Neoadjuvant cabozantinib restores CD8+ T cells in patients with locally advanced non-metastatic clear cell renal cell carcinoma: a phase 2 trial
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ABSTRACT:
PROVIDER: PRJNA1143551 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30116783_1.fastq.gz | Fastqsanger.gz | |||
| SRR30116783_2.fastq.gz | Fastqsanger.gz | |||
| SRR30116784_1.fastq.gz | Fastqsanger.gz | |||
| SRR30116784_2.fastq.gz | Fastqsanger.gz | |||
| SRR30116785_1.fastq.gz | Fastqsanger.gz |
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Project description:Background. There is evidence that the stromal compartment may influence breast cancer responsiveness to chemotherapy. Our aim was to detect a stromal cell signature (using a direct approach of microdissected stromal cells) associated with response to neoadjuvant chemotherapy in locally advanced breast cancer, considering tumor down staging (to at least ypT1a/b,ypN0), as the best response. Patients and methods. Forty four patients diagnosed with locally advanced breast cancer (29 classified as estrogen receptor (ER) positive and 15, as ER negative) were included. Neoadjuvant chemotherapy consisted of doxorubicin/cyclophosphamide, followed by paclitaxel. Response was defined as downstaging to maximum ypT1a-b/ypN0. Stromal cells were microdissected from fresh frozen tumor samples and gene expression profile was determined using Agilent SurePrint G3 Human Gene Expression Microarrays. Expression levels were compared using MeV (MultiExperiment Viewer) software, applying SAM (Significance analysis of microarrays). Gene set enrichment analysis was used to identify gene sets correlated with the phenotype downstaging. Results: After chemotherapy, nine patients presented disease downstaging to maximum ypT1a-b/ypN0. Using SAM test (FDR 17), 11 sequences were differentially expressed, all of which (except for H2AFJ) more expressed in responsive tumors. Gene list enrichment analysis revealed three genes involved in abnormal cytotoxic T cell physiology: TOX, LY75 and SH2D1A. Gene sets correlated with tumor downstaging (FDR < 0.01), were mainly involved in immune response or lymphocyte activation, both in ER positive and ER negative samples. Conclusion: In locally advanced breast cancer, stromal cells may present specific features of immune response that may be associated with chemotherapy response.
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Project description:Sitravatinib is an immunomodulatory tyrosine kinase inhibitor that can augment responses when combined with programmed death-1 (PD-1) inhibitors such as nivolumab. We report a phase 2 study of neoadjuvant sitravatinib in combination with nivolumab in patients with locally advanced clear cell renal cell carcinoma (ccRCC) prior to curative nephrectomy (NCT03680521). The primary endpoint was objective response rate (ORR) prior to surgery with a null hypothesis ORR = 5% and the alternative hypothesis set at ORR = 30%. Secondary endpoints included correlative immune effects and disease-free survival (DFS). Twenty patients were evaluable for safety and 17 for efficacy. The ORR was 11.8%, and 24-month DFS probability was 88·0% (95% CI 61.0 to 97.0). There were no grade 4/5 treatment-related adverse events. Correlative blood and tissue analyses showed changes in the tumour microenvironment resulting in an immunologically active tumour by the time of surgery. These data suggest that short-term neoadjuvant sitravatinib and nivolumab does not substantially increase ORR but can modulate the immune microenvironment and yield high DFS probabilities in patients with locally advanced ccRCC.
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Project description:To elucidate candidate genes and pathways associated with poor response, we retrospectively analyzed gene expression profiles in serial biopsies from women with locally advanced breast cancer who failed to respond to anthracycline-based chemo followed by taxane in the I-SPY Of the 221 patients who completed neoadjuvant chemotherapy, 215 patients had surgery with 73% not achieving a pathologic complete response (pathCR). In these patients, cDNA microarray expression profiles from pretreatment biopsy (T1) were compared to those biopsy specimens obtained 24-72 hours after initiation of treatment (T2) or in tumors surgically removed after chemotherapy (TS). Paired expression data for T1vsT2 and T1vsTS were available for 29 and 39 patients with no pathCR, respectively. Paired differential expression analyses were performed via Significance Analysis of Microarrays (SAM) and differentially expressed genes were subjected to Ingenuity Pathway Analysis
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Project description:Purpose: Identified the expression profile of lncRNA associated to neoadjuvant chemotherapy response in 11 tumor of locally advanced breast cancer patients Methods: We implemented the transcriptomic analysis from 11 breast cancer samples by paired-end RNA-Seq, as a case-control study (responders vs nonresponders group). Differential expression analysis for lncRNA and mRNA were made to identify lncRNA as predictive biomarkers. Results: We identified the over-expressed lncRNA GATA3-AS1 in nonresponders group. Additionally, we identified the pathways were differentially expressed lncRNA and mRNA are associated in neoadjuvant chemotherapy response. Conclusion: we propose lncRNA GATA3-AS1 as a potential predictive biomarker for patients with LABC luminal B-like subtype that will not respond to neoadjuvant chemotherapy
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Project description:Resistance to neoadjuvant chemotherapy is associated tumor recurrence of locally advanced rectal cancer (LARC), which remains an unmet demand to exploit potential therapeutic strategies to improve clinical outcomes. Here we demonstrated that aberrant activation of cell cycle pathways is correlated with resistance to neoadjuvant chemotherapy in LARC. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators with oxaliplatin identified that CDK4/6 inhibitors synergistically enhanced anti-tumor effects of oxaliplatin both intrinsic and acquired chemo-resistant colon cancer cells. Functional studies in both in vitro and in vivo models showed that CDK4/6 inhibitors significantly increased sensitivity to oxaliplatin. Integrative transcriptomic and chromatin profiling analysis revealed that CDK4/6 inhibitors induced DNA repair defects to enhance sensitivity of oxaliplatin through epigenetically suppression of DNA repair related genes. Mechanistically, CDK4/6 inhibition impairs DNA damage repair through a previously unrecognized RB1/TEAD4/HDAC1 co-repressor complex which contributes to the resistance to neoadjuvant chemotherapy in LARC. Together, our work revealed an important role of CDK4/6 pathway in LARC patients with neoadjuvant chemotherapy, suggesting that targeting CDK4/6 could provide a potentially effective treatment strategy for LARC.
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Project description:Resistance to neoadjuvant chemotherapy is associated tumor recurrence of locally advanced rectal cancer (LARC), which remains an unmet demand to exploit potential therapeutic strategies to improve clinical outcomes. Here we demonstrated that aberrant activation of cell cycle pathways is correlated with resistance to neoadjuvant chemotherapy in LARC. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators with oxaliplatin identified that CDK4/6 inhibitors synergistically enhanced anti-tumor effects of oxaliplatin both intrinsic and acquired chemo-resistant colon cancer cells. Functional studies in both in vitro and in vivo models showed that CDK4/6 inhibitors significantly increased sensitivity to oxaliplatin. Integrative transcriptomic and chromatin profiling analysis revealed that CDK4/6 inhibitors induced DNA repair defects to enhance sensitivity of oxaliplatin through epigenetically suppression of DNA repair related genes. Mechanistically, CDK4/6 inhibition impairs DNA damage repair through a previously unrecognized RB1/TEAD4/HDAC1 co-repressor complex which contributes to the resistance to neoadjuvant chemotherapy in LARC. Together, our work revealed an important role of CDK4/6 pathway in LARC patients with neoadjuvant chemotherapy, suggesting that targeting CDK4/6 could provide a potentially effective treatment strategy for LARC.
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