TBCRC 039: A phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer
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ABSTRACT:
PROVIDER: PRJNA973715 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR24624952_1.fastq.gz | Fastqsanger.gz | |||
| SRR24624952_2.fastq.gz | Fastqsanger.gz | |||
| SRR24624953_1.fastq.gz | Fastqsanger.gz | |||
| SRR24624953_2.fastq.gz | Fastqsanger.gz | |||
| SRR24624954_1.fastq.gz | Fastqsanger.gz |
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Project description:We conducted a randomized phase II study with nested window-of-opportunity in patients with TN-IBC. Patients were randomized to receive a 7-day run-in of ruxolitinib (RUX) alone or ruxolitinib plus paclitaxel (RUX+PAC) in a 1:2 ratio, followed by 12 weeks of neoadjuvant paclitaxel alone or in combination with ruxolitinib in a 1:2 ratio. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide, followed by modified radical mastectomy. Patients provided tumor tissue from research biopsies performed at baseline (pre-run-in) and after the completion of run-in therapy. Tumor tissue was evaluated for phosphorylated STAT3 (pSTAT3) using immunohistochemistry (IHC) and immunofluorescence, and a subset of cases were also analyze by RNA-seq. The primary objective was to evaluate the percent of patients whose tumors were pSTAT3-positive at baseline, and which subsequently became pSTAT3-negative after run-in therapy. Secondary endpoints included pathologic complete response (pCR), residual tumor burden (RCB) and event-free survival (EFS) from the date of surgery. There were 23 patients enrolled, 11 in RUX and 12 in RUX+PAC combination. The most common adverse events were fatigue and nausea. Two patients achieved pCR and 21 completed pre-operative therapy. We detected a decrease in pSTAT3 and IL6/JAK/STAT3 signaling pathways in post-run-in biopsies of RUX-treated samples, but this did not correlate with pCR, while RUX+PAC upregulated IL6/JAK/STAT3 signaling. Both treatments decreased GZM+ T cells implying immune suppression, which might have contributed to lack of efficacy.
2024-02-07 | GSE232764 | GEO
Project description:BackgroundPatients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC.MethodsWe conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR).ResultsOverall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells.ConclusionIn summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target.Trial registrationwww.Clinicaltrialsgov , NCT02876302. Registered 23 August 2016.
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2014-07-08 | E-GEOD-57429 | biostudies-arrayexpress
Project description:HCC1143, HCC70, HCC38, and SUM159PT cells were treated for 4 or 24 hrs with 1uM ruxolitinib. Control cells were treated for 24 hrs with DMSO (0.1%). The purpose was to determine changes in gene expresison patterns following inhibition of JAK1/2 in the cells. Three independent experiments were conducted for three biological replicates at each time point, for each cell line
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2012-02-16 | E-MTAB-552 | biostudies-arrayexpress
Project description:Transcription profiling by high throughput sequencing of the potato (genotype RH89-039-16) ArrayExpress Release Date: 2011-07-11 Person Roles: submitter Person Last Name: Soenderkaer Person First Name: Mads Person Mid Initials: Person Email: mson@bio.aau.dk Person Phone: 4530532492 Person Address: Sohngaardsholmsvej 49, 9000 Aalborg, Denmark Person Affiliation: Aalborg University
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Project description:Paclitaxel -resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of Aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. These findings are fully recapitulated in a patient derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.
2024-06-21 | GSE264630 | GEO
Project description:Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC). Despite the good initial responses, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), activation of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve and paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced the potency of BV6, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance
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