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1.
Clin Cancer Res ; 30(10): 2011-2016, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38441576

ABSTRACT

On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin-ejfv (EV) plus pembrolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. Substantial evidence of effectiveness was obtained from EV-103/KEYNOTE-869 (NCT03288545), a multicohort study. Across cohorts, a total of 121 patients received EV 1.25 mg/kg (maximum of 125 mg) intravenously on days 1 and 8 of a 21-day cycle plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68% (95% confidence interval, 59-76), including 12% with complete responses. The median DoR for the 82 responders was 22 months (range: 1+ to 46+). The safety profile of the combination comprised adverse reactions expected to occur with the corresponding monotherapies, but with overall increased frequency of adverse reactions, including skin toxicity, pneumonitis, and peripheral neuropathy. The article summarizes the data and the FDA thought process supporting accelerated approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by the FDA.


Subject(s)
Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal , Antineoplastic Combined Chemotherapy Protocols , Drug Approval , United States Food and Drug Administration , Humans , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , United States , Male , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aged , Female , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Middle Aged , Cisplatin/administration & dosage , Cisplatin/adverse effects , Cisplatin/therapeutic use , Aged, 80 and over , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/pathology , Urologic Neoplasms/drug therapy , Urologic Neoplasms/pathology , Treatment Outcome
2.
J Clin Oncol ; 42(14): 1687-1698, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38484203

ABSTRACT

PURPOSE: We performed a pooled analysis of multiple trials of poly(ADP-ribose) polymerase inhibitors (PARPi) in metastatic castration-resistant prostate cancer (mCRPC) to investigate the efficacy of PARPi in each individual homologous recombination repair (HRR) mutated (m) gene. PATIENTS AND METHODS: We pooled patient-level data from trials of PARPi in mCRPC that reported mutation status in individual HRR genes. Any HRR gene with available data across all the randomized trials of PARPi in first-line mCRPC was selected. The hazard ratios (HRs; 95% CI) for radiographic progression-free survival (rPFS; by blinded independent review) and overall survival (OS) of a PARPi plus an androgen receptor pathway inhibitor (ARPI) relative to placebo plus an ARPI in the pool of three randomized trials in first-line mCRPC were calculated using Kaplan-Meier estimates and a Cox proportional hazards model. RESULTS: In ATMm (N = 268), rPFS HR was 1.05 (0.74 to 1.49) and OS HR was 1.18 (0.82 to 1.71). In BRCA1m (N = 64), rPFS HR was 0.51 (0.23 to 1.1) and OS HR was 0.74 (0.34 to 1.61). In BRCA2m (N = 422), rPFS HR was 0.31 (0.23 to 0.42) and OS HR was 0.66 (0.49 to 0.89). In CDK12m (N = 164), rPFS HR was 0.50 (0.32 to 0.80) and OS HR was 0.63 (0.39 to 0.99). In CHEK2m (N = 172), rPFS HR was 1.06 (0.67 to 1.66) and OS HR was 1.53 (0.95 to 2.46). In PALB2m (N = 41) rPFS HR was 0.52 (0.23 to 1.17) and OS HR was 0.78 (0.34 to 1.8). CONCLUSION: In this pooled analysis, benefit from PARPi appeared greatest for patients with BRCA1m, BRCA2m, CDK12m, and PALB2m. Given limitations of this exploratory analysis, the apparent lack of benefit from PARPi in patients with CHEK2m or ATMm should be further explored in future clinical trials.


Subject(s)
BRCA2 Protein , Mutation , Poly(ADP-ribose) Polymerase Inhibitors , Prostatic Neoplasms, Castration-Resistant , Randomized Controlled Trials as Topic , Recombinational DNA Repair , Humans , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Male , Recombinational DNA Repair/genetics , BRCA2 Protein/genetics , BRCA1 Protein/genetics , United States , Checkpoint Kinase 2/genetics , Cyclin-Dependent Kinases/genetics , Cyclin-Dependent Kinases/antagonists & inhibitors , Ataxia Telangiectasia Mutated Proteins/genetics , Fanconi Anemia Complementation Group N Protein/genetics , Progression-Free Survival , Androgen Receptor Antagonists/therapeutic use , Aged , Receptors, Androgen/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
3.
JID Innov ; 3(2): 100181, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36960318

ABSTRACT

The documentation of the change in the number and appearance of pigmented cutaneous lesions over time is critical to the early detection of skin cancers and may provide preliminary signals of efficacy in early-phase therapeutic prevention trials for melanoma. Despite substantial progress in computer-aided diagnosis of melanoma, automated methods to assess the evolution of lesions are relatively undeveloped. This report describes the development and narrow validation of mathematical algorithms to register nevi between sequential digital photographs of large areas of skin and to align images for improved detection and quantification of changes. Serial posterior truncal photographs from a pre-existing database were processed and analyzed by the software, and the results were evaluated by a panel of clinicians using a separate Extensible Markup Language‒based application. The software had a high sensitivity for the detection of cutaneous lesions as small as 2 mm. The software registered lesions accurately, with occasional errors at the edges of the images. In one pilot study with 17 patients, the use of the software enabled clinicians to identify new and/or enlarged lesions in 3‒11 additional patients versus the unregistered images. Automated quantification of size change performed similarly to that of human raters. These results support the further development and broader validation of this technique.

4.
Cancer Chemother Pharmacol ; 88(4): 643-654, 2021 10.
Article in English | MEDLINE | ID: mdl-34164713

ABSTRACT

PURPOSE: We investigated the combination of tivantinib, a c-MET tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-VEGF-A antibody. METHODS: Patients with advanced solid tumors received bevacizumab (10 mg/kg intravenously every 2 weeks) and escalating doses of tivantinib (120-360 mg orally twice daily). In addition to safety and preliminary efficacy, we evaluated pharmacokinetics of tivantinib and its metabolites, as well as pharmacodynamic biomarkers in peripheral blood and skin. RESULTS: Eleven patients received the combination treatment, which was generally well tolerated. The main dose-limiting toxicity was grade 3 hypertension, which was observed in four patients. Other toxicities included lymphopenia and electrolyte disturbances. No exposure-toxicity relationship was observed for tivantinib or metabolites. No clinical responses were observed. Mean levels of the serum cytokine bFGF increased (p = 0.008) after the bevacizumab-only lead-in and decreased back to baseline (p = 0.047) after addition of tivantinib. Tivantinib reduced levels of both phospho-MET (7/11 patients) and tubulin (4/11 patients) in skin. CONCLUSIONS: The combination of tivantinib and bevacizumab produced toxicities that were largely consistent with the safety profiles of the individual drugs. The study was terminated prior to establishment of the recommended phase II dose (RP2D) due to concerns regarding the mechanism of tivantinib, as well as lack of clinical efficacy seen in this and other studies. Tivantinib reversed the upregulation of bFGF caused by bevacizumab, which has been considered a potential mechanism of resistance to therapies targeting the VEGF pathway. The findings from this study suggest that the mechanism of action of tivantinib in humans may involve inhibition of both c-MET and tubulin expression. TRIAL REGISTRATION: NCT01749384 (First posted 12/13/2012).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Neoplasms/drug therapy , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Tubulin/metabolism , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Bevacizumab/administration & dosage , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Neoplasms/pathology , Pyrrolidinones/administration & dosage , Quinolines/administration & dosage , Treatment Outcome
6.
J Nucl Med ; 57(11): 1771-1777, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27261519

ABSTRACT

Tumors escape antiangiogenic therapy by activation of proangiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We previously investigated targeted α-particle therapy with 225Ac-E4G10 as an antivascular approach and showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here, we investigated changes in tumor vascular morphology and functionality caused by 225Ac-E4G10. METHODS: We investigated remodeling of the tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4-kBq dose of 225Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphologic changes in the tumor blood-brain barrier microenvironment. Multicolor flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted MR imaged functional changes in the tumor vascular network. RESULTS: The mechanism of drug action is a combination of remodeling of the glioblastoma vascular microenvironment, relief of edema, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis were lessened, resulting in increased perfusion and reduced diffusion. Pharmacologic uptake of dasatinib into tumor was enhanced after α-particle therapy. CONCLUSION: Targeted antivascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of platelet-derived growth factor-driven glioblastoma.


Subject(s)
Alpha Particles/therapeutic use , Antibodies, Monoclonal/therapeutic use , Brain Neoplasms/radiotherapy , Glioblastoma/radiotherapy , Tumor Microenvironment , Animals , Blood-Brain Barrier , Brain Neoplasms/blood supply , Brain Neoplasms/pathology , Dasatinib/pharmacokinetics , Glioblastoma/blood supply , Glioblastoma/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplastic Stem Cells/radiation effects , T-Lymphocytes, Regulatory/immunology
7.
J Nucl Med ; 57(10): 1576-1582, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27127217

ABSTRACT

Glioblastoma is characterized by an aggressive and aberrant vascular network that promotes tumor progression and hinders effective treatment; the median survival is 16 mo despite standard-of-care therapies. There is a need to improve therapeutic options for this disease. We hypothesized that antibody targeting of the vascular endothelium of glioblastoma with cytotoxic short-range, high-energy α-particles would be an effective therapeutic approach. METHODS: E4G10, an antibody directed at an epitope of monomeric vascular endothelium cadherin that is expressed in tumor neovasculature and on endothelial progenitor cells in the bone marrow, was labeled with α-particle-emitting 225Ac. Pharmacokinetic studies investigated the tissue distribution and blood clearance of the 225Ac-E4G10 radioimmunoconstruct in a transgenic Nestin-tumor virus A (Ntva) mouse model of high-grade glioblastoma. Histologic analysis was used to demonstrate local therapeutic effects in treated brain tumor sections. Radioimmunotherapy with 225Ac-E4G10 was performed in Ntva mice to assess overall survival alone and in combination with temozolomide, the standard-of-care chemotherapeutic agent. RESULTS: 225Ac-E4G10 was found to accumulate in tissues expressing the target antigen. Antivascular α-particle therapy of glioblastoma in the transgenic Ntva model resulted in significantly improved survival compared with controls and potent control of tumor growth. Adding the chemotherapeutic temozolomide to the treatment increased survival to 30 d (vs. 9 d for vehicle-treated animals). Histologic analyses showed a remodeled glioblastoma vascular microenvironment. CONCLUSION: Targeted α-particle antivascular therapy is shown for the first time to be effective in increasing overall survival in a solid tumor in a clinically relevant transgenic glioblastoma mouse model.


Subject(s)
Blood Vessels/radiation effects , Brain Neoplasms/blood supply , Brain Neoplasms/radiotherapy , Glioblastoma/blood supply , Glioblastoma/radiotherapy , Radioimmunotherapy/methods , Actinium , Alpha Particles/therapeutic use , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal/therapeutic use , Blood Vessels/metabolism , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Line, Tumor , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Mice , Neoplasm Grading , Radiochemistry , Radiotherapy Dosage
8.
Cell Rep ; 8(4): 1077-92, 2014 Aug 21.
Article in English | MEDLINE | ID: mdl-25131208

ABSTRACT

γ-Secretase is composed of four proteins that are obligatory for protease activity: presenilin, nicastrin, Aph1, and Pen-2. Despite the progress toward understanding the function of these individual subunits, there is no information available pertaining to the modulation of γ-secretase in response to environmental changes in cells. Here, we show that hypoxia upregulates γ-secretase activity through a direct interaction with Hif-1α, revealing an unconventional function for Hif-1α as an enzyme subunit, which is distinct from its canonical role as a transcription factor. Moreover, hypoxia-induced cell invasion and metastasis are alleviated by either γ-secretase inhibitors or a dominant-negative Notch coactivator, indicating that γ-secretase/Notch signaling plays an essential role in controlling these cellular processes. The present study reveals a mechanism in which γ-secretase can achieve temporal control through conditional interactions with regulatory proteins, such as Hif-1α, under select physiological and pathological conditions.


Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Breast Neoplasms/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Lung Neoplasms/metabolism , Receptors, Notch/metabolism , Animals , Breast Neoplasms/pathology , Cell Hypoxia , Cell Line, Tumor , Enzyme Activation , Female , Humans , Lung Neoplasms/secondary , Mice, Nude , Neoplasm Transplantation , Protein Binding , Signal Transduction , Up-Regulation
9.
J Nucl Med ; 55(9): 1492-8, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24982438

ABSTRACT

UNLABELLED: Targeted α-particle radiation using the radioisotope (225)Ac is a promising form of therapy for various types of cancer. Historic obstacles to the use of (225)Ac have been the difficulty in finding suitable chelators to stably attach it to targeting vehicles such as peptides and monoclonal antibodies, the low specific activities of the products, and the lack of cost-effective radiolabeling procedures. We initially solved the first problem with a procedure involving 2 chemical steps that has been used as a standard in preclinical and clinical studies. However, this procedure involves the loss of 90% of the input (225)Ac. A more efficient, economical process is needed to facilitate the more widespread use of (225)Ac. METHODS: We conjugated representative antibodies with 2 forms of DOTA as well as other chelators as controls. We developed conditions to radiolabel these constructs in 1 chemical step and characterized their stability, immunoreactivity, biodistribution, and therapeutic efficacy in healthy and tumor-bearing mice. RESULTS: DOTA-antibody constructs were labeled to a wide range of specific activities in 1 chemical step at 37°C. Radiochemical yields were approximately 10-fold higher, and specific activities were up to 30-fold higher than with the previous approach. The products retained immunoreactivity and were stable to serum challenge in vitro and in mice. Labeling kinetics of DOTA-antibody constructs linked through a benzyl isothiocyanate linkage were more favorable than those linked through an N-hydroxysuccinimide linkage. Tissue distribution was similar but not identical between the constructs. The constructs produced specific therapeutic responses in a mouse model of acute myeloid leukemia. CONCLUSION: We have characterized an efficient, 1-step radiolabeling method that produces stable, therapeutically active conjugates of antibodies with (225)Ac at high specific activity. We propose that this technology greatly expands the possible clinical applications of (225)Ac monoclonal antibodies.


Subject(s)
Actinium/therapeutic use , Alpha Particles/therapeutic use , Antibodies, Monoclonal/therapeutic use , Isotope Labeling , Neoplasms, Experimental/radiotherapy , Radioimmunotherapy/methods , Animals , Drug Stability , Mice , Mice, Inbred BALB C , Quality Control , Tissue Distribution
10.
Nucleic Acids Res ; 39(6): 2458-69, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21030439

ABSTRACT

Long-term survival still eludes most patients with leukemia and non-Hodgkin's lymphoma. No approved therapies target the hallmark of the B cell, its mIgM, also known as the B-cell receptor (BCR). Aptamers are small oligonucleotides that can specifically bind to a wide range of target molecules and offer some advantages over antibodies as therapeutic agents. Here, we report the rational engineering of aptamer TD05 into multimeric forms reactive with the BCR that may be useful in biomedical applications. Systematic truncation of TD05 coupled with modification with locked nucleic acids (LNA) increased conformational stability and nuclease resistance. Trimeric and tetrameric versions with optimized polyethyleneglycol (PEG) linker lengths exhibited high avidity at physiological temperatures both in vitro and in vivo. Competition and protease studies showed that the multimeric, optimized aptamer bound to membrane-associated human mIgM, but not with soluble IgM in plasma, allowing the possibility of targeting leukemias and lymphomas in vivo. The B-cell specificity of the multivalent aptamer was confirmed on lymphoma cell lines and fresh clinical leukemia samples. The chemically engineered aptamers, with significantly improved kinetic and biochemical features, unique specificity and desirable pharmacological properties, may be useful in biomedical applications.


Subject(s)
Aptamers, Nucleotide/chemistry , Leukemia, B-Cell/metabolism , Lymphoma, B-Cell/metabolism , Receptors, Antigen, B-Cell/metabolism , Animals , Aptamers, Nucleotide/metabolism , Cell Line, Tumor , Female , Humans , Immunoglobulin M/metabolism , Mice , Mice, Nude , Oligonucleotides/chemistry
11.
Proc Natl Acad Sci U S A ; 106(9): 3585-90, 2009 Mar 03.
Article in English | MEDLINE | ID: mdl-19208811

ABSTRACT

High-throughput screening (HTS) assays used in drug discovery frequently use reporter enzymes such as firefly luciferase (FLuc) as indicators of target activity. An important caveat to consider, however, is that compounds can directly affect the reporter, leading to nonspecific but highly reproducible assay signal modulation. In rare cases, this activity appears counterintuitive; for example, some FLuc inhibitors, acting through posttranslational Fluc reporter stabilization, appear to activate gene expression. Previous efforts to characterize molecules that influence luciferase activity identified a subset of 3,5-diaryl-oxadiazole-containing compounds as FLuc inhibitors. Here, we evaluate a number of compounds with this structural motif for activity against FLuc. One such compound is PTC124 {3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid}, a molecule originally identified in a cell-based FLuc assay as having nonsense codon suppression activity [Welch EM, et al., Nature (2007) 447:87-91]. We find that the potency of FLuc inhibition for the tested compounds strictly correlates with their activity in a FLuc reporter cell-based nonsense codon assay, with PTC124 emerging as the most potent FLuc inhibitor (IC(50) = 7 +/- 1 nM). However, these compounds, including PTC124, fail to show nonsense codon suppression activity when Renilla reniformis luciferase (RLuc) is used as a reporter and are inactive against the RLuc enzyme. This suggests that the initial discovery of PTC124 may have been biased by its direct effect on the FLuc reporter, implicating firefly luciferase as a molecular target of PTC124. Our results demonstrate the value of understanding potential interactions between reporter enzymes and chemical compounds and emphasize the importance of implementing the appropriate control assays before interpreting HTS results.


Subject(s)
Codon, Nonsense/genetics , Down-Regulation/drug effects , Enzyme Inhibitors/pharmacology , Luciferases, Firefly/analysis , Luciferases, Firefly/metabolism , Oxadiazoles/pharmacology , Animals , Enzyme Activation , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Fireflies/enzymology , Fireflies/genetics , Genes, Reporter/genetics , Histone Deacetylase Inhibitors , Histone Deacetylases/metabolism , Luciferases, Firefly/genetics , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Substrate Specificity
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