Shikonin is a naphthoquinone isolated from the traditional Chinese medicine Lithospermum. It has been used in the treatment of various tumors. However, the effects of shikonin on such diseases have not been fully elucidated. In the present study, we detected the exosome release of a breast cancer cell line (MCF-7) with shikonin treatment and found a positive relationship between the level of secreted exosomes and cell proliferation. We next analyzed miRNA profiles in MCF-7 cells and exosomes and found that some miRNAs are specifically sorted and abundant in exosomes. Knockdown of the most abundant miRNAs in exosomes and the MCF-7 proliferation assay showed that miR-128 in exosomes negatively regulates the level of Bax in MCF-7 recipient cells and inhibits cell proliferation. These results show that shikonin inhibits the proliferation of MCF-7 cells through reducing tumor-derived exosomal miR-128. The current study suggests that shikonin suppresses MCF-7 growth by the inhibition of exosome release.
e21071 Background: Furmonertinib (AST2818) is a selective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which can irreversibly inhibit both EGFR sensitizing and T790M resistant mutations. However, like other EGFR-TKIs, progression is still unavoidable when treated with furmonertinib. Methods: In a multi-center, single-arm phase IIb study (NCT03452592), non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation received furmonertinib 80mg/d treatment until disease progression, death or treatment cessations for other reasons. This is a post-hoc analysis of the progression pattern and post-progression treatment. Results: A total of 220 patients were enrolled in this study. At baseline, 105 (48%) patients had central nervous system (CNS) metastases, 84 (38%) were EGFR L858R mutated and 9 (4%) were ECOG performance status 2. At data cut-off (December 31, 2020), 179 out of 220 (81%) patients had progressed assessed by investigators (patients who died before assessed as progression were excluded). The most frequent progression site was lung (n = 106，48%), followed by CNS (n = 33, 15%), lymph node (n = 22, 10%), liver (n = 20, 9%) and bone (n = 16, 7%). CNS progression rate were 3%, 8%, 13% and 15% at 3, 6, 12 and 18 months, respectively. After progression, 52% (93/179) patients continued furmonertinib monotherapy based on the judgement of continuous benefit by investigators which was permitted in the protocol. The median post-progression treatment time of furmonertinib was 3.02 months (range 0.03-18.27). Overall, 48% (86/179) patients discontinued furmonertinib and later-line treatments were decided by investigators. The post-progression survival (PPS) was 17.3 months in the furmonertinib-continued group and 12.4 months in the furmonertinib-not-continued group (HR 0.57 [95%CI 0.40-0.80], p = 0.0048). Conclusions: Although about half patients had CNS metastases at baseline, CNS progression rate was relatively low in this study. Post-progression continuous treatment of furmonertinib monotherapy might still bring survival benefit to certain NSCLC patients with EGFR T790M mutation which need further exploration. Clinical trial information: NCT03452592.
Abstract Background: In the primary analysis of RATIONALE-304 (NCT03663205), TIS + platinum-based chemo significantly improved clinical outcomes over chemo alone in treatment-naïve advanced nsq-NSCLC (median progression-free survival [PFS] by IRC [9.7 vs 7.6 months, HR=0.645, p=0.0044]). Here we report biomarker analysis of baseline tissue and blood TMB (tTMB and bTMB, respectively). Methods: Patients with nsq-NSCLC were randomized 2:1 to TIS + platinum + pemetrexed or platinum + pemetrexed. TMB scores were evaluated on baseline tumor and blood samples by OncoScreen Plus®. The Spearman’s rank correlation of tTMB with bTMB was assessed. PFS by independent review committee (primary endpoint) was assessed within subgroups defined by TMB status, using a Cox proportional hazard model with disease stage and programmed death-ligand 1 (PD-L1) expression as stratification factors. Interaction p-values < 0.05 were considered statistically significant without multiplicity adjustment. Results: Of 325 patients treated in RATIONALE-304, without an EGFR sensitizing mutation, 177 (54.5%) had evaluable tTMB and 107 (32.9%) had evaluable bTMB. Median tTMB and bTMB were 7.2 and 3.1 mut/Mb, respectively. There was a modest correlation between tTMB and bTMB (r=0.71, p < 0.001). Prolonged PFS benefit of adding TIS to chemo was oberved in patients with TMB-high status compared with TMB-low status (Table). Interaction analysis showed that neither tTMB nor bTMB significantly differentiated treatment-specific PFS benefit (interaction p-values > 0.05; Table). Conclusions: In this retrospective analysis, neither tTMB nor bTMB was significantly associated with PFS benefit, suggesting limited clinical utility of tTMB and bTMB in the setting of TIS + chemo as first-line therapy for advanced nsq-NSCLC. Association of TMB with PFS benefit of TIS + chemo vs chemo tTMB bTMB Cutoffs mut/Mb N HR (95% CI) Interaction Cutoffs mut/Mb N HR (95% CI) Interaction p-value p-value BEP 177 0.76 (0.46, 1.25) NA BEP 107 0.48 (0.26, 0.87) NA ≥ 8 (TMB-high) 80 0.52 (0.25, 1.10) 0.208 ≥ 4 (TMB-high) 47 0.30 (0.12, 0.75) 0.212 < 8 (TMB-low) 97 0.98 (0.51, 1.88) < 4 (TMB-low) 60 0.64 (0.29, 1.39) BEP, biomarker evaluable population; bTMB, blood tumor mutational burden; CI, confidence interval; HR, hazard ratio; Mb, megabase; mut, mutation; NA, not applicable; PFS, progression-free survival; TIS, tislelizumab; TMB, tumor mutational burden; tTMB, tissue tumor mutational burden Citation Format: Shun Lu, Meili Sun, Yunpeng Liu, Yanping Hu, Yanyan Xie, Zhehai Wang, Dong Wang, Zhenzhou Yang, Liang Liang, Yi Huo, Yun Zhang, Ruiqi Huang, Yang Shi, Zhirong Shen, Yan Yu. RATIONALE-304: The association of tumor mutational burden (TMB) with clinical outcomes of tislelizumab (TIS) + chemotherapy (chemo) versus chemo alone as first-line treatment for advanced non-squamous non-small cell lung cancer (nsq-NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB512.
Programmable DNA nanostructure self-assembly offers great potentials in nanomedicine, drug delivery, biosensing, and bioimaging. However, due to the intrinsically negatively charged DNA backbones, the instability of DNA nanostructures in physiological settings poses serious challenges to their practical applications. To overcome this challenge, a strategy that combines the magnesium-free DNA self-assembly and functionalization is proposed in this study. We hypothesize that naturally abundant spermidine may not only mediate the self-assembly of DNA nanostructures, but also shield them from harsh physiological environments. As a proof of concept, a DNA nanoprism is designed and synthesized successfully through spermidine. It is found that spermidine can mediate the isothermal self-assembly of DNA nanoprisms. Compared to conventional Mg2+-assembled DNA nanostructures, the spermidine-DNA nanoprism complex shows higher thermal stability and better enzymatic resistance than Mg2+-assembled DNA nanoprisms, and more importantly, it has a much higher cellular uptake efficacy in multiple cancerous cell lines. The internalization mechanism is identified as clathrin-mediated endocytosis. To demonstrate the suitability of this new nanomaterial for biomedical applications, an mTOR siRNA, after being conjugated into the complex, is efficiently delivered into cancer cells and shows excellent gene knockdown efficacy and anticancer capability. These findings indicate that the spermidine-DNA complex nanomaterials might be a promising platform for biomedical applications in the future.
Non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) have been found as subjects of poor prognosis. Whole-brain radiotherapy (WBRT), surgery, and stereotactic radiosurgery, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), or some combinations are the most commonly employed strategies for the treatment of treatments BMs. However, some patients are resistant to all these treatments.We present an NSCLC patient with progression of BMs after treatment with WBRT and EGFR-TKIs. The patient was diagnosed with multiple metastases on July 9, 2014, and treated with docetaxel plus cisplatin chemotherapy followed with gefitinib as the maintenance therapy. The patient showed recurrence of BMs after 8-months of chemotherapy. WBRT with 30 Gy was administrated in 10 fractions. Tumor progression of the brain was diagnosed with an magnetic resonance imaging scan after 2-months of WBRT.The patient was diagnosed as pulmonary adenocarcinoma with diffuse metastases in both lungs and multiple metastases in bone and brain. Progression of BMs was confirmed through magnetic resonance imaging.This patient was administered temozolomide (150 mg/m2/d for 5 days every 28-day cycle). As a whole, 6 cycles were performed after the progression of BMs from August 2015.The patient got complete brain remission and lived without discomfort. The intracranial lesion did not progress until the progression of the lung lesion and led to death on February 20, 2019. The intracranial progression-free survival was 42 months, whereas the overall survival was 55 months.For patients with NSCLC and BMs, temozolomide can be used as a treatment option, especially in patients with EGFR-TKIs resistance or without driver mutations.
513 Background: Colorectal cancer (CRC) is the third most frequently diagnosed cancer and is the fifth leading cause of cancer death in China. No standard care is available for patients with advanced CRC who failed the second-line treatment. Famitinib is a small-molecular, multi-target receptor tyrosine kinase inhibitor which primarily acts against angiogenesis. This phase II study was designed to evaluate the efficacy and safety of famitinib in the treatment of advanced colorectal cancer. Methods: This is a multi-center, randomized, double-blind, placebo-controlled, phase II clinical study (ClinicalTrials.gov Registration No.: NCT01762293). Totally 154 patients with advanced colorectal cancer who failed second or later-line treatments were randomized in a 2:1 ratio to receive either famitinib or placebo at 25 mg each day in each treatment cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints include overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and safety. The statistical analyses of endpoints were using intent-to-treat population. Results: Of 154 patients randomized, the mPFS was 2.8 and 1.5 months in the treatment group and control group, respectively (p=0.0034; HR=0.58). The ORR was 2.02% and 0.00% (p=0.54) and the DCR was 57.58% and 30.91% (p=0.0023) in the treatment group and control group, respectively. Analysis of OS data is ongoing. The frequently reported adverse events (AEs) include neutropenia, thrombocytopenia, hypertension, proteinuria, and hand-foot syndrome and were most grade 1/2. The incidences of serious adverse events (SAEs) for the famitinib and placebo groups were 11.11% and 9.09%, respectively (p=0.7884). Overall, famitinib was well tolerated and toxicities were manageable. Conclusions: Famitinib improved the PFS in patients with advanced metastatic colorectal cancer resulting in higher ORR and DCR in the treatment group with good safety and tolerability. Clinical trial information: NCT01762293.
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