Mercapturate pathway metabolites of sotorasib, a covalent inhibitor of KRAS G12C , are associated with renal toxicity in the Sprague Dawley rat
Sotorasib is a first-in class KRAS G12C covalent inhibitor in clinical development for the treatment of tumors with
the KRAS p.G12C mutation. In the nonclinical toxicology studies of sotorasib, the kidney was identified as a
target organ of toxicity in the rat but not the dog. Renal toxicity was characterized by degeneration and necrosis
of the proximal tubular epithelium localized to the outer stripe of the outer medulla (OSOM), which suggested
that renal metabolism was involved. Here, we describe an in vivo mechanistic rat study designed to investigate
the time course of the renal toxicity and sotorasib metabolites. Renal toxicity was dose- and time-dependent,
restricted to the OSOM, and the morphologic features progressed from vacuolation and necrosis to regeneration
of tubular epithelium. The renal toxicity correlated with increases in renal biomarkers of tubular injury.
Using mass spectrometry and matrix-assisted laser desorption/ionization, a strong temporal and spatial associ –
ation between renal toxicity and mercapturate pathway metabolites was observed. The rat is reported to be
particularly susceptible to the formation of nephrotoxic metabolites via this pathway. Taken together, the data
presented here and the literature support the hypothesis that sotorasib-related renal toxicity is mediated by a
toxic metabolite derived from the mercapturate and B-lyase pathway. Our understanding of the etiology of the rat
specific renal toxicity informs the translational risk assessment for patients.
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A New Safety Concern for Glaucoma Treatment Demonstrated by Mass Spectrometry Imaging of Benzalkonium Chloride Distribution in the Eye, an Experimental Study in Rabbits
We investigated in a rabbit model, the eye distribution of topically instilled benzalkonium (BAK) chloride a commonly used preservative in eye drops using mass spectrometry imaging. Three groups of three New Zealand rabbits each were used: a control one without instillation, one receiving 0.01%BAK twice a day for 5 months and one with 0.2%BAK one drop a day for 1 month. After sacrifice, eyes were embedded and frozen in tragacanth gum. Serial cryosections were alternately deposited on glass slides for histological (hematoxylin-eosin staining) and immunohistological controls (CD45, RLA-DR and vimentin
for inflammatory cell infiltration as well as vimentin for Mu¨ller glial cell activation) and ITO or stainless steel plates for MSI experiments using Matrix-assisted laser desorption ionization time-of-flight. The MSI results were confirmed by a roundrobin study on several adjacent sections conducted in two different laboratories using different sample preparation methods, mass spectrometers and data analysis softwares. BAK was shown to penetrate healthy eyes even after a short
duration and was not only detected on the ocular surface structures, but also in deeper tissues, especially in sensitive areas involved in glaucoma pathophysiology, such as the trabecular meshwork and the optic nerve areas, as confirmed by images with histological stainings. CD45-, RLA-DR- and vimentin-positive cells increased in treated eyes. Vimentin was found only in the inner layer of retina in normal eyes and increased in all retinal layers in treated eyes, confirming an activation response to a cell stress. This ocular toxicological study confirms the presence of BAK preservative in ocular surface structures as well
as in deeper structures involved in glaucoma disease. The inflammatory cell infiltration and Mu¨ller glial cell activation confirmed the deleterious effect of BAK. Although these results were obtained in animals, they highlight the importance of the safety-first principle for the treatment of glaucoma patients.
Multimodal stratification of predictive biomarker in lung cancer: A focus on immune checkpoint inhibitor
Dive into the complex landscape of immune checkpoint inhibitors (ICIs) in lung cancer in our poster presentation.
As the use of immunotherapy in early-stage non-small cell lung cancer (NSCLC) remains a challenge, we offer a spatially-informed approach to identify useful biomarkers. By using spatial biomarker assays, and analysis involving spatial transcriptomics and proteomics, we reveal the cell-to-cell interactions in the tumor microenvironment.
Download our poster to explore our findings and gain insights into the suitability of ICIs for personalized therapy
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Spatial distribution of B cells and lymphocyte clusters for the treatment of non-small cell lung cancer
Explore the spatial organization of tertiary lymphoid structures (TLS) in non-small cell lung cancer (NSCLC) and its impact on ant-PD-1 treatment response in our poster presentation.
Using high-plex imaging mass cytometry staining, we investigated the relationship between TLS spatial organization, the tumor microenvironment, and patient response to therapy. We leveraged deep learning for cell segmentation and characterization to identify that the presence of tumor-associated TLS correlates with a positive response to ant-PD-1 therapy.
Download our poster to dive into this spatial distribution insight and its potential impact on immunotherapies.
Highly sensitive analysis using EVOSEP-LC-MS/MS assay for targeted PD-L1 and PD-1 expression level for predicting response to immune checkpoint inhibitors
Explore our recent poster presentation, which dives into a highly sensitive analysis using an EVOSEP-LC-MS/MS assay, with a focus on targeted PD-L1 and PD-1 expression levels to predict responses to immune checkpoint inhibitors (ICIs).
We address the limitations of traditional PD-L1 and PD-1 immunoassays and their uncertain clinical value across tumor types. Through analysis of our robust method against routine immunoassays, and use of Overall Response Rate (ORR), we offer a new perspective on the predictive power of biomarkers for non-small cell lung cancer (NSCLC) therapy.
Download our poster to discover the potential of this innovative approach.
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LC/MS/MS VS. LC/HRMS: Identifying and quantifying oligonucleotides
LC/MS/MS and LC/HRMS are formidable instruments employed in mass spectrometry for the identification and quantification of Oligonucleotides (OGNTs). Utilizing these approaches, drug developers can obtain detailed insights into the composition and structure of molecules for biotechnology and pharmaceuticals.
Considerations for choosing the right approach for your drug development project will depend on:
- What instrument you have
- Where you want to go
- How much information you want to collect in a single injection
Discover which technique is best for you.
Optimizing small molecule drug development strategies: A step by step approach to a rugged method
Creating a rugged method for the development of small molecule drugs is crucial in the quest for successful therapies. A systematic approach not only guarantees data consistency and reliability but also empowers you to make well-informed decisions, ultimately boosting project efficiency and success.
To help you navigate the complexities and uncertainties that come with advancing small molecules for drug development, we’ve outlined a robust strategy that includes 7 crucial steps.
Download our fact sheet to learn more.
Investigation of immune-checkpoints for personalized therapy selection
Monoclonal antibody-based therapy targeting PD1 blockage has brought a transformative shift in the immunotherapeutic strategy against solid tumors. However, the limited effectiveness of this treatment stems from the absence of precise methodologies, such as immunohistochemistry, for identifying patients who could potentially respond well to immune checkpoint inhibitor therapy.
Because a single biomarker is not accurate enough to predict the interaction of the drug at the site of action, we developed a strategy to investigate the complexity of the tumor microenvironment, while also guiding patients towards combination therapy. Using multiplexed high throughput analysis, we have been able to investigate pathways of immune modulation at the molecular level to drug response and resistance.
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Sequential pathogenic events in Type I Diabetes
Type 1 diabetes (T1D) arises due to the autoimmune degradation of insulin producing β cells. In order to cure or halt this disease, understanding how cell types, cell states, and cell-cell interactions evolve during T1D development is essential.
Utilizing our proprietary imaging analysis tools, we were able to segment cells to identify cell populations for spatial analysis and further classification in diabetes with precision. Our deep data analysis workflows and advanced imagine techniques introduce new opportunities to investigate the pathology of T1D within the pancreas.
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Spatially-resolved tumor gene expression analysis
As cancer advances, tumor cells come into contact with new cell types within the microenvironment, but it is still unclear how the tumor cells adapt to new environments. Spatial transcriptomics is a powerful approach to uncover mechanisms that allow tumors to invade the microenvironment and help discover biomarkers for potential therapeutic targets.
In this application note, we outline how we fine-tuned and merged spatial transcriptomics with laser microdissection (LMD) to identify distinct patterns in genes in tumor cells throughout the stages of cancer progression.
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