Neoadjuvant Pazopanib and Molecular Analysis of Tissue Response in Renal Cell Carcinoma
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PROVIDER: PRJNA641945 | ENA |
REPOSITORIES: ENA
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Project description:Neoadjuvant Pazopanib and Molecular Analysis of Tissue Response in Renal Cell Carcinoma
| PRJNA641944 | ENA
Project description:The aim of the experiment was to discover differentially expressed miRNAs correlating with prolonged response to targeted therapy in patients with metastatic renal cell carcinoma treated with sunitinib or pazopanib
2018-02-08 | E-MTAB-6296 | biostudies-arrayexpress
Project description:BACKGROUNDSurgery remains the frontline therapy for patients with localized clear cell renal cell carcinoma (ccRCC); however, 20%-40% recur. Angiogenesis inhibitors have improved survival in metastatic patients and may result in responses in the neoadjuvant setting. The impact of these agents on the tumor genetic heterogeneity or the immune milieu is largely unknown. This phase II study was designed to evaluate safety, response, and effect on tumor tissue of neoadjuvant pazopanib.METHODSccRCC patients with localized disease received pazopanib (800 mg daily; median 8 weeks), followed by nephrectomy. Five tumors were examined for mutations by whole exome sequencing from samples collected before therapy and at nephrectomy. These samples underwent RNA sequencing; 17 samples were available for posttreatment assessment.RESULTSTwenty-one patients were enrolled. The overall response rate was 8 of 21 (38%). No patients with progressive disease. At 1-year, response-free survival and overall survival was 83% and 89%, respectively. The most frequent grade 3 toxicity was hypertension (33%, 7 of 21). Sequencing revealed strong concordance between pre- and posttreatment samples within individual tumors, suggesting tumors harbor stable core profiles. However, a reduction in private mutations followed treatment, suggesting a selective process favoring enrichment of driver mutations.CONCLUSIONNeoadjuvant pazopanib is safe and active in ccRCC. Future genomic analyses may enable the segregation of driver and passenger mutations. Furthermore, tumor infiltrating immune cells persist during therapy, suggesting that pazopanib can be combined with immune checkpoint inhibitors without dampening the immune response.FUNDINGSupport was provided by Novartis and GlaxoSmithKline as part of an investigator-initiated study.
| S-EPMC7710285 | biostudies-literature
Project description:Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.
2023-12-18 | GSE245372 | GEO
Project description:Background: The sequential and combination treatment with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in metastatic renal cell carcinoma (mRCC) patients has entered the clinical practice. The dissection of the molecular mechanisms governing the impact of TKIs on the immune system is critical to implement therapeutic approaches and generate biomarkers. We here investigated the immunomodulatory activity of pazopanib in peripheral blood mononuclear cells (PBMCs) of mRCC patients through an integrative genomic analysis pipeline. Results: The transcriptional analysis indicates a modulation of leukocyte functional orientation induced by pazopanib with an increase of immune effector cell subtypes and a decrease of immune suppressive populations. At the group level transcriptome profiles revealed perturbations to peak at 3 and decrease at 6 months. These included enrichments of modules associated with cytotoxic/NK (M3.6 and M8.46), plasma cells (M4.11), T cell (M4.15) and immune responses (M8.89). At individual patient level, pazopanib administration was associated with a decrease of the immunosuppressive module M9.34 in the majority of patients. Interestingly, a rapid increase of Interferon (IFN) modules (M1.2 and M3.4) was observed exclusively in patients displaying a strong enrichment in modules associated with cytotoxic/NK cells. Multicolor flow cytometry confirmed the association of pazopanib treatment with a decrease of immune suppressive cell subsets, including CD14+HLA-DRneg myeloid derived suppressor cells (MDSCs), CD14+ and CD14+PD-L1+ monocytes, CD15+ granulocytic MDSCs and CD4+CD25highFoxp3+ regulatory T cells. Concomitantly, a boost of activated CD3+PD-1dim T lymphocytes and cytotoxic CD3-CD16+CD56dim NK cells was observed. These changes were predominantly detectable after 3 months of therapy with pazopanib. Conclusions: As systems approach, pazopanib reshapes anti-tumor immunity by relieving immunosuppression and triggering cytotoxic mechanisms and IFN pathways. The peak of this immune modulation is observed after 3 months of therapy. Our data provides a strong rationale in support of combinatorial or sequential therapies based on TKIs and immunotherapy approaches and for implementing transcriptomic analysis of blood as biomarker of immune responses.
2021-06-28 | GSE146163 | GEO
Project description:Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma
| PRJNA1027897 | ENA
Project description:Each total RNA sample is hybridized to two different arrays: Affymetrix U133A (GPL96) and U133B (GPL97). For most of the normal tissue samples there is a renal clear cell carcinoma sample from the same patient. There is no matching tumor sample for normal sample N1. For most of the renal clear cell carcinoma samples there is a corresponding adjacent normal tissue sample from the same patient. There are no matching normal tissue samples for C011 or C032. Keywords = kidney Keywords = renal Keywords = RCC Keywords = carcinoma Keywords = cancer Keywords: parallel sample
2003-11-25 | E-GEOD-781 | biostudies-arrayexpress
Project description:Each total RNA sample is hybridized to two different arrays: Affymetrix U133A (GPL96) and U133B (GPL97). For most of the normal tissue samples there is a renal clear cell carcinoma sample from the same patient. There is no matching tumor sample for normal sample N1. For most of the renal clear cell carcinoma samples there is a corresponding adjacent normal tissue sample from the same patient. There are no matching normal tissue samples for C011 or C032. Keywords = kidney Keywords = renal Keywords = RCC Keywords = carcinoma Keywords = cancer Keywords: parallel sample
2003-11-25 | GSE781 | GEO
Project description:Differential neoadjuvant chemotherapy response in urothelial carcinoma molecular subtypes
| PRJNA716648 | ENA
Project description:Renal papillary cell carcinoma
| PRJNA749556 | ENA