Distinct Transcriptional Landscapes Identified by Radiographic Response in Metastatic Triple-Negative Breast Cancer Treated with Carboplatin, Nab-Paclitaxel, and Pembrolizumab in a Single-Arm Phase II Trial
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PROVIDER: PRJNA1010464 | ENA |
REPOSITORIES: ENA
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Project description:A single arm, Phase II trial of carboplatin, nab-paclitaxel, and pembrolizumab (CNP) in metastatic triple negative breast cancer (mTNBC) was designed to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), safety/tolerability, and identify pathologic and transcriptomic correlates of response to therapy.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel has been added to the arsenal of first line therapies, and the combination of gemcitabine and nab-paclitaxel has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying nab-paclitaxel (n-PTX) resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naive PDAC patients. To study the mechanisms of primary drug resistance, nab-paclitaxel-resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude mouse xenograft models. Molecular analyses identified the sustained induction of c-MYC in the nab-paclitaxel-resistant cells. Depletion of c-Myc restored nab-paclitaxel sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small molecule activator of protein phosphatase 2a (SMAP). Implications: The strategies we have devised, including the patient-derived primary cells and the unique drug resistant isogenic cells, are rapid and easily applied in vitro and in vivo platforms to better understand the mechanisms of drug resistance and for defining effective therapeutic options on a patient by patient basis
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Project description:Background:Longitudinal data on the impact of treatment on quality of life (QoL) in advanced non-small cell lung cancer (NSCLC) are limited. In this palliative setting, treatment that does not deteriorate QoL is key. Here we report longitudinal QoL in patients with squamous NSCLC, receiving ?4 cycles of nab-paclitaxel/carboplatin combination chemotherapy. Methods:Patients received nab-paclitaxel 100 mg/m2 days 1, 8, 15 + carboplatin area under the curve 6 mg•min/mL day 1 (q3w) for four cycles. QoL was assessed by the Lung Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L) at baseline and each cycle (day 1). Results:Two-hundred and six lesion-response-evaluable patients completed baseline + ?1 postbaseline QoL assessment and were QoL evaluable. LCSS average total score and symptom burden index improved from baseline throughout four cycles. In the LCSS pulmonary symptoms score, 46% of patients reported clinically meaningful improvement (?10 mm visual analog scale) from baseline. Individual EQ-5D-5L dimensions remained stable/improved in ?83% of patients; ?33% reported complete resolution of baseline problems at least once during four cycles. Generally, responders (unconfirmed complete/partial response) had higher scores vs nonresponders. Conclusion:In patients with squamous NSCLC, four cycles of nab-paclitaxel/carboplatin demonstrated clinically meaningful QoL improvements, with greater benefits in responders vs nonresponders.
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Project description:PurposeImmunotherapy has recently been shown to improve outcomes for advanced PD-L1-positive triple-negative breast cancer (TNBC) in the Impassion130 trial, leading to FDA approval of the first immune checkpoint inhibitor in combination with taxane chemotherapy. To further develop predictive biomarkers and improve therapeutic efficacy of the combination, interrogation of the tumor immune microenvironment before therapy as well as during each component of treatment is crucial. Here we use single-cell RNA sequencing (scRNA-seq) on tumor biopsies to assess immune cell changes from two patients with advanced TNBC treated in a prospective trial at predefined serial time points, before treatment, on taxane chemotherapy and on chemo-immunotherapy.MethodsBoth patients (one responder and one progressor) received the trial therapy, in cycle 1 nab-paclitaxel given as single agent, in cycle 2 nab-paclitaxel in combination with pembrolizumab. Tumor core biopsies were obtained at baseline, 3 weeks (after cycle 1, chemotherapy alone) and 6 weeks (after cycle 2, chemo-immunotherapy). Single-cell RNA sequencing (scRNA-seq) of both cancer cells and infiltrating immune cells isolated were performed from fresh tumor core biopsy specimens by 10 × chromium sequencing.ResultsScRNA-seq analysis showed significant baseline heterogeneity of tumor-infiltrating immune cell populations between the two patients as well as modulation of the tumor microenvironment by chemotherapy and immunotherapy. In the responding patient there was a population of PD-1high-expressing T cells which significantly decreased after nab-paclitaxel plus pembrolizumab treatment as well as a presence of tissue-resident memory T cells (TRM). In contrast, tumors from the patient with rapid disease progression showed a prevalent and persistent myeloid compartment.ConclusionsOur study provides a deep cellular analysis of on-treatment changes during chemo-immunotherapy for advanced TNBC, demonstrating not only feasibility of single-cell analyses on serial tumor biopsies but also the heterogeneity of TNBC and differences in on-treatment changes in responder versus progressor.
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Project description:Pancreatic adenocarcinoma is one of the most aggressive and lethal forms of cancer. Chemotherapy is the primary treatment for pancreatic cancer, but resistance to the drugs used remains a major challenge. A genome-wide CRISPR interference and knockout screen in the PANC-1 cell line with the drug nab-paclitaxel has identified a group of spindle assembly checkpoint (SAC) genes that enhance survival in nab-paclitaxel. Knockdown of these SAC genes (BUB1B, BUB3, and TTK) attenuates paclitaxel-induced cell death. Cells treated with the small molecule inhibitors BAY 1217389 or MPI 0479605, targeting the threonine tyrosine kinase (TTK), also enhance survival in paclitaxel. Overexpression of these SAC genes does not affect sensitivity to paclitaxel. These discoveries have helped to elucidate the mechanisms behind paclitaxel cytotoxicity. The outcomes of this investigation may pave the way for a deeper comprehension of the diverse responses of pancreatic cancer to therapies including paclitaxel. Additionally, they could facilitate the formulation of novel treatment approaches for pancreatic cancer.
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Project description:Triple negative breast cancer (TNBC) is the subtype of breast cancer most lacking in efficient treatment options. Although many TNBCs show remarkable responses to carboplatin-based chemotherapy, they often develop resistance over time. With increasing use of carboplatin in clinics, there is a pressing need to understand mechanisms causing carboplatin resistance and identify the vulnerabilities of carboplatin-resistant tumors. We generated carboplatin-resistance models based on the TNBC cell line MDA-MB-468 and patient derived xenograft (PDX) models of TNBCs. By combining the results of mass spectrometry-based proteome profiling and a kinome RNA interference screen, we assessed the molecular changes and vulnerabilities of carboplatin-resistant TNBCs. Using pharmacological inhibition of the identified targets, we validated the dependencies of carboplatin-resistant cells in vitro and in PDX models. We found that carboplatin resistance in TNBC is accompanied by drastic proteome rewiring. Carboplatin-induced metabolism alterations and upregulation of anti-oxidative response keep low levels of DNA damage and support cell replication in the presence of carboplatin. Carboplatin-resistant cells also exhibited longer mitosis due to dysregulation of mitotic checkpoint. Whereas the components of the mitotic checkpoints, AURKA and BUB1, are essential for the viability of carboplatin-resistant cells, the checkpoint kinases CHEK1 and WEE1 are indispensable for survival of carboplatin-treated resistant cells. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Abrogation of the mitotic checkpoint re-sensitizes carboplatin-resistant TNBCs to carboplatin. CHEK1 inhibition represents a potential strategy for the treatment of carboplatin-resistant TNBCs.
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