21NS107894-01
4/1/2019 – 3/31/2022
Major goal: Identifying novel immunotherapeutic strategies in a mouse DIPG model.
Co-Investigator
Immune-suppressive myeloid cells in the glioma microenvironment: Signaling mechanisms and novel therapeutic strategies
Castro M, Lowenstein P, Muraszko K
NIH R37-NS094804-01 (R01-NS094804)
9/1/2015 – 6/30/2022
Major goal: To elucidate the role played by CXCR4-CXCL12 signaling in the GBM microenvironment in mediating the accumulation of IMCs, facilitating tumor invasion and disease progression. We hypothesize that CXCR4 blockade will enhance the efficacy of anti-GBM immunotherapies and will uncover a novel therapeutic target for this devastating cancer.
Co-Investigator
Interactions between the tumor cells and the neuro-immune microenvironment in mutant IDH1 gliomas: implications for therapeutics
Castro M, Ljungman M, Lowenstein P, Sartor M, Venneti S, Zhao L
NIH/NINDS R01-NS10555603S1
5/1/2018 – 4/30/2023
Major goal: To study a subtype of gliomas which harbor mutations in the ATRX gene (mATRX), p53 mutations, and mutation in the enzyme, isocitrate dehydrogenase 1 (mIDH1). Our goal is to assess the molecular mechanisms by which mATRX and mIDH1 impact the biology of the tumors and influence the tumor immune microenvironment. We will also determine the response to immunotherapies.
Co-Investigator
Tuning biomaterials-immune cell interactions for treatment of glioblastoma multiforme
Castro M, Lowenstein P, Moon J
NIH R01-EB022563
9/7/2016 – 5/31/2020
Major goal: Despite recent advances in surgery, chemo-and radiation-therapy, patients with glioblastoma multiforme (GBM) have a grim prognosis. In this application, we propose to exploit our nanoparticle-based vaccine technology to achieve strong cellular and humoral immune responses against GBM. Overall, the work proposed will address current technical limitations in cancer vaccines and potentially lead to a new treatment option for patients suffering from brain cancer.
Principal Investigator
Immunotherapeutic approach for DIPG; pre-clinical testing
Castro M, Lowenstein P
Chad Tough Foundation and Sophie's Smile
7/1/2019 – 6/30/2029
Novel combined immunotherapeutic strategies for glioma: Using pet dogs with spontaneous high-grade glioma
Castro M, Lowenstein P, Pluhar E
NIH/NCI 1U01CA224160-01 (On subcontract with University of Minnesota)
9/01/2017 – 8/31/2022
Major goal: Develop and implement a phase I clinical trial for novel immunotherapies in dogs bearing GBM.
Co-Investigator
Novel Immune Mediated-Gene Therapy for Pediatric High-Grade Glioma
Castro M, Lowenstein P
Pediatric Brain Tumor Foundation (NYC) and the Samson Research Fund
7/1/2019 – 6/30/2023
Major Goal: Implement a novel gene thrapy mediated immune-therapeutic approach in preclinical models of pediatric high grade gliomas (pHGG)
Michigan Medicine Headline article about this project.
Principal Investigator
Tumor targeting of Nanoparticles as therapeutic siRNA carriers for pediatric high grade gliomas (pHGG)
Castro M, Lowenstein P
Ian's Friends Foundation
5/1/2021 – 4/30/2022
Major goal: Our laboratories focus is to develop novel therapeutic strategies to improve patient outcomes with malignant brain tumors.
Co-vInvestigator
PhaseOne – A non-randomized open-label, dose-finding trial
Lowenstein P
PhaseOne Foundation
1/1/2013 - Open
Brain Cancer: Novel Technologies, preclinical testing and clinical implementation
Castro M, Schwendeman S
Biosciences Initiative – Scientific Initiative Program
9/01/2020 – 8/31/2026
Major goals: Despite recent advances in surgery, chemo-and radiation-therapy, patients with high grade gliomas (GBM) face a dismal prognosis. We propose to exploit our nanoparticle-based technologies to achieve strong cellular and humoral immune responses against GBM. Additionally, we will also develop novel delivery platforms for chemotherapies and immune-mediated gene therapies for GBM. Overall, the work proposed will address current technical limitations in cancer vaccines and potentially lead to a new treatment option for patients suffering from malignant brain cancer.
Co-Investigator
Principal Investigator
