A5076502795- Ovarian cancer diagnosis and treatment
- Immune cells in cancer
- PARP inhibition in cancer therapy
- Reproductive System and Pregnancy
- DNA Repair Mechanisms
- Glioma Diagnosis and Treatment
- Cancer Immunotherapy and Biomarkers
- Cancer Genomics and Diagnostics
- Cancer Treatment and Pharmacology
- Immune Cell Function and Interaction
- Glycosylation and Glycoproteins Research
- Monoclonal and Polyclonal Antibodies Research
- Acute Lymphoblastic Leukemia research
- Mathematical Biology Tumor Growth
- Brain Metastases and Treatment
- Cancer Research and Treatments
- Macrophage Migration Inhibitory Factor
- Immunotherapy and Immune Responses
- Single-cell and spatial transcriptomics
- BRCA gene mutations in cancer
- Neutropenia and Cancer Infections
- Blood disorders and treatments
- Protein Degradation and Inhibitors
- Inflammatory Myopathies and Dermatomyositis
- Neuroendocrine Tumor Research Advances
National Institutes of Health
1999-2024
National Cancer Institute
2017-2024
Center for Cancer Research
2018-2024
National Institute of Arthritis and Musculoskeletal and Skin Diseases
1999
Monotherapy with prexasertib demonstrated modest activity in BRCA wild-type, recurrent triple-negative breast cancer, highlighting the unmet need for combination treatment strategies. Neutropenia, anemia, and thrombocytopenia are common use of but manageable supportive care measures. Prophylactic granulocyte colony stimulating factor should be considered to avoid dose reductions or delays. Pharmacodynamic studies showed induced DNA damage peripheral immune cells.Cell cycle checkpoint kinase...
Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene ( BRCA )–mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway as cytotoxic further validated activity of CHK1 inhibitor (CHK1i)...
Abstract Background NEO201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens from patients with colorectal cancer. NEO-201 binds to core 1 or extended O-glycans expressed by its target cells. Here, we present outcomes phase I trial of in advanced solid tumors that have not responded standard treatments. Methods This was single site, open label 3 + dose escalation clinical trial. administered intravenously every two weeks 28-day cycle at level (DL) (1...
Ovarian cancer is the most lethal gynecologic and intrinsically resistant to checkpoint immunotherapies. We sought augment innate immunity, building on previous work with IFNs monocytes.Preclinical experiments were designed define mechanisms of cell death mediated by combination α γ monocytes. translated these preclinical findings into a phase I trial autologous IFN-activated monocytes administered intraperitoneally platinum-resistant or -refractory ovarian patients.IFN-treated induced...
2530 Background: The humanized IgG1 monoclonal antibody NEO-201 binds to Core 1 and/or extended O-glycans expressed by several human solid and blood tumors, as well neutrophils, mediates killing of cancer cells, regulatory T cells (Tregs) granulocytic myeloid-derived suppressor (gMDSCs) via ADCC CDC. Resistance PD-1/PD-L1 blockade may be due the accumulation Tregs gMDSCs in tumor microenvironment (TME). was proven bind reduce amount circulating patients. This supports rationale ongoing phase...
2031 Background: Therapies targeting multiple survival pathways simultaneously may be more effective for high-grade gliomas, a disease highly resistant to treatment. Our preclinical studies have shown potent anti-glioma effects of TG02 and synergy with temozolomide (TMZ) through modulation transcription cellular metabolism. A phase I/II trial was launched test the combination TMZ in recurrent malignant gliomas herein we report I results. Methods: Adults astrocytoma, KPS ≥ 60, normal organ...
6038 Background: Preclinical data suggest cell cycle checkpoint inhibition induces greater death in BRCA mutant HGSOC by causing replication stress and dysregulation of DNA damage responses. We hypothesized that prexasertib, a kinase 1 (CHK1) inhibitor, would be active mutated patients. Methods: conducted single center, two-stage phase II study prexasertib (105mg/m 2 IV every weeks) patients with known germline or somatic mutations. The primary endpoint was RECIST response rate (RR)....
Most therapies for recurrent high grade gliomas have not been successful, largely due to the complexity of disease. Our preclinical studies demonstrated anti-glioma effects TG02 and synergy with temozolomide (TMZ) through modulation transcription metabolism. We hypothesize that given multiple mechanisms established efficacy TMZ, combined treatment may be effective malignant gliomas. launched a phase I/II trial herein report I results. Adults high-grade astrocytoma, KPS ≥ 60, normal organ...
Background Humanized IgG1 mAb NEO-201 binds core 1 O-glycans and showed antibody-dependent cell-mediated cytotoxicity (ADCC) activity against cancer cells expressing O-glycans.1 kills cells, neutrophils, immune suppressor (iSCs), including regulatory T (Tregs) granulocytic myeloid-derived (gMDSCs) via ADCC complement-dependent cytotoxicity.2 Resistance to PD-1/PDL1 blockade may be due accumulation of iSCs in the tumor microenvironment.3 Elevated neutrophil-to-lymphocyte ratio (NLR)...
<div>AbstractPurpose:<p>Ovarian cancer is the most lethal gynecologic and intrinsically resistant to checkpoint immunotherapies. We sought augment innate immunity, building on previous work with IFNs monocytes.</p>Patients Methods:<p>Preclinical experiments were designed define mechanisms of cell death mediated by combination α γ monocytes. translated these preclinical findings into a phase I trial autologous IFN-activated monocytes administered intraperitoneally...
<div>AbstractPurpose:<p>Ovarian cancer is the most lethal gynecologic and intrinsically resistant to checkpoint immunotherapies. We sought augment innate immunity, building on previous work with IFNs monocytes.</p>Patients Methods:<p>Preclinical experiments were designed define mechanisms of cell death mediated by combination α γ monocytes. translated these preclinical findings into a phase I trial autologous IFN-activated monocytes administered intraperitoneally...
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Temozolomide (TMZ) is an oral alkylating agent which the most common chemotherapy used in neuro-oncology and typically well tolerated. The adverse events include fatigue, nausea, vomiting, headache, constipation serious being myelosuppression. Review of literature uncovered rare reports acute reactions to TMZ, limited skin rashes eruptions. Neuro-Oncology Branch has initiated a natural history study clinical course current status are interrogated. A retrospective analysis this protocol was...
Biomarkers of response to immunotherapy are critical evaluate efficacy and ultimately select patients most likely benefit from this potentially toxic treatment. Peripheral blood mononuclear cells (PBMC) easily collected offer abundant lymphocytes, yet the molecular determinants relevant a therapeutic have not been determined. To identify such cells, rare, we developed four state-of-the-art flow cytometry assays that quantify 65 unique proteins on single-cells for comprehensive,...
Abstract BACKGROUND Therapies targeting multiple survival pathways are desirable for high-grade gliomas. TG02 (Zotiraciclib), a CDK9 inhibitor, regulates transcription and metabolism of tumor cells synergizes with temozolomide. A phase I/II trial was launched to test the TG02/temozolomide combined treatment in recurrent astrocytomas. Phase I results reported here. METHODS Adults astrocytoma, KPS≥60, adequate organ function, < 2 prior relapses were enrolled. Primary endpoint dose limiting...
Abstract Background: Platinum-resistance is associated with a poor prognosis in HGSOC and has limited treatment options. Inhibition of CHK1 shown activity BRCAwt HGSOC. Here, we report the clinical tolerability second generation inhibitor, prexasertib, platinum-resistant (NCT02203513). Methods: Eligibility included recurrent women without germline or somatic BRCA mutation, ECOG PS 0-2, good end organ function, measurable disease. The primary endpoint was response rate (RR). Secondary...
Abstract PARP inhibitors (PARPis) have changed the treatment paradigm in BRCA -mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for novel therapeutic strategies. Using high-throughput drug screens, we identified ATR/CHK1 pathway as cytotoxic, and further validated monotherapy activity of CHK1 inhibitor (CHK1i), prexasertib, PARPi-resistant HGSC cells animal models. As a proof-of-concept trial,...