BIIB021, a synthetic Hsp90 inhibitor,has broad application against tumors with acquired multidrug resistance

17‐AAG, the first‐generation clinical Hsp90 inhibitor, exhibits promising antitumor activity in clinical studies, but is limited by poor solubility and hepatotoxicity. To pursue compounds with better biopharmaceutical properties, we have developed a series of fully synthetic orally bioavailable inhibitors of Hsp90. Here, we report that 17‐AAG and other ansamycin derivatives are inactive in P‐gp and/or MRP‐1 expressing cell lines and sensitivity could be restored by coadministration of P‐gp or MRP inhibitors. In contrast, the synthetic Hsp90 inhibitor, BIIB021 was active in these models. Accordingly, BIIB021 was considerably more active than 17‐AAG against adrenocortical carcinoma, a tumor that naturally expresses P‐gp, both in vitro and in vivo. This efflux pump‐mediated resistance is manifested in both cytotoxicity assays and measurements of target inhibition, such as client protein degradation. Other than this, the cytotoxic activity of BIIB021 was also not influenced by loss of NQO1 or Bcl‐2 overexpression, molecular lesions that do not prevent client loss but are nonetheless associated with reduced cell killing by 17‐AAG. Our results indicate that the activity of 17‐AAG and other ansamycins may be curtailed in tumors that have upregulated efflux pumps or antiapoptotic proteins or other genetic alterations. These data indicate that the new generation of synthetic anti‐Hsp90 drugs, exemplified by BIIB021 that is currently undergoing Phase II testing, may have broader application against tumors with acquired multidrug resistance or tumors located in organs protected by MDR proteins, such as the adrenal glands, brain and testis.     

Phase II study of motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate

Purpose

Motesanib (AMG 706) is a multitargeted anticancer agent with an inhibitory action on the human vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and the cellular stem-cell factor receptor (KIT). The aim of this single-arm phase II clinical study was to assess the efficacy and safety of single-agent motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate.

Methods

All patients had experienced progression or relapse while undergoing with imatinib as 400 mg/day or higher. The patients were administered 125 mg of motesanib once daily. The primary endpoint was overall response. Efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumor, and safety was assessed according to the Common Terminology Criteria for Adverse Events (version 3).

Results

Of 35 enrolled and treated patients, no patient showed a complete response, and one patient showed a partial response (PR). Seven had stable disease (SD) for at least 24 months, two of whom continued to have SD for more than 2 years. The median progression-free survival time was 16.1 weeks. Motesanib was well tolerated; commonly reported treatment-related adverse events were hypertension, diarrhea, and fatigue. Anemia was the only hematological toxicity that was reported.

Conclusions

One patient showed PR, and seven patients showed SD more than 24 weeks. Motesanib was found to be safe and well tolerated. The observed toxicities were consistent with Phase I study findings.     

食管间质瘤的临床特点及病理改变

目的:了解食管间质瘤的特殊临床病理改变.方法: 收集21例食管间质瘤的临床病理资料,每例常规光镜切片观察,作免疫组织化学SMA ,S100,CD34,CD117,CKp抗体等标记.结果: 食管间质瘤临床症状以吞咽困难为主,肿瘤直径＜3.0cm者17例,>6.0cm的4例.肿瘤无出血坏死,瘤细胞以梭形细胞为主,核分裂0-4个/50HPF.免疫组化染色:CD34阳性20例(20/21),CD117阳性(20/21),SMA阳性20例(20/21),S100蛋白阳性1例(1/21). 结论:食管间质瘤临床症状与食道癌相似,病理改变以良性肿瘤为主.     

胃间质瘤的临床病理改变

目的：了解胃间质瘤的特殊临床病理改变。方法：收集37例胃间质瘤的临床病理资料，常规光镜切片观察，免疫组化SMA，S100，CD34，CD117，CKp标记。2例恶性胃间质瘤新鲜组织常规电镜切片，观察超微结构。结果：胃间质瘤临床症状以上腹痛、肿块和呕血为主。良性间质瘤直径〈4．5cm，无出血坏死，瘤细胞以梭形细胞为主，核分裂0—2个／50HPF。多数恶性间质瘤直径〉5cm（20／25），有出血坏死，瘤细胞多形性，核分裂6—564／HPF。免疫组化标记：肿瘤细胞以CD34和CD117阳性为主。电镜观察2例恶性间质瘤的瘤细胞中细胞器稀少，无密体密斑、神经内分泌颗粒和细胞外基板。结论：胃间质瘤临床症状与胃癌相似，良性和恶性胃间质瘤的病理诊断依据组织学改变和免疫组化染色。免疫组化和电镜观察示胃间质瘤以未分化型为主。     

食管间质瘤的临床特点及病理改变

目的：了解食管间质瘤的特殊临床病理改变。方法：收集21例食管间质瘤的临床病理资料,每例常规光镜切片观察,作免疫组织化学SMA,S100,CD34,CD117,CKp抗体等标记。结果：食管间质瘤临床症状以吞咽困难为主,肿瘤直径〈3．0cm者17例,〉6．0cm的4例。肿瘤无出血坏死,瘤细胞以梭形细胞为主,核分裂0—4个／50HPF。免疫组化染色：CD34阳性20例（20／21）,CD117阳性（20／21）,SMA阳性20例（20／21）,S100蛋白阳性1例（1／21）。结论：食管间质瘤临床症状与食道癌相似,病理改变以良性肿瘤为主。     

Phase I dose-escalation study of the HSP90 inhibitor AUY922 in Japanese patients with advanced solid tumors

Purpose

AUY922 is a potent non-geldanamycin inhibitor of heat-shock protein 90. This study was carried out in Japanese patients to determine the maximum tolerated dose (MTD), and to characterize safety, tolerability and pharmacokinetics of single-agent AUY922.

Methods

Japanese patients with advanced solid tumors whose disease had progressed on at least one line of standard therapy, or for whom no standard therapy existed, were treated with AUY922 (intravenous, once-weekly, 28-day cycle, starting dose 8 mg/m²).

Results

Thirty-one patients were treated. Two DLTs were reported in one patient of the 54 mg/m² cohort; fatigue and decreased appetite (both Grade 3, resolving to Grade 1 within 8 days). No MTD was determined, and the dose recommended for Phase II studies was determined to be 70 mg/m² once-weekly. Most common drug-related toxicities were diarrhea, night blindness and nausea. Grade 1 and 2 visual toxicities at high AUY922 doses  ≥22 mg/m² were observed. Ten patients (32 %) achieved a best overall response of stable disease, and one patient (3 %) achieved a confirmed partial response.

Conclusion

Overall, AUY922 exhibited acceptable toxicities and demonstrated potential clinical activity in Japanese patients, with similar safety and pharmacokinetic profiles to those reported in a preceding global Phase I study in Western patients (CAUY922A2101).     

Phase I study of panobinostat and imatinib in patients with treatment-refractory metastatic gastrointestinal stromal tumors

Background:

Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST.

Methods:

Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a ‘3 plus 3'' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels.

Results:

Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6).

Conclusion:

Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.     

胃肠道间质瘤的分子生物学研究

 胃肠道间质瘤（GIST）是新近得以深入认识的肿瘤，尤其在GIST分子生物学研究领域获得的重要进展被迅速运用到临床诊断及治疗中，使基础研究与临床应用紧密结合。GIST的分子遗传学机制也是新型分子靶向治疗的研究和应用获得成功的又一典范，因此，GIST日益受到学者们的广泛关注，文章主要对GIST的分子生物学研究进展作一介绍。     

胃肠道间质瘤19例临床病理分析

目的:探讨胃肠道间质瘤(gastrointestinalstromaltumors,GIST)的临床病理、免疫组化特征、鉴别诊断和治疗方法。方法:应用光镜观察形态特征,应用免疫组化SP法对胃肠道和胃肠外腹腔内原诊断为平滑肌瘤、平滑肌母细胞瘤和平滑肌肉瘤24例检测CD117、CD34、Vimentin、SMA和S100,获得19例GIST。结果:19例GIST占同期消化系统间叶肿瘤的79.2%(19/24)。抗体表达情况:CD11794.7%(18/19)、CD3463.2%(12/19)、Vimentin100%(19/19)、SMA15.8%(3/19)阳性和S100表达全部阴性。结论:GIST是消化道最常见的间叶性肿瘤。CD117、CD34、SMA和S100联合使用可协助鉴别诊断GIST。细胞密集、明显核异形、肿瘤性坏死以及核分裂数>5/50HP可作为恶性参考指标,手术切除是主要的治疗方式。     

Imatinib resistance in gastrointestinal stromal tumors

Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed.     

Long-term outcomes of a phase II study of neoadjuvant imatinib in large gastrointestinal stromal tumors of the stomach

Gastric Cancer - Neoadjuvant treatment is recommended for large GISTs due to their friability and risk of extensive operations; however, studies on the indications and long-term results of this...     

胃肠间质瘤的外科治疗问题

 靶向治疗的问世使得胃肠间质瘤（GIST）的治疗发生了革命性的变化，但依然应强调外科原则和技巧在治疗GIST中的重要性。对位于食管、胃肠道、结直肠的GIST病例的治疗经验进行了总结。术中外科医师应尽可能完整切除肿瘤，如果术中无法完整切除，可予伊马替尼治疗。由于GIST甚少经淋巴途径转移，故不必常规行淋巴结清扫术。     

Controversies in the management of gastrointestinal stromal tumors

Major advances in the medical treatment of gastrointestinal tumors (GISTs) have improved survival for both patients with advanced disease and those diagnosed with high‐risk primary tumors. The Consensus approaches to best practice management of gastrointestinal stromal tumors, published in this journal in 2008, provided guidance for the management of GIST to both clinicians and regulatory authorities. Since then, clinical trials have demonstrated the benefit of adjuvant imatinib in high‐risk patients, and mature data from advanced GIST studies suggest that a small but significant proportion of patients with advanced disease can achieve long‐term benefit with ongoing imatinib treatment. Other evolving management strategies include the controversial use of palliative or debulking surgery to improve outcomes in advanced GIST and the development of promising new multikinase inhibitors, such as regorafenib, which has established benefit in the third‐line setting. This review provides an update of recent developments in GIST management and discusses new controversies that these advances have generated.     

胃肠道间质瘤诊断方法的研究进展

胃肠道间质瘤（gastrointestinal stromal tumor,GIST）是起源于胃肠道间叶组织的肿瘤,由于GIST存在恶性潜能,且多数GIST患者无明显临床症状,所以GIST的早期发现、诊断和治疗显得尤为重要。GIST通常在内窥镜、超声内镜（endoscopic ultrasound,EUS）检查中发现。GIST的诊断取决于形态学和免疫组织化学染色,因此组织样本的充足性是其关键。近年来,新的成像技术的应用和分子生物学的发展提高了GIST的诊断准确率,并为GIST的预后及辅助治疗提供了依据。     

Phase II, open-label study of PTK787/ZK222584 for the treatment of metastatic gastrointestinal stromal tumors resistant to imatinib mesylate.

BACKGROUND: We evaluated safety and efficacy of PTK787/ZK222584 (PTK/ZK), a novel tyrosine kinase inhibitor of KIT, platelet-derived growth factor receptors and vascular endothelial cell growth factor receptors (VEGFRs), in patients with imatinib-resistant gastrointestinal stromal tumor (GIST). This is the first study of PTK/ZK in this population. PATIENTS AND METHODS: Patients with metastatic GIST that had progressed after >/= 4-week treatment with imatinib mesylate were eligible. Prior VEGFR-2 inhibitor therapy was not permitted. PTK/ZK 1250 mg orally once-daily was administered to 15 patients (accrued as a two-stage procedure), most of whom (n = 11) had been unsuccessfully treated with imatinib 800 mg daily, until treatment failure. Patients were monitored at 4- to 8-week intervals. RESULTS: All 15 patients enrolled were eligible; two (13%) achieved partial response (PR), eight (53%) had stable disease (SD) >/=3 months, and five (33%) progressed. The clinical benefit rate (PR + SD) was 67% (95% CI 38% to 86%). Median time to progression was 8.5 months (range 0.9-24.8+ months). Three patients had not progressed at the time of analysis, including one PR at 24.8 months and two SDs at 16.6 and 18.6 months on treatment. PTK/ZK was generally well tolerated. CONCLUSION: PTK/ZK 1250 mg p.o. once daily is active and well tolerated in patients with imatinib-resistant GIST.     

胃肠道内外间质瘤影像表现与病理危险级别相关分析

目的:探讨胃肠道内外间质瘤CT、MR表现及临床病理特点,及两者相关性。方法:回顾性分析我院27例经手术病理证实的胃肠道内、外间质瘤影像表现及其临床病理资料,对照分析影像表现与免疫组化、病理危险级别相关性。结果:27例病例均为单发病灶。病变位于胃11例,小肠5例,直肠2例,十二指肠1例,胃肠道外肠系膜及腹膜后8例。10例病灶呈圆形,其中6例位于胃,4例呈椭圆形,13例呈分叶形。直径＞5.0cm 17例,直径＜5.0cm 10例。其中19例病灶密度不均,18例病灶内见局部液化坏死,3例出现溃疡、3例出现瘘道,8例病灶密度均匀。增强扫描动脉期23例病灶边缘索条状或血管样强化,实质期全部病灶实性成分均表现进一步强化。其中4例出现肝脏转移,4例出现周围侵犯,均未出现区域淋巴结转移。病理结果:CD117（+）、CD34（+）23例,CD117（+）、CD34（-）3例,CD117（-）、CD34（+）1例;病理危险级别分组:极低危险组1例、低危险组5例、中危险组3例、高危险组18例。结论:胃肠道间质瘤影像表现具有一定特征性,病灶直径大于5.0cm,形态不规则,密度不均和/或伴液化坏死、瘘道形成,增强出现索条或血管样强化,出现周围侵犯及转移等影像表现常提示病理危险级别为中、高危险组,即恶性表现,预后不良。     

A clinicopathologic and immunohistochemical study of gastrointestinal stromal tumors.

The clinicopathologic and immunohistochemical features in 120 cases of gastrointestinal stromal tumor (GIST) were reviewed. Excluding 24 cases of gastric schwannoma, 96 cases of GIST consisting of 62 benign tumors and 34 sarcoma (low grade, 17; high grade, 17), with 9 cases arising in the esophagus, 57 in the stomach, 28 in the small intestine, and 2 in the colon, were studied. All esophagus and colon tumors were benign and resembled a conventional leiomyoma histologically. However, the gastric and small intestine benign tumors mostly showed histologic features of cellular or epithelioid leiomyoma. Immunohistochemically, desmin caused a positive reaction in all esophagus and colon tumors, but only 26% of gastric and small intestine tumors. However, muscle-specific actin (HHF35) caused a positive reaction in most GIST (92%). The 10-year survival rates of the patients with gastric sarcoma and those with intestinal sarcoma were 74% and 17%, respectively. These results showed that histologic and immunohistochemical features were distinctly different, depending on the location in the gastrointestinal tract; that most GIST, excluding schwannoma, had smooth muscle differentiation; and that sarcomas had a more favorable prognosis when they occurred in the stomach rather than the intestine.     

胃肠道恶性间质瘤的临床病理分析及免疫组化观察

目的探讨胃肠道恶性间质瘤的临床病理及免疫组化特点和诊断标准.方法对11例恶性间质瘤(GIST)进行常规病理检查及免疫组化染色.结果 GIST由梭形细胞和上皮细胞组成,大多数恶性GIST CD34( ),Vimenti( ),Desmin(-),Actin(-),S-100(-);手术切除是GIST最好的治疗方法.结论 GIST是胃肠道常见的非上皮性肿瘤,缺乏定向分化.免疫组化在鉴别GIST中有重要意义.     

Contemporary treatment of gastrointestinal stromal tumors

Great revolutionary changes have occurred in the diagnosis and treatment of gastrointestinal stromal tumor(GIST) due to the discovery and development of molecularly targeted therapy with imatinib and sunitinib, which have led to publication of several clinical guidelines for GIST. However, despite enhanced understanding of the clinical and molecular nature of GIST, there are many problems still remain. In this paper, I will focus on three GIST issues of great interest including: 1) laparoscopic surgery for GIST and gastrointestinal submucosal tumors; 2)multidisciplinary treatments for GIST, such as adjuvant therapy, neoadjuvant therapy, surgery during imatinib treatment, and surgery for focally imatinib-resistant GIST; and 3)the diagnosis and treatment of imatinib-resistant GIST.