An update on the status of HSP90 inhibitors in cancer clinical trials

Cell Stress and Chaperones, Journal Year: 2024, Volume and Issue: 29(4), P. 519 - 539

Published: June 13, 2024

The evolutionary conserved molecular chaperone HSP90 plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although, the functionality of is tightly regulated, cancer cells exhibit a unique dependence on this chaperone, leading to its overexpression, which has been associated with poor prognosis certain malignancies. While various strategies targeting heat shock proteins involved carcinogenesis have explored, only inhibition consistently and effectively resulted proteasomal degradation proteins. To date, total 22 inhibitors tested 186 clinical trials, as reported clinicaltrials.gov. Among these 60% completed, 10% are currently active, while 30% suspended, terminated, or withdrawn. used single agents combination other drugs for treatment types trials. Notably, improved outcomes observed when therapies, they synergistic antitumor effect. However, agents, shown limited activity due drug related toxicity therapy resistance. Recently, active trials conducted Japan evaluating TAS-116 (pimitespib) demonstrated promising results low monotherapy immune check point inhibitor nivolumab. Exploratory biomarker analyses performed target engagement that suggests potential identifying patient populations may respond favorably therapy. In review, we discuss advances made past five years regarding their implications anti-cancer therapeutics. Our focus lies efficacy, forecast, pharmacodynamic biomarkers, published Through comprehensive aim shed light progress therapeutic treatment.

Language: Английский

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A pan-cancer clinical platform to predict immunotherapy outcomes and prioritize immuno-oncology combinations in early-phase trials

Med, Journal Year: 2023, Volume and Issue: 4(10), P. 710 - 727.e5

Published: Aug. 11, 2023

Immunotherapy is effective, but current biomarkers for patient selection have proven modest sensitivity. Here, we developed VIGex, an optimized gene signature based on the expression level of 12 genes involved in immune response with RNA sequencing.We implemented VIGex using nCounter platform (Nanostring) a large clinical cohort encompassing 909 tumor samples across 45 types. was as continuous variable, cutoffs selected to detect three main categories (hot, intermediate-cold and cold) different inflammatory status microenvironment.Hot tumors had highest scores exhibited increased abundance tumor-infiltrating lymphocytes compared cold. varied depending origin anatomic site metastases, liver metastases showing immunosuppressive microenvironment. The predictive power VIGex-Hot observed 98 refractory solid from patients treated early-phase immunotherapy trials its performance confirmed through extensive metanalysis 13 clinically annotated datasets 877 agents. Last, generated pan-cancer biomarker that integrates levels targets under development trials.Our results support utility tool aid clinicians personalized interventions.BBVA Foundation; 202-2021 Division Medical Oncology Hematology Fellowship award; Princess Margaret Cancer Center.

Language: Английский

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Optimizing dose-schedule regimens with bayesian adaptive designs: opportunities and challenges

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 23, 2023

Due to the small sample sizes in early-phase clinical trials, toxicity and efficacy profiles of dose-schedule regimens determined for subsequent trials may not be well established. The recent development novel anti-tumor treatments combination therapies further complicates problem. Therefore, there is an increasing recognition essential place optimizing regimens, new strategies are now urgently needed. Bayesian adaptive designs provide a potentially effective way evaluate several doses schedules simultaneously single trial with higher efficiency, but real-world implementation examples such still few. In this paper, we cover critical factors associated optimization review related innovative designs. assumptions, characteristics, limitations, application scenarios those introduced. also summarizes some unresolved issues future research opportunities optimization.

Language: Английский

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Currently Used Methods to Evaluate the Efficacy of Therapeutic Drugs and Kidney Safety

Biomolecules, Journal Year: 2023, Volume and Issue: 13(11), P. 1581 - 1581

Published: Oct. 26, 2023

Kidney diseases with kidney failure or damage, such as chronic disease (CKD) and acute injury (AKI), are common clinical problems worldwide have rapidly increased in prevalence, affecting millions of people recent decades. A series novel diagnostic predictive biomarkers been discovered over the past decade, enhancing investigation renal dysfunction preclinical studies risk assessment for humans. Since multiple causes lead to failure, animal extensively used identify specific understanding potential targets nephropathy events therapeutic insights into progression. Mice most commonly model investigate mechanism human nephropathy, current alternative methods, including vitro silico models, can offer quicker, cheaper, more effective methods avoid reduce unethical procedures usage. This review provides modern approaches, nonanimal assays, that be applied study nonclinical safety. These situations could utilized drug development provide information on disease.

Language: Английский

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Analysis of Different Types of Cancer Biomarkers

Transactions on Materials Biotechnology and Life Sciences, Journal Year: 2024, Volume and Issue: 5, P. 26 - 32

Published: Oct. 10, 2024

Malignant tumor is still the most important disease threatening people's lives and health, people often have fear of ‘talking about cancer’. Cancer biomarkers are essential for reaching better clinical effectiveness long-term outcomes, as well reducing pain decreasing disease-related social costs. The high burden malignancies worldwide highlights underutilization cancer diagnosis, prognosis, treatment effect, drug potency prediction. Novel strategies urgently needed to discover translate molecular diagnostics from experimental research practice. Nowadays, significant advancements been achieved in study biomarkers, such Diagnostic, Prognostic, Predictive, Pharmacodynamic, so on. accurate detection markers can provide more valuable medical information practice help realize personalized medicine. This article summarizes some patients looks forward studies on specificity mechanism biomarkers.

Language: Английский

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Critical importance of correctly defining and reporting secondary endpoints when assessing the ethics of research biopsies

Clinical Trials, Journal Year: 2024, Volume and Issue: 21(5), P. 650 - 656

Published: April 23, 2024

This article reviews the implementation challenges to American Society of Clinical Oncology's ethical framework for including research biopsies in oncology clinical trials. The primary relate definitions secondary endpoints, scientific and regulatory framework, incentive structure that encourages inclusion biopsies. Principles stewardship require trials community correctly articulate goals any biopsies, especially those are required patient enroll on a trial receive an investigational agent. Furthermore, it is important sufficiently justify characterization (as distinguished from exploratory) protect interest participants, report accurate complete information ClinicalTrials.gov published literature.

Language: Английский

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Sequential chromogenic immunohistochemistry: spatial analysis of lymph nodes identifies contact interactions between plasmacytoid dendritic cells and plasmablasts

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 14, 2023

Abstract Recent clinical observations highlight the importance of spatial organization immune cells into lymphoid structures for success cancer immunotherapy and patient survival. Sequential chromogenic immunohistochemistry (scIHC) supports analysis multiple biomarkers on a single tissue section thus providing unique information about relative location cell types assessment disease states. Unfortunately, widespread implementation scIHC is limited by lack standardized, rigorous guide to development customized biomarker panels need user-friendly pipelines able streamline extraction meaningful data. Here, we examine major steps from classical IHC protocols impact they have procedure. We report practical examples illustrations most common complications that can arise during setup new panel how avoid them. described in detail prevent detect cross- reactivity between secondary reagents carry over detection antibodies. developed novel pipeline based non-rigid deformation correction, Cellpose-inspired automated segmentation computational network masking low-quality The resulting was used study regional lymph nodes head neck patients. identified contact interactions plasmablasts plasmacytoid dendritic vivo . Given TLR receptors, which are highly expressed play key role vaccine efficacy, significance this cell-cell interaction decisively warrants further studies. In conclusion, work streamlines scIHC, will ultimately improve our understanding responses cancer.

Language: Английский

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Data from Sequential Chromogenic IHC: Spatial Analysis of Lymph Nodes Identifies Contact Interactions between Plasmacytoid Dendritic Cells and Plasmablasts

Published: June 24, 2023

<div><p>Recent clinical observations have emphasized the critical role that spatial organization of immune cells in lymphoid structures plays success cancer immunotherapy and patient survival. However, implementing sequential chromogenic IHC (scIHC) to analyze multiple biomarkers on a single tissue section has been limited because lack standardized, rigorous guide development customized biomarker panels need for user-friendly analysis pipelines can extract meaningful data. In this context, we provide comprehensive novel scIHC, using practical examples illustrations highlight most common complications arise during setup new panel, detailed instructions how prevent detect cross-reactivity between secondary reagents carryover detection antibodies. We also developed pipeline based non-rigid deformation correction, Cellpose-inspired automated cell segmentation, computational network masking low-quality applied panel study regional lymph nodes from patients with head neck cancer, identifying contact interactions plasmablasts plasmacytoid dendritic <i>in vivo</i>. Given Toll-like receptors, which are highly expressed cells, play key vaccine efficacy, significance cell–cell interaction decisively warrants further studies. summary, work provides streamlined approach scIHC will ultimately improve our understanding responses cancer.</p>Significance:<p>We present developing investigate context cancer. This revealed cancer.</p></div>

Language: Английский

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Sequential Chromogenic IHC: Spatial Analysis of Lymph Nodes Identifies Contact Interactions between Plasmacytoid Dendritic Cells and Plasmablasts

Cancer Research Communications, Journal Year: 2023, Volume and Issue: 3(7), P. 1237 - 1247

Published: June 24, 2023

Recent clinical observations have emphasized the critical role that spatial organization of immune cells in lymphoid structures plays success cancer immunotherapy and patient survival. However, implementing sequential chromogenic IHC (scIHC) to analyze multiple biomarkers on a single tissue section has been limited because lack standardized, rigorous guide development customized biomarker panels need for user-friendly analysis pipelines can extract meaningful data. In this context, we provide comprehensive novel scIHC, using practical examples illustrations highlight most common complications arise during setup new panel, detailed instructions how prevent detect cross-reactivity between secondary reagents carryover detection antibodies. We also developed pipeline based non-rigid deformation correction, Cellpose-inspired automated cell segmentation, computational network masking low-quality applied panel study regional lymph nodes from patients with head neck cancer, identifying contact interactions plasmablasts plasmacytoid dendritic vivo. Given Toll-like receptors, which are highly expressed cells, play key vaccine efficacy, significance cell-cell interaction decisively warrants further studies. summary, work provides streamlined approach scIHC will ultimately improve our understanding responses cancer.We present developing investigate context cancer. This revealed

Language: Английский

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A risk stratification model for toxicities in phase 1 immunotherapy trials

European Journal of Cancer, Journal Year: 2022, Volume and Issue: 175, P. 11 - 18

Published: Sept. 6, 2022

Despite the increased number of novel immunotherapy (IO) agents under current development, their toxicity profile remains to be fully elucidated.An IO risk stratification model was developed based on 5 different variables: treatment-related deaths; rate grade ≥3 adverse events or treatment-emergent events; ≥2 encephalopathy central nervous system toxicity; cytokine release syndrome; and type dose-limiting toxicity. Phase 1 trials published from January 2014 December 2020 were reviewed categorised our into three categories: low-, intermediate- high-risk. Clinical trial variables associated with high-risk category. To review quality reporting across phase trials, a subset studies further examined by use ASCO/SITC Trial Reporting in Immuno-Oncology (TRIO) standards.Different compounds demonstrated diverse profiles. In multivariable analysis, combination versus single agent treatment, testing anti-programmed death-1/programmed death ligand-1 (anti-PD1/L1), anti-cytotoxic t-lymphocyte antigen-4 (anti-CTLA4) antibodies anti-cancer vaccines higher risk. None dataset reported all items included TRIO standards.Our results have important implications for future clinical design. Additionally, standards are urgently needed.

Language: Английский

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