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Retraction Note: The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells. 撤稿说明:驱动蛋白 Eg5 抑制剂 K858 在诱导乳腺癌细胞凋亡的同时也诱导了与存活素相关的化疗抗性。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-01 DOI: 10.1007/s10637-024-01469-5
Francesca De Iuliis, Ludovica Taglieri, Gerardo Salerno, Anna Giuffrida, Bernardina Milana, Sabrina Giantulli, Simone Carradori, Ida Silvestri, Susanna Scarpa
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引用次数: 0
Phase II trial of multi-kinase inhibitor ESK981 in patients with metastatic castration-resistant prostate cancer. 多激酶抑制剂 ESK981 在转移性耐阉割前列腺癌患者中的 II 期试验。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-09-03 DOI: 10.1007/s10637-024-01463-x
Elisabeth I Heath, Wei Chen, Lance Heilbrun, Jae E Choi, Kimberlee Dobson, Melanie Smith, Tomasz Maj, Ulka Vaishampayan, Ilona Kryczek, Weiping Zou, Arul M Chinnaiyan, Yuanyuan Qiao

ESK981 is a potent tyrosine kinase and PIKfyve lipid kinase inhibitor. This phase II trial evaluated the efficacy of ESK981 as a single agent in patients with androgen receptor-positive (AR +) metastatic castration-resistant prostate cancer (mCRPC). Eligible patients had mCRPC with progression on AR-targeted agents and without prior chemotherapy treatment. Each patient received 160 mg ESK981 once daily for 5 days per week for 4 weeks per cycle (except for an adverse event (AE) occurrence). The primary endpoints were a 50% reduction in prostate-specific antigen (PSA50), and safety. Secondary endpoints included the time and the duration of PSA response, PSA progression rates, PSA progression free survival (PFS) and overall survival (OS). Exploratory investigations included whole exome sequencing in patients before treatment, and morphological evaluation of biopsy samples pre- and post-treatment. PSA was evaluated in 13 patients. Only one patient (7.7% two-sided 95% Wilson CI (0.4%, 33.3%)) experienced a reduction in their PSA levels by 50% or more. The most common grade 3 treatment-related AEs were cardiac disorders, diarrhea, hypertension, alanine transaminase and aspartate transaminase elevations. No grade 4-5 events occurred. Median PFS was 1.8 months, and median OS was 12.1 months. Peripheral immune cells showed increased T cell activation and cytokine production in two patients who received 12-weeks of ESK981. Although relatively well tolerated, ESK981 alone showed no anti-tumor activity in patients with AR + mCRPC and its further evaluation as a single agent in AR + mCRPC is not warranted. (Trial registration: ClinicalTrials.gov, NCT03456804. Registration date: March 7, 2018).

ESK981 是一种强效的酪氨酸激酶和 PIKfyve 脂质激酶抑制剂。这项II期试验评估了ESK981单药治疗雄激素受体阳性(AR+)转移性耐受性前列腺癌(mCRPC)患者的疗效。符合条件的mCRPC患者在使用AR靶向药物后病情有所进展,且之前未接受过化疗。每位患者接受 160 毫克 ESK981 治疗,每天一次,每周 5 天,每个周期 4 周(发生不良事件 (AE) 的情况除外)。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 PSA 反应时间和持续时间、PSA 进展率、PSA 无进展生存期(PFS)和总生存期(OS)。探索性研究包括患者治疗前的全外显子组测序,以及治疗前后活检样本的形态学评估。对13名患者进行了PSA评估。只有一名患者(7.7%,双侧 95% Wilson CI (0.4%, 33.3%))的 PSA 水平下降了 50% 或更多。最常见的 3 级治疗相关不良反应是心脏功能紊乱、腹泻、高血压、丙氨酸转氨酶和天冬氨酸转氨酶升高。没有发生 4-5 级事件。中位PFS为1.8个月,中位OS为12.1个月。在接受12周ESK981治疗的两名患者中,外周免疫细胞显示T细胞活化和细胞因子分泌增加。尽管ESK981的耐受性相对较好,但在AR + mCRPC患者中单独使用ESK981没有显示出抗肿瘤活性,因此没有必要将其作为AR + mCRPC的单药进行进一步评估。(试验注册:试验注册:ClinicalTrials.gov,NCT03456804。注册日期:2018年3月7日)。
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引用次数: 0
A randomized phase 1 study of safety, tolerability, and pharmacokinetics of MK-1088, a novel dual adenosine receptor antagonist, in healthy adult participants. 一项关于新型双重腺苷受体拮抗剂 MK-1088 在健康成年参与者中的安全性、耐受性和药代动力学的 1 期随机研究。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-10 DOI: 10.1007/s10637-024-01462-y
Pranav Gupta, Manash Chatterjee, Yeonil Kim, Kathleen Deschamps, Lieselotte Lemoine, Kristien Van Dyck, Catherine Zhou Matthews, Sylvie Rottey, Aubrey Stoch, Eseng Lai

This phase 1 first-in-human study evaluated the safety, tolerability, and pharmacokinetics of MK-1088, a novel, small-molecule dual inhibitor of adenosine A2A and A2B receptors. Healthy adult participants were enrolled in two panels (n = 8 each) and randomly assigned to receive MK-1088 (n = 6) or placebo (n = 2) orally in each of five treatment periods. Participants in panel A received single ascending doses of MK-1088 at 1, 10, 50, and 150 mg or placebo in a fasted or fed (50 mg only) state. Participants in panel B received MK-1088 at 3, 25, 100, and 224 mg or placebo in a fasted state. Primary objectives were to evaluate safety, tolerability, and plasma pharmacokinetics following a single dose of MK-1088. The secondary objective was to evaluate the effects of a high-fat meal on pharmacokinetics. All participants (n = 16) completed the study (median age: 33 years [range: 20-43]; all were male). Treatment-related adverse events (AEs) occurred in 1 of 6 (17%), 4 of 6 (67%), 4 of 6 (67%), and 2 of 6 (33%) participants after receiving MK-1088 at 3, 25, 100, and 224 mg, respectively. No serious AEs or deaths due to any cause occurred. MK-1088 was rapidly absorbed after a single dose; half-life was ~ 11 h in the 100-224 mg dose range. The target concentration at 12 h (> 0.3 µM) was exceeded at the 50-mg dose level. MK-1088 plasma pharmacokinetics increased dose proportionately. A high-fat meal did not significantly affect pharmacokinetics at the 50-mg dose. MK-1088 was well tolerated and demonstrated dose-proportional pharmacokinetic properties that were not affected by a high-fat meal.

这项1期首次人体试验评估了MK-1088的安全性、耐受性和药代动力学,MK-1088是一种新型小分子腺苷A2A和A2B受体双重抑制剂。健康的成年参与者被分为两个小组(每组 8 人),随机分配在五个疗程中的每个疗程口服 MK-1088(6 人)或安慰剂(2 人)。小组 A 的参与者在空腹或进食(仅 50 毫克)状态下接受单次递增剂量 1、10、50 和 150 毫克的 MK-1088 或安慰剂。B 组参与者在禁食状态下接受 3、25、100 和 224 毫克剂量的 MK-1088 或安慰剂。首要目标是评估单剂量服用 MK-1088 后的安全性、耐受性和血浆药代动力学。次要目标是评估高脂餐对药代动力学的影响。所有参与者(n = 16)均完成了研究(中位年龄:33 岁 [范围:20-43];均为男性)。接受 3 毫克、25 毫克、100 毫克和 224 毫克剂量的 MK-1088 后,6 位参与者中分别有 1 位(17%)、4 位(67%)、4 位(67%)和 2 位(33%)发生了与治疗相关的不良事件(AEs)。没有发生任何严重的AE或死亡病例。单次服用 MK-1088 后吸收迅速;在 100-224 毫克剂量范围内,半衰期约为 11 小时。50 毫克剂量水平在 12 小时内超过了目标浓度(> 0.3 µM)。MK-1088 的血浆药代动力学与剂量成正比。50 毫克剂量时,高脂餐对药代动力学无明显影响。MK-1088 的耐受性良好,其药代动力学特性与剂量成正比,不受高脂餐的影响。
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引用次数: 0
Depth of response and treatment outcomes of immune checkpoint inhibitor-based therapy in patients with advanced non-small cell lung cancer and high PD-L1 expression: An exploratory analysis of retrospective multicenter cohort. 以免疫检查点抑制剂为基础的疗法对PD-L1高表达的晚期非小细胞肺癌患者的反应深度和治疗效果:回顾性多中心队列的探索性分析。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-21 DOI: 10.1007/s10637-024-01467-7
Yusuke Tachibana, Kenji Morimoto, Tadaaki Yamada, Hayato Kawachi, Motohiro Tamiya, Yoshiki Negi, Yasuhiro Goto, Akira Nakao, Shinsuke Shiotsu, Keiko Tanimura, Takayuki Takeda, Asuka Okada, Taishi Harada, Koji Date, Yusuke Chihara, Isao Hasegawa, Nobuyo Tamiya, Yuki Katayama, Naoya Nishioka, Masahiro Iwasaku, Shinsaku Tokuda, Takashi Kijima, Koichi Takayama

The association between depth of response (DpR) and treatment outcomes has been documented across various types of cancer. Immune checkpoint inhibitor (ICI)-based treatment is globally used as first-line treatment for non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression ≥ 50%. However, in this population, the significance of DpR is not elucidated. Patients with advanced NSCLC and PD-L1 expression ≥ 50% who received ICI-monotherapy or ICI plus chemotherapy were retrospectively enrolled into this study. Treatment responses were grouped into DpR 'quartiles' by percentage of maximal tumor reduction (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, and Q4 =  ≥ 76%), and no tumor reduction (NTR). The association between DpR and survival rates were determined using hazard ratios (HR) generated by the Cox proportional hazards model. The Kaplan-Meier method was used to determine survival outcomes. A total of 349 patients were included, of which 214 and 135 patients received pembrolizumab monotherapy and ICI plus chemotherapy, respectively, as first-line treatments. The majority of the patients were male. All DpR quartiles, especially Q4, showed an association with progression-free survival (PFS)/overall survival (OS). In the Q4 cohort, patients who received pembrolizumab had a longer PFS than those who received ICI plus chemotherapy. High DpR was associated with longer PFS and OS, with a more pronounced effect observed with pembrolizumab monotherapy than with ICI plus chemotherapy.

各种类型癌症的反应深度(DpR)与治疗效果之间的关系均有文献记载。基于免疫检查点抑制剂(ICI)的治疗在全球被用作程序性死亡配体1(PD-L1)表达≥50%的非小细胞肺癌(NSCLC)的一线治疗。然而,在这一人群中,DpR的重要性尚未得到阐明。本研究回顾性纳入了接受 ICI 单药治疗或 ICI 加化疗的 PD-L1 表达≥50%的晚期 NSCLC 患者。治疗反应按最大肿瘤缩小百分比分为DpR "四分位"(Q1 = 1-25%、Q2 = 26-50%、Q3 = 51-75%、Q4 = ≥ 76%)和无肿瘤缩小(NTR)。DpR 与生存率之间的关系通过 Cox 比例危险模型产生的危险比(HR)来确定。Kaplan-Meier 法用于确定生存结果。共纳入了349名患者,其中214名和135名患者分别接受了pembrolizumab单药治疗和ICI加化疗作为一线治疗。大部分患者为男性。所有DpR四分位数,尤其是Q4,都与无进展生存期(PFS)/总生存期(OS)相关。在 Q4 组群中,接受 pembrolizumab 治疗的患者比接受 ICI 加化疗的患者的无进展生存期更长。高DpR与更长的PFS和OS有关,与ICI联合化疗相比,pembrolizumab单药的效果更明显。
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引用次数: 0
Design optimization of Fucoidan-coating Cationic Liposomes for enhance Gemcitabine delivery. 优化褐藻糖胶包覆阳离子脂质体的设计,以增强吉西他滨的给药效果。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-18 DOI: 10.1007/s10637-024-01455-x
Epiphane K Silli, Zhenjiang Zheng, Xintao Zhou, Mengfei Li, Jiali Tang, Ruizhe Guo, Chunlu Tan, Ying Wang

Obstacles facing chemotherapeutic drugs for cancers led scientists to load Gemcitabine (GEM) into nanocarriers like liposomes, known for their nontoxicity profile and targeting capacity. The liposomal nanostructures containing GEM were coated with Fucoidan (FU) due to its anti-tumor properties by targeting cancer cells. Thus four different cationic liposomes formulations were prepared by thin-film hydration method in optimal conditions: DOTAP (formulation A); DPPC/DOTAP (4:1 molar ratio, formulation B), DPPC/DMPC/DOTAP (4:1:1 molar ratio, formulation C) and DPPC/DMPC/DOTAP/DSPE-mPEG2000 (4:1:1:0.1 molar ratio, formulation D). They were studied to identify lipid-compositions offering effective GEM-entrapment and successful coating of FU on the liposome surface. Additional qualitative characteristics, such as particle size, polydispersity index, zeta potential, stability and in vitro drug release were then evaluated. Formulation C gave the best GEM-entrapment efficiency (EE) but formed aggregates when coated with FU, giving non-homogenous large size particles then not suitable for effective delivery. It was the same situation with formulation A and B. Only the formulation D showed a good GEM-EE (> 80%) and affinity by successful coating FU from three different algae species. The PEGylated formulation D coated of FU, with regard to storage stability and drug release studies, revealed to be a promising approach on design of optimal drug delivery system.

癌症化疗药物面临的障碍促使科学家们将吉西他滨(GEM)装入脂质体等纳米载体中,脂质体以其无毒性和靶向能力而闻名。由于褐藻糖胶(FU)具有靶向癌细胞的抗肿瘤特性,含有 GEM 的脂质体纳米结构被涂上了褐藻糖胶(FU)。因此,在最佳条件下采用薄膜水合法制备了四种不同的阳离子脂质体配方:DOTAP(配方 A)、DPPC/DOTAP(摩尔比 4:1,配方 B)、DPPC/DMPC/DOTAP(摩尔比 4:1:1,配方 C)和 DPPC/DMPC/DOTAP/DSPE-MPEG2000(摩尔比 4:1:1:0.1,配方 D)。对它们进行了研究,以确定能有效诱捕 GEM 并成功将 FU 包覆在脂质体表面的脂质成分。然后还评估了其他质量特性,如粒度、多分散指数、zeta 电位、稳定性和体外药物释放。配方 C 的 GEM 诱导效率(EE)最高,但在包覆 FU 时会形成聚集体,形成非均质的大尺寸颗粒,不适合有效给药。只有配方 D 成功包覆了三种不同藻类的 FU,显示出良好的 GEM-EE (> 80%)和亲和力。就储存稳定性和药物释放研究而言,包覆 FU 的 PEG 化配方 D 是设计最佳给药系统的一种可行方法。
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引用次数: 0
Targeting multiple receptor tyrosine kinases with sitravatinib: A Phase 1b study in advanced renal cell carcinoma and castrate-resistant prostate cancer. 利用西曲替尼靶向多种受体酪氨酸激酶:晚期肾细胞癌和阉割耐药前列腺癌的 1b 期研究。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-21 DOI: 10.1007/s10637-024-01465-9
Shubham Pant, Byoung Chul Cho, Christos E Kyriakopoulos, Alexander Spira, Nizar Tannir, Theresa L Werner, Xiaohong Yan, Saskia Neuteboom, Richard Chao, Sanjay Goel

Sitravatinib (MGCD516) is an oral inhibitor of several closely related oncogenic tyrosine kinase receptors that include VEGFR-2 (vascular endothelial growth factor receptor-2), AXL, and MET (mesenchymal-epithelial transition). The safety and antitumor activity of sitravatinib are reported in patients from two histologic cohorts (anti-angiogenesis-refractory clear cell renal cell carcinoma [RCC] and castrate-resistant prostate cancer [CRPC] with bone metastases) who participated in a Phase 1/1b study. The patients were enrolled using a 3-stage design that was based on observed objective responses. Objective response rate (ORR) was the primary endpoint. Duration of response, progression-free survival (PFS), overall survival (OS), and safety were also assessed. Overall, 48 patients (RCC n = 38, CRPC n = 10) received ≥ 1 dose of sitravatinib. Both cohorts were heavily pretreated (median number of prior systemic therapies: RCC cohort 3, CRPC cohort 6). In the RCC cohort, ORR was 25.9%, P = 0.015 (null hypothesis [ORR ≤ 10%] was rejected). Responses were durable (median duration 13.2 months). Median PFS was 9.5 months and median OS was 30.0 months. No objective responses were seen in the CRPC cohort; median PFS and OS were 5.8 months and 10.1 months, respectively. Across both cohorts, diarrhea (72.9%), fatigue (54.2%), and hypertension (52.1%) were the most frequent all-cause treatment-emergent adverse events (TEAEs). Diarrhea and vomiting (both, 6.3%) were the most frequent serious TEAEs considered related to study treatment. Sitravatinib demonstrated an acceptable safety profile and promising clinical activity in patients with clear cell RCC refractory to prior angiogenesis inhibitor therapy. Strong indicators for clinical activity were not seen in patients with CRPC and bone metastases. Clinical trial registration:ClinicalTrials.gov NCT02219711.

西曲替尼(MGCD516)是一种口服抑制剂,可抑制几种密切相关的致癌酪氨酸激酶受体,包括VEGFR-2(血管内皮生长因子受体-2)、AXL和MET(间充质-上皮转化)。本研究报告了西曲替尼的安全性和抗肿瘤活性,研究对象是参加1/1b期研究的两个组织学组群(抗血管生成难治性透明细胞肾细胞癌[RCC]和伴有骨转移的阉割耐药前列腺癌[CRPC])的患者。根据观察到的客观反应,患者采用三阶段设计入组。客观反应率(ORR)是主要终点。此外,还对反应持续时间、无进展生存期(PFS)、总生存期(OS)和安全性进行了评估。总体而言,48名患者(RCC n = 38,CRPC n = 10)接受了≥1个剂量的西曲替尼治疗。两组患者均接受过大量预处理(既往接受过系统疗法的中位数:RCC组3例,CRPC组6例)。在RCC队列中,ORR为25.9%,P=0.015(拒绝零假设[ORR≤10%])。反应是持久的(中位持续时间为 13.2 个月)。中位 PFS 为 9.5 个月,中位 OS 为 30.0 个月。CRPC队列中未出现客观应答;中位PFS和OS分别为5.8个月和10.1个月。在两个队列中,腹泻(72.9%)、疲劳(54.2%)和高血压(52.1%)是最常见的全因治疗突发不良事件(TEAEs)。腹泻和呕吐(均为6.3%)是最常见的与研究治疗相关的严重TEAE。在既往接受过血管生成抑制剂治疗但难治的透明细胞RCC患者中,西曲拉替尼表现出了可接受的安全性和良好的临床活性。在CRPC和骨转移患者中未发现临床活性的强烈指标。临床试验注册:ClinicalTrials.gov NCT02219711。
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引用次数: 0
Advancements of prodrug technologies for enhanced drug selectivity in pharmacotherapies. 推进原药技术,提高药物治疗中的药物选择性。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-13 DOI: 10.1007/s10637-024-01460-0
Helin Li, Wenjing Zhang, Qiu Meng, Qi Shuai

The therapeutic effects of many pharmacotherapies have been explored, but disadvantages such as low drug specificity, drug resistance and side effects makes their effective delivery to target sites a great challenge. Consequently, a distinctive prodrug-based technology have emerged as an effective treatments because of their distinctive advantages, such as high drug loading capacity, precise targeting, reduced side effects and spatial and temporal controllability. In particular, the use of gamma/X-ray-mediated strategies in radiotherapy is a new strategy that could enable the precise drug release from implanted devices. This review presents readers with the current state of prodrug therapy and reports the design protocols of rational and effective prodrugs for clinical use.

人们探索了许多药物疗法的治疗效果,但由于药物特异性低、耐药性和副作用等缺点,将药物有效送达靶点成为一项巨大挑战。因此,一种独特的原药技术因其独特的优势而成为一种有效的治疗方法,如高载药量、精确靶向、减少副作用和时空可控性等。特别是,在放射治疗中使用伽马/X 射线介导的策略是一种新策略,可使药物从植入装置中精确释放。本综述向读者介绍了原药治疗的现状,并报告了临床使用的合理有效的原药设计方案。
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引用次数: 0
Treatment response to durvalumab plus tremelimumab after progression with previous immune checkpoint inhibitor in unresectable hepatocellular carcinoma. 无法切除的肝细胞癌患者在使用前一种免疫检查点抑制剂治疗进展后,对durvalumab加tremelimumab的治疗反应。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-30 DOI: 10.1007/s10637-024-01470-y
Nami Mori, Nobuharu Tamaki, Shintaro Takaki, Keiji Tsuji, Toshifumi Tada, Shinichiro Nakamura, Hironori Ochi, Toshie Mashiba, Masao Doisaki, Hiroyuki Marusawa, Haruhiko Kobashi, Hideki Fujii, Chikara Ogawa, Michiko Nonogi, Hirotaka Arai, Yasushi Uchida, Naohito Urawa, Ryoichi Narita, Takehiro Akahane, Masahiko Kondo, Yutaka Yasui, Kaoru Tsuchiya, Namiki Izumi, Masayuki Kurosaki

Although immune checkpoint inhibitors (ICI) are used for unresectable hepatocellular carcinoma (HCC), it is unclear whether sequential ICI treatment-durvalumab plus tremelimumab (DT) after progression on atezolizumab plus bevacizumab (AB)-is effective for HCC. In this nationwide multicenter study, we aimed to investigate the effect of DT treatment based on the timing of treatment. A total of 85 patients receiving DT treatment were enrolled. The primary endpoint is treatment response at week 8 among patients receiving first-line DT treatment, those receiving second-line or later treatment without prior AB therapy, and those receiving second-line or later treatment with prior AB therapy. Objective response rates (ORRs) in patients with first-line treatment, second-line treatment without AB, and second-line treatment with prior AB were 44%, 54%, and 5%, respectively (p < 0.001). Similarly, disease control rates (DCRs) were 69%, 91%, and 26%, respectively (p < 0.001). ORR and DCR were significantly lower in patients with prior AB treatment. Progression free survival (PFS) was significantly shortened in patients receiving second-line therapy following prior AB treatment and an adjusted hazard ratio (95% confidence interval) in those patients for PFS, using first-line therapy as a reference, was 2.35 (1.1-5.1, p = 0.03). In conclusion, the impact of DT sequencing following AB treatment was limited. However, even after second-line treatment, the treatment effect can be equivalent to that of first-line treatment in cases with no history of AB treatment. Thus, prior treatment history should be taken into account when initiating DT treatment.

尽管免疫检查点抑制剂(ICI)可用于治疗不可切除的肝细胞癌(HCC),但目前尚不清楚ICI序贯治疗--在阿特珠单抗加贝伐单抗(AB)治疗进展后的durvalumab加tremelimumab(DT)--对HCC是否有效。在这项全国性多中心研究中,我们旨在根据治疗时机调查DT治疗的效果。共有 85 名患者接受了 DT 治疗。主要终点是接受一线 DT 治疗的患者、接受二线或二线以上治疗但之前未接受 AB 治疗的患者以及接受二线或二线以上治疗但之前接受 AB 治疗的患者在第 8 周时的治疗反应。接受一线治疗、未接受 AB 治疗的二线治疗和接受二线治疗且之前接受过 AB 治疗的患者的客观反应率(ORR)分别为 44%、54% 和 5%(P<0.05)。
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引用次数: 0
Broad-spectrum anti-cancer activity of fused human arginase variants. 融合人精氨酸酶变体的广谱抗癌活性。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-20 DOI: 10.1007/s10637-024-01466-8
Yenisetti Rajendra Prasad, J Anakha, Snehal Sainath Jawalekar, Abhay H Pande

The rapid increase in cancer cases worldwide necessitates the development of novel therapeutic approaches. Therapies targeting cancer's altered metabolism, especially those that deplete critical amino acids, have emerged as promising ones, some of which are already being used in clinical practice and many others are under development. This study reports the anti-cancer activity of two novel fused human arginase I (FHA) variants, FHA-3 and FHA-12, assessed using the NCI-60 human tumor cell line panel. Both variants have demonstrated a range of potencies in a single-dose assay (10 µM), but FHA-3 was found to be more potent with significant growth inhibition in most tested cell lines. To calculate 50% growth inhibition (GI50), FHA-3 was further evaluated in a five-dose assay, where notable anti-cancer activity was observed across the nine cancer types of the NCI-60 panel. Our results demonstrated the broad-spectrum anti-cancer activity of novel FHA variants, with FHA-3 being the most potent. Further studies elucidating its efficacy in animal models will help explore its therapeutic potential.

随着全球癌症病例的迅速增加,有必要开发新的治疗方法。针对癌症新陈代谢改变的疗法,特别是那些消耗关键氨基酸的疗法,已经成为很有前景的疗法,其中一些已经用于临床实践,还有许多正在开发中。本研究报告了两种新型融合人精氨酸酶 I(FHA)变体 FHA-3 和 FHA-12(使用 NCI-60 人类肿瘤细胞系面板进行评估)的抗癌活性。这两种变体在单剂量试验(10 µM)中表现出不同的效力,但 FHA-3 的效力更强,能显著抑制大多数受试细胞系的生长。为了计算50%的生长抑制率(GI50),FHA-3在五剂量试验中进行了进一步评估,在NCI-60小组的九种癌症类型中观察到了显著的抗癌活性。我们的研究结果表明,新型 FHA 变体具有广谱抗癌活性,其中 FHA-3 的抗癌活性最强。进一步研究阐明其在动物模型中的疗效将有助于探索其治疗潜力。
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引用次数: 0
A phase 1b study of the ERK inhibitor MK-8353 plus pembrolizumab in patients with advanced solid tumors ERK抑制剂MK-8353联合pembrolizumab治疗晚期实体瘤患者的1b期研究
IF 3.4 3区 医学 Q2 ONCOLOGY Pub Date : 2024-09-14 DOI: 10.1007/s10637-024-01461-z
Nehal J. Lakhani, Howard Burris, Wilson H. Miller, Mo Huang, Lin-Chi Chen, Lillian L. Siu

Combining a checkpoint inhibitor with an inhibitor of extracellular signal-regulated kinase (ERK) may result in synergistic antitumor activity. We evaluated MK-8353, an ERK1 and ERK2 inhibitor, plus pembrolizumab in a phase 1b study in patients with advanced solid tumors. This open-label, nonrandomized, dose-escalation study (NCT02972034) enrolled adults with advanced solid tumors previously treated with 1‒5 prior lines of therapy. MK-8353 was administered orally in combination with pembrolizumab 200 mg every 3 weeks as follows: twice daily (arm A; MK-8353 50‒350 mg), once daily (arm B; MK-8353 50‒600 mg), or once daily every other week (arm C; MK-8353 50‒300 mg). The primary objective was evaluation of safety via occurrence of dose-limiting toxicities (DLTs). A secondary objective was objective response by RECIST v1.1 per investigator assessment. Among 110 evaluable patients (arm A, n = 22; arm B, n = 50; arm C, n = 38), median age was 58.0 (range, 35‒79) years and 50% had received 1 or 2 prior lines of therapy. DLTs occurred in 19 patients (n = 6 [27%], n = 8 [16%], and n = 5 [13%], respectively); the most frequent was grade 3 maculopapular rash (n = 15). Grade 3/4 treatment-related AEs occurred in 35% of patients; the most common were maculopapular rash (13%) and increased lipase (5%); none were grade 5. Eight patients (7%) attained an objective response (arm B, n = 7 [complete response, n = 1; partial response, n = 6]; arm C, n = 1 [complete response]). In conclusion, MK-8353 once daily plus pembrolizumab could be administered with a manageable toxicity profile but had modest antitumor activity in patients with advanced solid tumors.

将检查点抑制剂与细胞外信号调节激酶(ERK)抑制剂结合使用可能会产生协同抗肿瘤活性。在一项针对晚期实体瘤患者的 1b 期研究中,我们评估了 ERK1 和 ERK2 抑制剂 MK-8353 联合 pembrolizumab 的疗效。这项开放标签、非随机、剂量递增研究(NCT02972034)招募了既往接受过1-5种疗法的晚期实体瘤成人患者。MK-8353与pembrolizumab 200 mg联合口服给药,每3周一次,给药方式如下:每日两次(A组;MK-8353 50-350 mg)、每日一次(B组;MK-8353 50-600 mg)或隔周一次(C组;MK-8353 50-300 mg)。首要目标是通过剂量限制性毒性(DLT)的发生评估安全性。次要目标是根据 RECIST v1.1 评估研究者的客观反应。在 110 名可评估的患者中(A 组,22 人;B 组,50 人;C 组,38 人),中位年龄为 58.0 岁(35-79 岁),50% 的患者之前接受过 1 或 2 种疗法。19名患者出现了DLT(分别为6例[27%]、8例[16%]和5例[13%]);最常见的是3级斑丘疹(15例)。35%的患者出现了3/4级治疗相关不良反应;最常见的是斑丘疹(13%)和脂肪酶升高(5%);无5级不良反应。8名患者(7%)获得了客观应答(B组,n = 7 [完全应答,n = 1;部分应答,n = 6];C组,n = 1 [完全应答])。总之,MK-8353每日一次联合pembrolizumab治疗晚期实体瘤患者的毒性可控,但具有适度的抗肿瘤活性。
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Investigational New Drugs
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