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Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab in patients with metastatic castration-resistant prostate cancer. 多酪氨酸激酶抑制剂 ESK981 联合 PD-1 抑制剂 nivolumab 治疗转移性耐阉割前列腺癌患者的 II 期试验。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-11-06 DOI: 10.1007/s10637-024-01482-8
Elisabeth I Heath, Wei Chen, Jae E Choi, Kimberlee Dobson, Melanie Smith, Tomasz Maj, Ilona Kryczek, Weiping Zou, Arul M Chinnaiyan, Yuanyuan Qiao

Increasing the response rates of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) presents a significant challenge. ESK981 is a multi-tyrosine kinase and PIKfyve lipid kinase inhibitor that augments immunotherapeutic responses. In this phase II study, ESK981 was combined with the PD-1 blocking monoclonal antibody nivolumab to test for potentially improved response rates in patients with mCRPC who have progressed on androgen receptor (AR)-targeted agents and chemotherapy. Eligible patients received ESK981 orally once daily for five consecutive days, followed by a two-day break. Patients were also treated with nivolumab intravenously on Day 1 of each 28-day cycle. The primary endpoints were a 50% reduction in prostate-specific antigen (PSA50), and safety. Secondary endpoints included radiographic progression free survival (rPFS) and overall survival (OS). Additional investigations included whole exome sequencing in patients. Ten patients were enrolled. The maximum PSA decline from baseline of 14% was achieved in only one patient. Grade 3 treatment-related adverse events (AEs) included fatigue, anemia, and lymphopenia. There were no Grade 4 events. The median rPFS was 3.7 months (95% CI, 1.6-8.4). The median OS was 9.6 months (95% CI, 1.8-22.4). The study was terminated due to futility after 10 patients. Whole exome sequencing identified AR amplification in 63% of patients (5/8). ESK981 + nivolumab showed no antitumor activity in patients with AR-positive (AR+) mCRPC. Further evaluation of ESK981 combined with the PD-1 inhibitor nivolumab in AR + mCRPC patients is not warranted. (Trial registration: ClinicalTrials.gov NCT04159896. Registration date: November 12, 2019.).

提高免疫检查点抑制剂对转移性去势抵抗性前列腺癌(mCRPC)患者的应答率是一项重大挑战。ESK981 是一种多酪氨酸激酶和 PIKfyve 脂质激酶抑制剂,可增强免疫治疗反应。在这项II期研究中,ESK981与PD-1阻断单克隆抗体nivolumab联用,以检测雄激素受体(AR)靶向药物和化疗后病情进展的mCRPC患者的应答率是否可能得到改善。符合条件的患者连续五天每天口服一次ESK981,然后休息两天。患者还在每个28天周期的第1天静脉注射nivolumab。主要终点是前列腺特异性抗原(PSA50)降低50%和安全性。次要终点包括放射学无进展生存期(rPFS)和总生存期(OS)。其他研究还包括对患者进行全外显子组测序。共有 10 名患者入组。只有一名患者达到了 PSA 从基线下降 14% 的最大值。3级治疗相关不良事件(AEs)包括疲劳、贫血和淋巴细胞减少。没有出现 4 级事件。中位 RPFS 为 3.7 个月(95% CI,1.6-8.4)。中位OS为9.6个月(95% CI,1.8-22.4)。研究在10例患者后因无效而终止。全外显子组测序发现63%的患者(5/8)存在AR扩增。在AR阳性(AR+)mCRPC患者中,ESK981 + nivolumab没有显示出抗肿瘤活性。ESK981与PD-1抑制剂nivolumab联合治疗AR+ mCRPC患者的效果不值得进一步评估。(试验注册:临床试验注册:ClinicalTrials.gov NCT04159896。注册日期:2019年11月12日)。
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引用次数: 0
Modernizing the assessment and reporting of adverse events in oncology clinical trials using complementary statistical approaches: a case study of the MOTIVATE trial. 利用互补统计方法实现肿瘤临床试验中不良事件评估和报告的现代化:MOTIVATE 试验案例研究。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-11-04 DOI: 10.1007/s10637-024-01481-9
Mathilde Morisseau, Carlos Gomez-Roca, Marie Viala, Audrey Rabeau, Delphine Loirat, Nadia Munsch, Kristell Thomas, Cécile Pages, Iphigenie Korakis, Vincent Sibaud, Jean-Pierre Delord, Thomas Filleron, Bastien Cabarrou

The reporting of adverse events (AEs) is fundamental to characterize safety profiles of novel therapeutic drug classes, however, conventional analysis strategies are suboptimal tools for this task. We therefore attempted to contribute to the modernization of AE analysis by encompassing the dimension of time, the duration and the recurrent nature of AEs induced by these extended treatment durations. This paper presents and highlights the benefits of alternative approaches to modernize AE analysis based on the MOTIVATE prospective study modeling immune-related AEs (irAEs) in patients with solid tumors (regardless of the primary site) treated with immune checkpoint inhibitor irrespective of disease stage. The probability of presenting an irAE over time was estimated using the prevalence function. The time-to-onset (TTO) and the mean number of recurrent irAEs were also assessed. Among the 147 patients analyzed, 39.7% had a melanoma, 37.7% a non-small cell lung cancer (NSCLC) and 74.8% were treated for metastatic disease. Despite a higher proportion of melanoma patients presenting at least one irAE, the prevalence of irAEs was lower in melanoma than in NSCLC patients over time. TTO analysis showed that irAEs occurred earlier in NSCLC patients whereas melanoma patients experienced more recurrent irAEs over the long-term. The prevalence function of non-metastatic and metastatic patients revealed different long-term toxicity profiles. These alternative methodologies capture different toxicity patterns (time-to-onset, recurrent, acute episodic or long-term moderate AEs) and provide a more consistent safety assessment for new therapeutics, thereby assisting clinicians and health authorities in their therapeutic decision-making processes.

不良事件(AEs)报告是描述新型治疗药物安全性特征的基础,然而,传统的分析策略并不是完成这项任务的最佳工具。因此,我们尝试将时间维度、疗程和这些延长的疗程所诱发的 AE 的复发性纳入 AE 分析,从而为 AE 分析的现代化做出贡献。本文以 MOTIVATE 前瞻性研究为基础,对接受免疫检查点抑制剂治疗的实体瘤患者(无论原发部位)(无论疾病分期)的免疫相关 AEs(irAEs)进行建模,介绍并强调了现代化 AE 分析替代方法的益处。使用流行率函数估算了随着时间推移出现irAE的概率。此外,还评估了发病时间(TTO)和复发虹膜不良反应的平均次数。在分析的147名患者中,39.7%患有黑色素瘤,37.7%患有非小细胞肺癌(NSCLC),74.8%接受了转移性疾病治疗。尽管黑色素瘤患者中出现至少一种虹膜AE的比例较高,但随着时间的推移,黑色素瘤患者的虹膜AE发生率低于非小细胞肺癌患者。TTO分析表明,NSCLC患者的虹膜AE发生较早,而黑色素瘤患者的虹膜AE长期复发率较高。非转移性和转移性患者的患病率函数显示了不同的长期毒性特征。这些替代方法捕捉到了不同的毒性模式(发病时间、复发性、急性发作性或长期中度 AEs),为新疗法提供了更一致的安全性评估,从而帮助临床医生和卫生机构做出治疗决策。
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引用次数: 0
A phase II study of ME2136 (Asenapine Maleate) plus standard antiemetic therapy for patients, including diabetic patients, receiving cisplatin-based chemotherapy. 一项关于 ME2136(马来酸阿塞那平)联合标准止吐疗法的 II 期研究,适用于接受顺铂化疗的患者,包括糖尿病患者。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-26 DOI: 10.1007/s10637-024-01480-w
Satoshi Hamauchi, Hirofumi Yasui, Tomoya Yokota, Takahiro Tsushima, Kunihiro Fushiki, Tateaki Naito, Akira Ono, Nobuhiro Kado, Yusuke Onozawa, Haruyasu Murakami, Toshiaki Takahashi, Yasuyuki Hirashima, Keita Mori, Kentaro Yamazaki

Olanzapine combined with the neurokinin-1 receptor antagonist, palonosetron and dexamethasone is the standard treatment for chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). However, the use of olanzapine poses challenges in patients with diabetes mellitus (DM) due to the potential risk of hyperglycemia. ME2136, antipsychotic similar to olanzapine, is associated with a lower risk of hyperglycemia. This study investigated the antiemetic efficacy and safety of ME2136 for HEC. This single-arm phase 2 study examined the safety and efficacy of ME2136 5 mg for 4 days in combination with triplet-combination antiemetic therapy. Two cohorts were established for the safety assessment: DM and non-DM. Eligible patients had malignant tumors and were receiving cisplatin-based chemotherapy for the first time. The primary endpoint was the complete response (CR) rate, defined as the percentage of patients without vomiting and not requiring rescue medications in the delayed phase (24-120 h). Between December 2020 and January 2022, 40 patients were enrolled, with 20 in each cohort. All patients were included in the safety analysis and 35 in the efficacy analysis. The CR rate in the delayed phase was 71.4% [60% CI 63.1-78.6%] for all patients, 66.7% in the DM cohort, and 76.5% in the non-DM cohort. No treatment-related adverse events ≥ grade 3, including hyperglycemia, were reported. ME2136, when combined with standard triplet-combination antiemetic therapy, is expected to exert similar antiemetic effects to the standard treatment for CINV due to HEC. Currently, ME2136-02 trial is underway to examine the safety and efficacy of triplet-combination antiemetic therapy and a 5-day treatment with ME2136. This study was registered with the Japan Registry of Clinical Trials (jRCT2041200071) on 10 December 2020. Clinical trial registration: This study was registered with the Japan Registry of Clinical Trials (jRCT2041200071) on 10 December 2020.

奥氮平联合神经激肽-1受体拮抗剂帕洛诺司琼和地塞米松是治疗高致吐性化疗(HEC)引起的化疗诱发恶心和呕吐(CINV)的标准疗法。然而,由于奥氮平具有潜在的高血糖风险,因此对糖尿病(DM)患者使用奥氮平会带来挑战。与奥氮平相似的抗精神病药物 ME2136 与较低的高血糖风险相关。本研究调查了 ME2136 治疗 HEC 的止吐疗效和安全性。这项单臂 2 期研究考察了 ME2136 5 毫克、4 天联合三联止吐疗法的安全性和疗效。安全性评估分为两组:DM组和非DM组。符合条件的患者均患有恶性肿瘤,并首次接受顺铂化疗。主要终点是完全应答率(CR),即在延迟期(24-120 h)内无呕吐且无需使用抢救药物的患者比例。2020 年 12 月至 2022 年 1 月期间,共有 40 名患者入组,每组 20 人。所有患者均纳入安全性分析,35 名患者纳入疗效分析。所有患者在延迟阶段的 CR 率为 71.4% [60% CI 63.1-78.6%],DM 队列为 66.7%,非 DM 队列为 76.5%。未报告≥3级的治疗相关不良事件,包括高血糖。ME2136与标准三联止吐疗法联合使用时,预计可发挥与标准治疗HEC所致CINV相似的止吐效果。目前,ME2136-02 试验正在进行中,以检验三联止吐疗法和 ME2136 5 天疗法的安全性和有效性。该研究已于 2020 年 12 月 10 日在日本临床试验注册中心注册(jRCT2041200071)。临床试验注册:本研究已于 2020 年 12 月 10 日在日本临床试验注册中心注册(jRCT2041200071)。
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引用次数: 0
Anti-ovarian cancer migration and toxicity characteristics of a platinum(IV) pro-drug with axial HDAC inhibitor ligands in zebrafish models. 铂(IV)原药与轴向 HDAC 抑制剂配体在斑马鱼模型中的抗卵巢癌迁移和毒性特征。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-21 DOI: 10.1007/s10637-024-01479-3
Salma Begum, Scheldon D Irvin, Carol K Cox, Zhouyang Huang, Justin J Wilson, Jerry D Monroe, Yann Gibert

Ovarian cancer is the fifth leading cause of cancer related death in the United States. Cisplatin is a platinum-based anti-cancer drug used against ovarian cancer that enters malignant cells and then damages DNA causing cell death. Typically, ovarian cancer cells become resistant to cisplatin making it necessary to increase subsequent dosage, which usually leads to side-effects including irreversible damage to kidney and auditory system tissue. Ovarian cancer resistance is often associated with upregulation of histone deacetylase (HDAC) enzymes that cause DNA to adopt a closed configuration which reduces the ability of cisplatin to target and damage DNA. Compound B, a platinum(IV) complex with two axial phenylbutyrate (PBA) HDAC inhibitor ligands attached to a cisplatin core, can simultaneously inhibit HDAC activity and damage DNA causing decreased cancer cell viability in cisplatin-sensitive (A2780) and -resistant (A2780cis) ovarian cancer cell lines. However, compound B was not previously evaluated in vivo. As simultaneously inhibiting HDAC-mediated resistance with cisplatin treatment could potentiate the platinum drug's effect, we first confirmed the anti-cancer effect of compound B in the A2780 and A2780cis cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide spectrophotometric assay. Then, we used zebrafish embryo and transgenic animal models to comparatively analyze the effect of cisplatin, compound B, and controls on general organismal, auditory, and renal system toxicity, and cancer metastasis. We found that lower dosages of compound B (0.3 or 0.6 µM) than of cisplatin (2.0 µM) could cause similar or decreased levels of general, auditory, and renal tissue toxicity, and at 0.6 µM, compound B reduces cancer metastasis more than 2.0 µM cisplatin.

卵巢癌是美国癌症致死的第五大原因。顺铂是一种以铂为基础的抗癌药物,用于治疗卵巢癌,它能进入恶性细胞,然后破坏 DNA,导致细胞死亡。通常情况下,卵巢癌细胞会对顺铂产生耐药性,因此必须增加后续剂量,这通常会导致副作用,包括对肾脏和听觉系统组织造成不可逆的损害。卵巢癌的耐药性通常与组蛋白去乙酰化酶(HDAC)的上调有关,HDAC 可使 DNA 采用封闭构型,从而降低顺铂靶向和损伤 DNA 的能力。化合物 B 是一种铂(IV)复合物,带有两个轴向苯丁酸(PBA)HDAC 抑制剂配体,连接在顺铂核心上,可以同时抑制 HDAC 活性和损伤 DNA,从而降低顺铂敏感(A2780)和抗性(A2780cis)卵巢癌细胞系的癌细胞活力。不过,化合物 B 以前未在体内进行过评估。由于在顺铂治疗的同时抑制 HDAC 介导的抗药性可增强铂类药物的效果,我们首先使用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四氮唑分光光度法证实了化合物 B 在 A2780 和 A2780cis 细胞系中的抗癌效果。然后,我们利用斑马鱼胚胎和转基因动物模型比较分析了顺铂、化合物 B 和对照组对一般机体、听觉和肾脏系统毒性以及癌症转移的影响。我们发现,与顺铂(2.0 µM)相比,较低剂量的化合物 B(0.3 或 0.6 µM)可引起相似或更低程度的全身、听觉和肾组织毒性,而在 0.6 µM时,化合物 B 比 2.0 µM的顺铂更能减少癌症转移。
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引用次数: 0
Unraveling the potential biomarkers of immune checkpoint inhibitors in advanced ovarian cancer: a comprehensive review. 解读免疫检查点抑制剂在晚期卵巢癌中的潜在生物标志物:综述。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-21 DOI: 10.1007/s10637-024-01478-4
Jian-Rong Na, Yaqin Liu, Kun Fang, Yuan Tan, Pan-Pan Liang, Mei Yan, Jiao-Jiao Chu, Jian-Mei Gao, Dongsheng Chen, Shu-Xiang Zhang

The ongoing research on the role of immunotherapy in advanced ovarian cancer (OC) and current clinical trials indicate that patients shown limited response to immune checkpoint inhibitor (ICI) monotherapy. When combined with other treatments or drugs, the efficacy of immunotherapy will be significantly improved. Biomarkers can be used to identify patients with better responses, thereby improving the precision and efficacy of immunotherapy. Key biomarkers for advanced OC include homologous repair deficiency, programmed death-ligand (PD-L) 1 expression, chemokines, and tumor infiltrating lymphocytes. These biomarkers could be applied in the future to select the most suitable patient populations. This review comprehensively examines the research and development of biomarkers in OC immunotherapy from three omics perspectives: genomics, transcriptomics, and proteomics, which may provide guidance for the effectiveness of OC immunotherapy strategies.

关于免疫疗法在晚期卵巢癌(OC)中作用的持续研究和目前的临床试验表明,患者对免疫检查点抑制剂(ICI)单一疗法的反应有限。如果与其他治疗方法或药物联合使用,免疫疗法的疗效将显著提高。生物标志物可用于识别反应较好的患者,从而提高免疫疗法的精准度和疗效。晚期卵巢癌的主要生物标志物包括同源修复缺陷、程序性死亡配体(PD-L)1 表达、趋化因子和肿瘤浸润淋巴细胞。这些生物标志物将来可用于选择最适合的患者群体。本综述从基因组学、转录组学和蛋白质组学这三个omics角度全面探讨了OC免疫疗法中生物标记物的研究与开发,这些标记物可为OC免疫疗法策略的有效性提供指导。
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引用次数: 0
Exposure-response relationships of venetoclax in combination with carfilzomib and dexamethasone in relapsed/refractory t(11;14) multiple myeloma patients. Venetoclax与卡非佐米和地塞米松联合治疗复发/难治性t(11;14)多发性骨髓瘤患者的暴露-反应关系。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-10 DOI: 10.1007/s10637-024-01471-x
Mohamed Ali Badawi, Benjamin Engelhardt, Edyta Dobkowska, Rong Deng, Jonathan L Kaufman, Rajeev Menon, Ahmed Hamed Salem

Venetoclax is a first in class BCL-2 inhibitor, currently under investigation for the treatment of t(11;14) multiple myeloma (MM). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships of venetoclax when combined with carfilzomib and dexamethasone (VenKd) in t(11;14)-positive relapsed or refractory (R/R) MM patients from a phase 2 study. Fifty-seven patients receiving VenKd or Kd were included in the analysis. Efficacy endpoints included progression-free survival and clinical response rates of overall response, very good partial response or better and complete response or better. Grade ≥ 3 neutropenia, Grade ≥ 3 infections, Grade ≥ 3 treatment-emergent adverse events and any grade serious treatment-emergent adverse events were evaluated. The analysis demonstrated that adding venetoclax to Kd resulted in increased ORR, ≥VGPR and ≥ CR rates compared to the control arm. Within the venetoclax treatment arms (VenKd), no significant exposure-efficacy relationships were observed for ORR and ≥ VGPR rates. Higher ≥ CR rates trended with higher venetoclax exposures. While both 400 mg and 800 mg venetoclax in VenKd arms were generally tolerated, higher rates of Grade ≥ 3 neutropenia were observed with higher venetoclax exposures. Higher venetoclax exposures however were not associated with increased rates of Grade ≥ 3 treatment-emergent adverse events, Grade ≥ 3 infections, or serious treatment-emergent adverse events (any grade). These results confirm the benefit of adding venetoclax to carfilzomib and dexamethasone and support continued evaluation of venetoclax 400-800 mg once daily in this combination in t(11;14)-positive R/R MM patients. NCT02899052 registered April 18, 2017.

Venetoclax是首款BCL-2抑制剂,目前正在研究用于治疗t(11;14)多发性骨髓瘤(MM)。这项分析的目的是描述Venetoclax与卡非佐米和地塞米松(VenKd)联合治疗t(11;14)阳性复发或难治性(R/R)MM患者的暴露-疗效关系和暴露-安全性关系。57名接受VenKd或Kd治疗的患者被纳入分析。疗效终点包括无进展生存期和总体反应、很好的部分反应或更好的临床反应率以及完全反应或更好的临床反应率。对≥3级中性粒细胞减少、≥3级感染、≥3级治疗突发不良事件和任何级别的严重治疗突发不良事件进行了评估。分析表明,与对照组相比,在Kd中加入venetoclax可提高ORR、≥VGPR和≥CR率。在 Venetoclax 治疗组(VenKd)中,未观察到 ORR 和≥VGPR 率有显著的暴露-疗效关系。Venetoclax暴露量越高,≥CR率越高。虽然VenKd治疗组中400毫克和800毫克的venetoclax一般都能耐受,但venetoclax暴露量越高,≥3级中性粒细胞减少率越高。然而,较高的 Venetoclax 暴露与≥ 3 级治疗突发不良事件、≥ 3 级感染或严重治疗突发不良事件(任何级别)发生率的增加无关。这些结果证实了在卡非佐米和地塞米松基础上加用venetoclax的益处,并支持继续评估在t(11;14)阳性R/R MM患者中每日一次联合应用venetoclax 400-800毫克的效果。NCT02899052于2017年4月18日注册。
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引用次数: 0
Predictive value of ZFHX4 mutation for the efficacy of immune checkpoint inhibitors in non-small cell lung cancer and melanoma. ZFHX4突变对免疫检查点抑制剂在非小细胞肺癌和黑色素瘤中疗效的预测价值。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-05 DOI: 10.1007/s10637-024-01477-5
Cong Fu, Haoran Gu, Lin Sun, Zhouyu Wang, Qin Zhang, Ningning Luo, Dongsheng Chen, Tong Zhou

Studies have shown that the Zinc finger homeobox 4 (ZFHX4) might be a factor in the prognosis of malignancies. However, little is known about the association between the ZFHX4 mutation and the effectiveness of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and melanoma. Three public ICIs-treated NSCLC cohorts were divided into discovery cohort (n=75) and validation cohort (n=62), which were used to evaluate the relationship between ZFHX4 mutation and ICIs effectiveness in NSCLC. Seven ICIs-treated melanoma cohorts (n = 418) were used to analyze the relationship between ZFHX4 mutation and immunotherapy efficacy in melanoma. NSCLC and skin cutaneous melanoma (SKCM) cohorts from The Cancer Genome Atlas (TCGA) were used to investigate underlying mechanism. Patients with ZFHX4 mutant-type (ZFHX4-Mut) showed a superior objective response rate (ORR) (P < 0.01) and longer progression-free survival (PFS) (P < 0.05) than patients with ZFHX4 wild-type (ZFHX4-WT) in NSCLC cohorts. In the melanoma cohorts, patients carrying ZFHX4-Mut had a higher ORR (P = 0.042) and longer overall survival (OS) (P = 0.011). Besides, patients with NSCLC and melanoma harboring ZFHX4-Mut had a higher tumor mutation burden (TMB) (P<0.001) and tumor neoantigen burden (TNB) (P<0.001) than those harboring ZFHX4-WT. ZFHX4 mutation was associated with higher levels of plasma B cells, activated CD4+ memory T cells, and CD8+ T cells. Seven DNA damage repair pathways were significantly enriched in the ZFHX4-Mut group. ZFHX4 mutation could serve as a predicter for the efficacy of ICIs therapy in NSCLC and melanoma.

研究表明,锌指同源染色体 4(ZFHX4)可能是影响恶性肿瘤预后的一个因素。然而,人们对ZFHX4突变与免疫检查点抑制剂(ICIs)在非小细胞肺癌(NSCLC)和黑色素瘤中的疗效之间的关系知之甚少。三个公开的ICIs治疗NSCLC队列分为发现队列(75人)和验证队列(62人),用于评估ZFHX4突变与ICIs在NSCLC中疗效的关系。7个经ICIs治疗的黑色素瘤队列(n=418)用于分析ZFHX4突变与黑色素瘤免疫疗法疗效之间的关系。癌症基因组图谱(TCGA)中的NSCLC和皮肤黑色素瘤(SKCM)队列被用来研究其潜在机制。在NSCLC队列中,ZFHX4突变型(ZFHX4-Mut)患者的客观反应率(ORR)(P<0.01)和无进展生存期(PFS)(P<0.05)均优于ZFHX4野生型(ZFHX4-WT)患者。在黑色素瘤队列中,携带ZFHX4-突变型的患者有更高的ORR(P = 0.042)和更长的总生存期(OS)(P = 0.011)。此外,携带ZFHX4-突变基因的非小细胞肺癌和黑色素瘤患者的肿瘤突变负荷(TMB)较高(P = 0.011)。
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引用次数: 0
Clinical research progress of fruquintinib in the treatment of malignant tumors. 夫鲁喹替尼治疗恶性肿瘤的临床研究进展。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-01 DOI: 10.1007/s10637-024-01476-6
Shihao Zhao, Wenhui Wang, Jingyi Li, Zhigang Li, Zhanbo Liu, Shunchao Zhang, Zhaoqi Chen, Hongling Wang, Xiangqi Wang, Juntao Wang

Malignant tumors represent an important cause of mortality within the global population. Tumor angiogenesis, recognized as one of the key hallmarks of malignant tumors, is crucial for supplying essential nutrients and oxygen for tumor growth. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are key drivers of tumor angiogenesis. Targeted therapeutic interventions not only effectively inhibit tumor growth by specifically blocking tumor angiogenesis but have also made breakthroughs in the treatment of malignant tumors. Fruquintinib, an anti-angiogenic small molecule drug developed independently in China, functions as a potent tyrosine kinase inhibitor with high selectivity. It effectively curtails tumor growth by binding to and inhibiting VEGFR-1, VEGFR-2, and VEGFR-3. Additionally, fruquintinib offers several advantages including minimal off-target toxicity, robust resistance profiles, and commendable efficacy. This agent can be used alone or in combination with other treatments. It has shown high effectiveness and survival benefits across various malignant tumors such as colorectal cancer, gastric cancer, non-small cell lung cancer, breast cancer, and other malignant tumors. Therefore, this article conducts a systematic review encompassing the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib. Through this review, we aimed to offer a reference for the clinical application and subsequent development of fruquintinib.

恶性肿瘤是导致全球人口死亡的一个重要原因。肿瘤血管生成被认为是恶性肿瘤的主要特征之一,对于为肿瘤生长提供必需的营养物质和氧气至关重要。血管内皮生长因子(VEGF)及其受体(VEGFR)是肿瘤血管生成的关键驱动因素。靶向治疗干预不仅通过特异性阻断肿瘤血管生成来有效抑制肿瘤生长,而且在治疗恶性肿瘤方面也取得了突破性进展。我国自主研发的抗血管生成小分子药物福罗替尼是一种强效酪氨酸激酶抑制剂,具有高选择性。它通过与血管内皮生长因子受体(VEGFR-1)、血管内皮生长因子受体(VEGFR-2)和血管内皮生长因子受体(VEGFR-3)结合并抑制它们,从而有效抑制肿瘤生长。此外,fruquintinib 还具有多种优势,包括最小的脱靶毒性、强大的耐药性特征和值得称赞的疗效。这种药物可单独使用,也可与其他疗法联合使用。它在结直肠癌、胃癌、非小细胞肺癌、乳腺癌等各种恶性肿瘤中显示出较高的有效性和生存率。因此,本文对fruquintinib的作用机制、药代动力学、临床疗效和安全性进行了系统综述。通过综述,我们希望为fruquintinib的临床应用和后续开发提供参考。
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引用次数: 0
Gremlin1: a BMP antagonist with therapeutic potential in Oncology. Gremlin1:一种具有肿瘤治疗潜力的 BMP 拮抗剂。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-09-30 DOI: 10.1007/s10637-024-01474-8
Zhao Jin, Yanshuo Cao

Gremlins, originating from early 20th-century Western folklore, are mythical creatures known for causing mechanical malfunctions and electronic failures, aptly dubbed "little devils". Analogously, GREM1 acts like a horde of these mischievous entities by antagonizing the bone morphogenetic protein (BMP signaling) pathway or through other non-BMP dependent mechanisms (such as binding to Fibroblast Growth Factor Receptor 1and Epidermal Growth Factor Receptor) contributing to the malignant progression of various cancers. The overexpression of GREM1 promotes tumor cell growth and survival, enhances angiogenesis within the tumor microenvironment, and creates favorable conditions for tumor development and dissemination. Consequently, inhibiting the activity of GREM1 or blocking its interaction with BMP presents a promising strategy for suppressing tumor growth and metastasis. However, the role of GREM1 in cancer remains a subject of debate, with evidence suggesting both oncogenic and tumor-suppressive functions. Currently, several pharmaceutical companies are researching the GREM1 target, with some advancing to Phase I/II clinical trials. This article will provide a detailed overview of the GREM1 target and explore its potential role in cancer therapy.

小精灵(Gremlins)起源于 20 世纪早期的西方民间传说,是一种以造成机械故障和电子故障而闻名的神话生物,被戏称为 "小恶魔"。类似地,GREM1 就像这些调皮捣蛋的小精灵一样,通过拮抗骨形态发生蛋白(BMP)信号通路,或通过其他非 BMP 依赖性机制(如与成纤维细胞生长因子受体 1 和表皮生长因子受体结合),导致各种癌症的恶性发展。GREM1 的过度表达会促进肿瘤细胞的生长和存活,增强肿瘤微环境中的血管生成,为肿瘤的发展和扩散创造有利条件。因此,抑制 GREM1 的活性或阻断其与 BMP 的相互作用是抑制肿瘤生长和转移的有效策略。然而,GREM1 在癌症中的作用仍存在争议,有证据表明它具有致癌和抑制肿瘤的功能。目前,多家制药公司正在研究 GREM1 靶点,其中一些已进入 I/II 期临床试验阶段。本文将详细介绍 GREM1 靶点,并探讨其在癌症治疗中的潜在作用。
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引用次数: 0
Targeting MDM2-mediated suppression of p53 with idasanutlin: a promising therapeutic approach for acute lymphoblastic leukemia. 用idasanutlin靶向MDM2介导的p53抑制:一种治疗急性淋巴细胞白血病的前景看好的方法。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-09-21 DOI: 10.1007/s10637-024-01473-9
Seyda Gungordu, Erhan Aptullahoglu

Despite available treatments for acute lymphoblastic leukemia (ALL), the disease's high clinical variability necessitates new therapeutic strategies, particularly for patients with high-risk features. The tumor suppressor protein p53, encoded by the TP53 gene and known as the guardian of the genome, plays a crucial role in preventing tumor development. Over 90% of ALL cases initially harbor wild-type TP53. Reactivation of p53, which is encoded from the wild type TP53 but lost its function for several reasons, is an attractive therapeutic approach in cancer treatment. p53 can be activated in a non-genotoxic manner by targeting its primary repressor, the MDM2 protein. Clinical trials involving MDM2 inhibitors are currently being conducted in a growing body of investigation, reflecting of the interest in incorporating these treatments into cancer treatment strategies. Early-phase clinical trials have demonstrated the promise of idasanutlin (RG7388), one of the developed compounds. It is a second-generation MDM2-p53 binding antagonist with enhanced potency, selectivity, and bioavailability. The aim of this study is to evaluate the efficacy of RG7388 as a therapeutic strategy for ALL and to investigate its potential impact on improving treatment outcomes for high-risk patients. RG7388 potently decreased the viability in five out of six ALL cell lines with diverse TP53 mutation profiles, whereas only one cell line exhibited high resistance. RG7388 induced a pro-apoptotic gene expression signature with upregulation of p53-target genes involved in the intrinsic and extrinsic pathways of apoptosis. Consequently, RG7388 led to a concentration-dependent increase in caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase. In this research, RG7388 was investigated with pre-clinical methods in ALL cells as a novel treatment strategy. This study suggests further functional research and in-vivo evaluation, and it highlights the prospect of treating p53-functional ALL with MDM2 inhibitors.

尽管目前已有治疗急性淋巴细胞白血病(ALL)的方法,但这种疾病的临床变异性很大,因此需要新的治疗策略,尤其是针对具有高危特征的患者。肿瘤抑制蛋白 p53 由 TP53 基因编码,被称为基因组的守护者,在防止肿瘤发生方面发挥着至关重要的作用。90%以上的 ALL 病例最初都携带野生型 TP53。p53 由野生型 TP53 编码,但由于多种原因失去了其功能,重新激活 p53 是治疗癌症的一种有吸引力的方法。目前正在进行的涉及 MDM2 抑制剂的临床试验越来越多,反映了人们对将这些治疗方法纳入癌症治疗策略的兴趣。早期临床试验已经证明了开发的化合物之一 idasanutlin(RG7388)的前景。它是第二代 MDM2-p53 结合拮抗剂,具有更强的效力、选择性和生物利用度。本研究旨在评估 RG7388 作为 ALL 治疗策略的疗效,并探讨其对改善高危患者治疗效果的潜在影响。在六种具有不同TP53突变特征的ALL细胞系中,RG7388能有效降低其中五种细胞系的存活率,而只有一种细胞系表现出高度耐药性。RG7388 诱导了一种促凋亡基因表达特征,上调了参与细胞凋亡内在和外在途径的 p53 靶基因。因此,RG7388 会导致 caspase-3/7 活性和裂解聚(ADP-核糖)聚合酶的浓度依赖性增加。本研究采用临床前方法对 RG7388 作为一种新型治疗策略在 ALL 细胞中进行了研究。本研究建议进一步开展功能研究和体内评估,并强调了用MDM2抑制剂治疗p53功能性ALL的前景。
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引用次数: 0
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