Proteomic resistance biomarkers for PI3K inhibitor in triple negative breast cancer patient-derived xenograft models

PI3K pathway activation is frequently observed in triple negative breast cancer (TNBC). However, single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor, BKM120. Baseline and post-treatment PDX tumors were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth inhibition (%TGI) ranged from 35% in the least sensitive to 84% in the most sensitive model. Several biomarkers showed significant association with resistance, including elevated baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment-induced increases in the levels of phosphorylated forms of Aurora kinases. Interestingly, increased AKT phosphorylation or PTEN loss at baseline were not significantly correlated to %TGI. These results provide important insights into biomarker development for PI3K inhibitors in TNBC

An Analysis of the Sensitivity of Proteogenomic Mapping of Somatic Mutations and Novel Splicing Events in Cancer

Improvements in mass spectrometry (MS)-based peptide sequencing provide a new opportunity to determine whether polymorphisms, mutations, and splice variants identified in cancer cells are translated. Herein, we apply a proteogenomic data integration tool (QUILTS) to illustrate protein variant discovery using whole genome, whole transcriptome, and global proteome datasets generated from a pair of luminal and basal-like breast-cancer-patient-derived xenografts (PDX). The sensitivity of proteogenomic analysis for singe nucleotide variant (SNV) expression and novel splice junction (NSJ) detection was probed using multiple MS/MS sample process replicates defined here as an independent tandem MS experiment using identical sample material. Despite analysis of over 30 sample process replicates, only about 10% of SNVs (somatic and germline) detected by both DNA and RNA sequencing were observed as peptides. An even smaller proportion of peptides corresponding to NSJ observed by RNA sequencing were detected (<0.1%). Peptides mapping to DNA-detected SNVs without a detectable mRNA transcript were also observed, suggesting that transcriptome coverage was incomplete (∼80%). In contrast to germline variants, somatic variants were less likely to be detected at the peptide level in the basal-like tumor than in the luminal tumor, raising the possibility of differential translation or protein degradation effects. In conclusion, this large-scale proteogenomic integration allowed us to determine the degree to which mutations are translated and identify gaps in sequence coverage, thereby benchmarking current technology and progress toward whole cancer proteome and transcriptome analysis

Combining the Tyrosine Kinase Inhibitor Cabozantinib and the mTORC1/2 Inhibitor Sapanisertib Blocks ERK Pathway Activity and Suppresses Tumor Growth in Renal Cell Carcinoma.

UNLABELLED: Current treatment approaches for renal cell carcinoma (RCC) face challenges in achieving durable tumor responses due to tumor heterogeneity and drug resistance. Combination therapies that leverage tumor molecular profiles could offer an avenue for enhancing treatment efficacy and addressing the limitations of current therapies. To identify effective strategies for treating RCC, we selected ten drugs guided by tumor biology to test in six RCC patient-derived xenograft (PDX) models. The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib and mTORC1/2 inhibitor sapanisertib emerged as the most effective drugs, particularly when combined. The combination demonstrated favorable tolerability and inhibited tumor growth or induced tumor regression in all models, including two from patients who experienced treatment failure with FDA-approved TKI and immunotherapy combinations. In cabozantinib-treated samples, imaging analysis revealed a significant reduction in vascular density, and single-nucleus RNA sequencing (snRNA-seq) analysis indicated a decreased proportion of endothelial cells in the tumors. SnRNA-seq data further identified a tumor subpopulation enriched with cell-cycle activity that exhibited heightened sensitivity to the cabozantinib and sapanisertib combination. Conversely, activation of the epithelial-mesenchymal transition pathway, detected at the protein level, was associated with drug resistance in residual tumors following combination treatment. The combination effectively restrained ERK phosphorylation and reduced expression of ERK downstream transcription factors and their target genes implicated in cell-cycle control and apoptosis. This study highlights the potential of the cabozantinib plus sapanisertib combination as a promising treatment approach for patients with RCC, particularly those whose tumors progressed on immune checkpoint inhibitors and other TKIs. SIGNIFICANCE: The molecular-guided therapeutic strategy of combining cabozantinib and sapanisertib restrains ERK activity to effectively suppress growth of renal cell carcinomas, including those unresponsive to immune checkpoint inhibitors

Comprehensive characterization of 536 patient-derived xenograft models prioritizes candidatesfor targeted treatment.

Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications and subclone events, and the potential PDX models for NCI-MATCH trials. Lastly, we provide a web portal having comprehensive pan-cancer PDX genomic profiles and source code to facilitate identification of more druggable events and further insights into PDXs\u27 recapitulation of human tumors

Evaluation on the Development of Circular Agriculture in Guizhou Province Based on Entropy Method

Vigorously developing agricultural circular economy is an effective way to achieve sustainable agricultural development, and a strategic measure to ease the pressure on agricultural resources, protect ecological and clean resources, and promote sustainable agricultural and rural economic development. From the theoretical perspective of circular agriculture, this paper builds the evaluation indicator system for circular agriculture, and uses entropy method to carry out the comprehensive evaluation of the development level of agricultural circular economy in Guizhou Province from 2003 to 2012. At the same time, this paper analyzes the obstacles to the development of agricultural circular economy in Guizhou Province in 2012, and sets forth the relevant recommendations based on these limitations, in order to improve the development level of circular agriculture in Guizhou Province

Comprehensive Benefit Analysis on Development Models of Circular Agriculture in Wangcang County of Sichuan Province

Taking Wangcang County of Sichuan Province as an example, this paper made comprehensive benefit analysis on models of circular agriculture in Wangcang County. Major models include “pig – biogas – fruit”, “pig – biogas – vegetable”, and “pig – biogas - tea”. It made cost benefit analysis of economic, social and ecological benefits. Through benefit analysis charts, it obtained that the net present value of each household building biogas pool is 6029 yuan. In this way, it significantly improved ecological environment and social benefits, and the agricultural economic development model gradually changes to sustainable development model. However, there are still problems of insufficient government input and single model of agricultural circular economy. Therefore, government should increase input and develop diversified agricultural circular economical models in accordance with local situations, to realize sustainable agricultural development

Inspiration of Direct Grain Production Subsidy System in Typical Countries and Regions

Through comparison of direct grain production subsidy system in typical countries and regions, such as the United States, EU, Japan and South Korea, this paper evaluated the performance of direct grain production subsidy system. On the basis of comparison and analysis, it summed up experience of the direct grain production subsidy system in typical countries and regions. Finally, it came up with countermeasures and recommendations for improving the direct grain production subsidy system in China

Analysis on After-effects of Direct Subsidies for Grain Production in China

Long term of grain production subsidy policy can be guaranteed only with sound and sustainable development of economy, stable growth of fiscal revenues, and improvement of subsidy system. In combination with social survey, this paper analyzed after-effects of direct subsidies for grain production in China from pressure of grain production subsidies on central finance and local finance, consequence possibly brought about by classified bearing of direct subsidies for grain production, effectiveness of direct subsidies on stimulating grain production, and effect of direct subsidies on production of other agricultural products. It is concluded that direct subsidies for grain production should be shifted to direct subsides for agricultural production, which will be the reform and development trend of financial support for agriculture