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1.
Cancer Res Commun ; 4(9): 2415-2426, 2024 Sep 01.
Article in English | MEDLINE | ID: mdl-39177285

ABSTRACT

PURPOSE: In preclinical models, glucocorticoid receptor (GR) signaling drives resistance to taxane chemotherapy in multiple solid tumors via upregulation of antiapoptotic pathways. ORIC-101 is a potent and selective GR antagonist that was investigated in combination with taxane chemotherapy as an anticancer regimen preclinically and in a phase 1 clinical trial. PATIENTS AND METHODS: The ability of ORIC-101 to reverse taxane resistance was assessed in cell lines and xenograft models, and a phase 1 study (NCT03928314) was conducted in patients with advanced solid tumors to determine the dose, safety, and antitumor activity of ORIC-101 with nab-paclitaxel. RESULTS: ORIC-101 reversed chemoprotection induced by glucocorticoids in vitro and achieved tumor regressions when combined with paclitaxel in both taxane-naïve and -resistant xenograft models. In the phase 1 study, 21 patients were treated in dose escalation and 62 patients were treated in dose expansion. All patients in dose expansion had previously progressed on a taxane-based regimen. In dose escalation, five objective responses were observed. A preplanned futility analysis in dose expansion showed a 3.2% (95% confidence interval, 0.4-11.2) objective response rate with a median progression-free survival of 2 months (95% confidence interval, 1.8-2.8) across all four cohorts, leading to study termination. Pharmacodynamic analysis of tissue and plasma showed GR pathway downregulation in most patients in cycle 1. CONCLUSIONS: ORIC-101 with nab-paclitaxel showed limited clinical activity in taxane-resistant solid tumors. Despite clear inhibition of GR pathway signaling, the insufficient clinical signal underscores the challenges of targeting a single resistance pathway when multiple mechanisms of resistance may be in play. SIGNIFICANCE: Glucocorticoid receptor (GR) upregulation is a mechanism of resistance to taxane chemotherapy in preclinical cancer models. ORIC-101 is a small molecule GR inhibitor. In this phase 1 study, ORIC-101 plus nab-paclitaxel did not show meaningful clinical benefit in patients who previously progressed on taxanes despite successful GR pathway downregulation.


Subject(s)
Albumins , Antineoplastic Combined Chemotherapy Protocols , Neoplasms , Paclitaxel , Receptors, Glucocorticoid , Humans , Paclitaxel/therapeutic use , Paclitaxel/administration & dosage , Paclitaxel/pharmacology , Female , Neoplasms/drug therapy , Neoplasms/pathology , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Glucocorticoid/metabolism , Male , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aged , Albumins/administration & dosage , Albumins/therapeutic use , Albumins/pharmacology , Animals , Adult , Mice , Xenograft Model Antitumor Assays , Drug Resistance, Neoplasm/drug effects , Cell Line, Tumor
2.
Future Oncol ; 20(16): 1057-1067, 2024.
Article in English | MEDLINE | ID: mdl-38348690

ABSTRACT

Neuregulin 1 (NRG1) fusions are oncogenic drivers that have been detected in non-small-cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. NRG1 fusions are rare, occurring in less than 1% of solid tumors. Patients with NRG1 fusion positive (NRG1+) cancer have limited therapeutic options. Zenocutuzumab is a novel, bispecific IgG1 antibody that targets both HER2 and HER3 proteins and inhibits NRG1 binding through a 'Dock & Block®' mechanism of action. Here, we describe the rationale and design of the phase II component of the eNRGy trial, part of the overall, open-label phase I/II, multicenter trial exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab in patients with NRG1+ NSCLC, PDAC or other solid tumors.


eNRGy: a clinical trial of zenocutuzumab for cancer caused by NRG1 gene fusionsNRG1 gene fusions are rare mutations that cause cancer cells to grow. These fusions are found in many different types of cancer. Tumors with NRG1 gene fusions do not respond well to standard treatment options. Zenocutuzumab, or Zeno, is a treatment that is being tested to see if it can stop cancer that is growing because of NRG1 gene fusions. Here, we describe the reasoning for and design of an ongoing clinical trial (eNRGy) designed to study the efficacy (how well it works) and safety of Zeno in patients with cancer that has NRG1 gene fusions. The eNRGy trial is recruiting patients with cancer that has NRG1 gene fusions, including non-small-cell lung cancer, pancreatic cancer and others. Patients who join this trial will receive Zeno once every 2 weeks until their cancer grows. The main goal (primary end point) of this trial is to determine the percentage of patients whose tumors decrease in size by 30% or more. The eNRGy trial is currently enrolling patients. For more information, refer to ClinicalTrials.gov (Identifier: NCT02912949), visit https://nrg1.com/, or call 1-833-NRG-1234.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Neuregulin-1 , Humans , Neuregulin-1/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Female , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Neoplasms/drug therapy , Neoplasms/genetics , Male , Receptor, ErbB-3/genetics , Receptor, ErbB-2/genetics , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/metabolism , Oncogene Proteins, Fusion/genetics , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/adverse effects , Adult , Middle Aged
3.
Front Immunol ; 12: 754083, 2021.
Article in English | MEDLINE | ID: mdl-34712241

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) are a hetero geneous group of cells, which can suppress the immune response, promote tumor progression and impair the efficacy of immunotherapies. Consequently, the pharmacological targeting of MDSC is emerging as a new immunotherapeutic strategy to stimulate the natural anti-tumor immune response and potentiate the efficacy of immunotherapies. Herein, we leveraged genetically modified models and a small molecule inhibitor to validate Calcium-Calmodulin Kinase Kinase 2 (CaMKK2) as a druggable target to control MDSC accumulation in tumor-bearing mice. The results indicated that deletion of CaMKK2 in the host attenuated the growth of engrafted tumor cells, and this phenomenon was associated with increased antitumor T cell response and decreased accumulation of MDSC. The adoptive transfer of MDSC was sufficient to restore the ability of the tumor to grow in Camkk2-/- mice, confirming the key role of MDSC in the mechanism of tumor rejection. In vitro studies indicated that blocking of CaMKK2 is sufficient to impair the yield of MDSC. Surprisingly, MDSC generated from Camkk2-/- bone marrow cells also showed a higher ability to terminally differentiate toward more immunogenic cell types (e.g inflammatory macrophages and dendritic cells) compared to wild type (WT). Higher intracellular levels of reactive oxygen species (ROS) accumulated in Camkk2-/- MDSC, increasing their susceptibility to apoptosis and promoting their terminal differentiation toward more mature myeloid cells. Mechanistic studies indicated that AMP-activated protein kinase (AMPK), which is a known CaMKK2 proximal target controlling the oxidative stress response, fine-tunes ROS accumulation in MDSC. Accordingly, failure to activate the CaMKK2-AMPK axis can account for the elevated ROS levels in Camkk2-/- MDSC. These results highlight CaMKK2 as an important regulator of the MDSC lifecycle, identifying this kinase as a new druggable target to restrain MDSC expansion and enhance the efficacy of anti-tumor immunotherapy.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Kinase/physiology , Myeloid-Derived Suppressor Cells/enzymology , Neoplasm Proteins/physiology , AMP-Activated Protein Kinases/physiology , Adoptive Transfer , Animals , Apoptosis , Calcium-Calmodulin-Dependent Protein Kinase Kinase/deficiency , Calcium-Calmodulin-Dependent Protein Kinase Kinase/genetics , Female , Lymphocyte Depletion , Lymphoma/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Mitochondria/metabolism , Myeloid-Derived Suppressor Cells/physiology , Myeloid-Derived Suppressor Cells/transplantation , Myelopoiesis , Reactive Oxygen Species , Tumor Microenvironment
4.
Am J Hematol ; 95(6): 662-671, 2020 06.
Article in English | MEDLINE | ID: mdl-32162718

ABSTRACT

Older AML patients have low remission rates and poor survival outcomes with standard chemotherapy. Microtransplantation (MST) refers to infusion of allogeneic hematopoietic stem cells without substantial engraftment. MST has been shown to improve clinical outcomes compared with chemotherapy alone. This is the first trial reporting on broad correlative studies to define immunologic mechanisms of action of MST in older AML patients. Older patients with newly diagnosed AML were eligible for enrollment, receiving induction chemotherapy with cytarabine (100 mg/m2) on days 1-7 and idarubicin (12 mg/m2) on days 1-3 (7 + 3). MST was administered 24 hours later. Patients with complete response (CR) were eligible for consolidation with high dose cytarabine (HiDAC) and a second cycle of MST. Responses were evaluated according to standard criteria per NCCN. Immune correlative studies were performed. Sixteen patients were enrolled and received 7 + 3 and MST (median age 73 years). Nine (56%) had high-risk and seven (44%) had standard-risk cytogenetics. Ten episodes of CRS were observed. No cases of GVHD or treatment-related mortality were reported. Event-free survival (EFS) was 50% at 6 months and 19% at 1 year. Overall survival (OS) was 63% at 6 months and 44% at 1 year. Donor microchimerism was not detected. Longitudinal changes were noted in NGS, TCR sequencing, and cytokine assays. Addition of MST to induction and consolidation chemotherapy was well tolerated in older AML patients. Inferior survival outcomes in our study may be attributed to a higher proportion of very elderly patients with high-risk features. Potential immunologic mechanisms of activity of MST include attenuation of inflammatory cytokines and emergence of tumor-specific T cell clones.


Subject(s)
Cytarabine/administration & dosage , Hematopoietic Stem Cell Transplantation , Idarubicin/administration & dosage , Induction Chemotherapy , Leukemia, Myeloid, Acute , Aged , Allografts , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Pilot Projects , Risk Factors
6.
Cancer ; 123(8): 1363-1371, 2017 Apr 15.
Article in English | MEDLINE | ID: mdl-27984652

ABSTRACT

BACKGROUND: No consensus exists regarding the use of radiotherapy (RT) in conjunction with high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) for patients with relapsed/refractory classical Hodgkin lymphoma (HL). The objectives of the current study were to characterize practice patterns and assess the efficacy and toxicity of RT at 2 major transplantation centers. METHODS: Eligible patients underwent HDC/ASCT from 2006 through 2015 using the combination of either carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) or cyclophosphamide, BCNU, and etoposide (CBV). RESULTS: For the cohort of 189 patients, the 4-year overall survival rate was 80%, the progression-free survival rate was 67%, and the local control (LC) rate was 68%. RT was used within 4 months of ASCT for 22 patients (12%) and was given more often for disease that was early stage, primary refractory, or [18 F]fluorodeoxyglucose (FDG)-avid at the time of HDC/ASCT. Disease recurrence occurring after HDC/ASCT was associated with primary refractory disease and FDG-avidity at the time of HDC/ASCT. RT was not found to be associated with LC, progression-free survival, or overall survival on univariate analysis. In a model incorporating primary refractory HL and FDG-avid disease at the time of HDC/ASCT, RT was found to be associated with a decreased risk of local disease recurrence (hazard ratio, 0.3; P = .02). In patients with primary refractory HL and/or FDG-avid disease at the time of HDC/ASCT, the 4-year LC rate was 81% with RT versus 49% without RT (P = .03). There was one case of Common Terminology Criteria for Adverse Events grade ≥ 3 RT-related toxicity (acute grade 3 pancytopenia). CONCLUSIONS: In patients undergoing ASCT for relapsed/refractory HL, peritransplantation RT was used more often for disease that was early stage, primary refractory, or FDG-avid after salvage conventional-dose chemotherapy. RT was associated with improved LC of high-risk localized disease and was well tolerated with modern techniques. Cancer 2017;123:1363-1371. © 2016 American Cancer Society.


Subject(s)
Hematopoietic Stem Cell Transplantation , Hodgkin Disease/diagnosis , Hodgkin Disease/therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , Drug Resistance, Neoplasm , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Hodgkin Disease/mortality , Humans , Male , Middle Aged , Neoplasm Staging , Positron-Emission Tomography , Radiotherapy, Adjuvant/adverse effects , Radiotherapy, Adjuvant/methods , Recurrence , Transplantation, Autologous , Treatment Outcome , Young Adult
7.
Am J Hematol Oncol ; 12(9): 8-13, 2016 Sep.
Article in English | MEDLINE | ID: mdl-29449908

ABSTRACT

18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) has been the most important advance in the assessment of Hodgkin lymphoma (HL) since the introduction of computed tomography (CT). In the frontline management of HL, FDG-PET combined with low-dose CT has emerged as the modality of choice for staging and treatment response assessment. Substantial data have accumulated over the past several years supporting the use of PET/CT in the evaluation and management of relapsed or refractory HL, as well. In this article, we review the role of PET/CT after the frontline treatment of HL, as well as the prognostic utility of PET/CT before autologous and allogeneic stem cell transplantation. We also review the use of PET/CT as a part of response-adapted treatment strategies in relapsed or refractory HL and implications for current and future clinical practice.

8.
Am J Hematol ; 90(7): 657-64, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25808792

ABSTRACT

The treatment of patients with chronic lymphocytic leukemia (CLL), an indolent B-cell lymphoma is in the midst of a transformation. There are a large number of promising new therapeutic agents and cellular therapies being studied which exhibit remarkable activity, favorable toxicity profiles, convenient administration schedules, and treatment options are rapidly expanding. The recent advances in the management of CLL exemplify the value of translational medicine. This review highlights key aspects of B-cell receptor (BCR) signaling in relation to novel inhibitors of the BCR signaling pathway, currently at various stages of preclinical and clinical development.


Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Phosphoinositide-3 Kinase Inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Antigen, B-Cell/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase , Antibodies, Monoclonal/therapeutic use , Antimetabolites, Antineoplastic/therapeutic use , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Gene Expression Regulation , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, B-Cell/metabolism , Signal Transduction/drug effects
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