脊索瘤信号通路与分子靶向治疗

脊索瘤是一种少见的骨组织恶性肿瘤,来源于残留胚胎脊索组织,占骨原发恶性肿瘤的1%~4%。主要发生于颅底、脊柱及骶尾部的中轴骨组织。肿瘤发生部位特殊,故手术完整切除困难,而传统放疗及化疗的效果亦欠佳,因此脊索瘤常常侵犯周围组织,并多次复发。近年来关于脊索瘤的分子生物学方面研究日益深入,受体酪氨酸激酶及其下游信号通路Akt/mTOR、Ras/MEK/ERK,以及其他信号通路,如STAT3、NF-κB等在脊索瘤中相继被发现,相关分子靶向药物的研究也进入Ⅰ期和Ⅱ期临床试验阶段。本文就目前研究较多的几条脊索瘤信号通路及分子靶向治疗进展作一综述。     

靶向FGFR的肿瘤治疗新进展

成纤维细胞生长因子受体(FGFR)信号的异常在多种肿瘤中被发现,FGFR信号的异常参与了肿瘤发生的多项进程,包括细胞存活、增殖、炎性反应、迁移、血管生成、上皮间质转化及耐药.故FGFR是治疗肿瘤有应用前景的靶点,越来越多的FGFR抑制剂进入临床前研究及临床研究阶段,部分FGFR抑制剂已被批准应用于临床.但是获得性耐药及...     

MAP2K1 Mutations in Advanced Colorectal Cancer Predict Poor Response to Anti-EGFR Therapy and to Vertical Targeting of MAPK Pathway

BackgroundMAP2K1 mutations, otherwise known as MEK mutations, are rare oncogenic alterations that have been implicated in MAPK pathway activation. The impact of MAP2K1 mutations in colorectal cancer on EGFR antibody response has not been characterized.Patients and MethodsAntitumor activity was assessed in mouse xenograft models with SW48 cell lines harboring MAP2K1 mutation, and protein expression of the RAS signaling pathway was studied by Western blot analysis. We retrospectively identified patients with MAP2K1-mutated metastatic colorectal cancer patients treated at City of Hope Comprehensive Cancer Center between 2015 and 2020 using next-generation sequencing. Patients’ tumor characteristics, treatment response, and outcome are described. Additional patients with the MAP2K1 mutation were identified from The Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center oncogenomic databases.ResultsAntitumor activity in mouse xenograft models demonstrated efficacy with combination therapy with EGFR and MEK inhibition with either BRAF or ERK inhibitors. Five patients treated at City of Hope between 2015 and 2020 harbored a MAP2K1 mutation at a frequency of 1%. APC and TP53 were common coalterations. All disease was RAS and BRAF wild type, except 1 case that harbored a concurrent KRAS mutation. Four RAS/BRAF wild-type MAP2K1-mutated patients was treated with anti-EGFR, anti-EGFR + MEK and BRAF inhibitors, and anti-EGFR + ERK inhibitors. All 4 patients experienced disease progression.ConclusionMAP2K1 mutation in colorectal cancer is associated with poor response to EGFR inhibition. EGFR inhibition with or without MEK, BRAF, or ERK inhibitors did not result in any clinical benefit in our limited experience.     

Targeting CAM-DR and Mitochondrial Transfer for the Treatment of Multiple Myeloma

The prognosis of patients with multiple myeloma (MM) has improved dramatically with the introduction of new therapeutic drugs, but the disease eventually becomes drug-resistant, following an intractable and incurable course. A myeloma niche (MM niche) develops in the bone marrow microenvironment and plays an important role in the drug resistance mechanism of MM. In particular, adhesion between MM cells and bone marrow stromal cells mediated by adhesion molecules induces cell adhesion-mediated drug resistance (CAM-DR). Analyses of the role of mitochondria in cancer cells, including MM cells, has revealed that the mechanism leading to drug resistance involves exchange of mitochondria between cells (mitochondrial transfer) via tunneling nanotubes (TNTs) within the MM niche. Here, we describe the discovery of these drug resistance mechanisms and the identification of promising therapeutic agents primarily targeting CAM-DR, mitochondrial transfer, and TNTs.     

Personalized medicine in CLL: Current status and future perspectives

Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in the Western Hemisphere. Despite advances in research and the development of effective treatment regimens, CLL is still largely an incurable disease. Although several prognostic factors have been identified in recent years, most of the new prognostic factors are not utilized, and treatment decisions are still based on clinical staging and limited use of cytogenetic analysis. Patients with advanced disease are treated at diagnosis, whereas others, regardless of their prognostic indicators, are offered treatment only at disease progression. Furthermore, treatment guidelines for elderly or “unfit” patients are unavailable because most CLL trials have included mostly younger, healthier patients. Given theheterogeneity of the clinical manifestations and prognosis of CLL, patients are likely to benefit from a personalized therapeutic approach. Recent advances in CLL pathobiology research, the use of high-throughput technologies, and most importantly, the introduction of novel targeted therapies with high efficacy and low toxicity are currently transforming the treatment of CLL. A personalized approach that includes early intervention in selected patients with CLL is likely to bring physicians closer to the goal of attaining cures in most patients with CLL.     

Caveolin-1 in Breast Cancer: Single Molecule Regulation of Multiple Key Signaling Pathways

Caveolin-1 is a 22-kD trans-membrane protein enriched in particular plasma membrane invaginations knownas caveolae. Cav-1 expression is often dysregulated in human breast cancers, being commonly upregulated incancer cells and downregulated in stromal cells. As an intracellular scaffolding protein, Cav-1, is involved inseveral vital biological regulations including endocytosis, transcytosis, vesicular transport, and signaling pathways.Several pathways are modulated by Cav-1 including estrogen receptor, EGFR, Her2/neu, TGFβ, and mTOR andrepresent as major drivers in mammary carcinogenesis. Expression and role of Cav-1 in breast carcinogenesisis highly variable depending on the stage of tumor development as well as context of the cell. However, recentdata have shown that downregulation of Cav-1 expression in stromal breast tumors is associated with frequentrelapse, resistance to therapy, and poor outcome. Modification of Cav-1 expression for translational cancertherapy is particularly challenging since numerous signaling pathways might be affected. This review focuses onpresent understanding of Cav-1 in breast carcinogenesis and its potential role as a new biomarker for predictingtherapeutic response and prognosis as well as new target for therapeutic manipulation.     

Pharmacokinetics-directed Intravenous Busulfan Combined With High-dose Melphalan and Bortezomib as a Conditioning Regimen for Patients With Multiple Myeloma

BackgroundHigh-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has a well-established role in the treatment of patients with multiple myeloma. Melphalan 200 mg/m² (Mel200) is the most commonly used preparative regimen. Several studies have provided evidence for potential synergism and safety when combining bortezomib (Btz) or busulfan (Bu) with melphalan (Mel).Patients and MethodsWe conducted a prospective phase II study to investigate the safety and efficacy of conditioning with pharmacokinetics (PK)-directed intravenous (IV) Bu with Btz and Mel. Bu dosing was adjusted to target a total area under the curve (AUC) of 20,000 μM × min. Patients received Btz (1 mg/m² × 4 doses) and Mel (140 mg/m²).ResultsA total of 19 subjects were enrolled. Their median age was 55 years, and the median follow-up period was 23.7 months. PK testing resulted in 86% of patients achieving an estimated total AUC of 20,000 ± 2500 μM × min. The overall response rate (ORR) at day +100 after ASCT was 100% in the evaluable patients, with 11% of patients achieving a complete response. The 2-year progression-free survival rate was 57.9% (95% confidence interval [CI], 38%-89%), and the 2-year overall survival rate was 88.5% (95% CI, 76%-100%). The most common grade 3 and 4 toxicities were febrile neutropenia, dysphagia/odynophagia, and oral mucositis. No case of hepatic sinusoidal obstruction syndrome developed. One treatment-related mortality occurred before day +100.ConclusionA preparative regimen of PK-directed IV Bu with Btz and Mel led to an ORR of 100% with acceptable toxicity and should be considered for direct comparison with the Mel200 regimen in future trials.     

中西医结合治疗老年性多发性骨髓瘤的临床效果观察

目的：对老年性多发性骨髓瘤患者采用中西医结合治疗,观察和分析其治疗的临床效果。方法将68例老年性多发性骨髓瘤患者按照随机数字表法分为对照组和治疗组。对照组：采用VAD方案进行化疗;治疗组：在对照组治疗基础上加用中药治疗。结果经过治疗后,治疗组有效率和不良反应发生率分别为85．29％（29／34）、5．88％（2／34）,与对照组67．65％（23／34）、20．59％（7／34）比较,P均＜0．05。治疗前后,2组患者的骨髓浆细胞数和M蛋白值均出现明显下降,但与对照组比较,治疗组下降更明显（ P＜0．05）;与治疗前比较,对照组治疗后血红蛋白值和β2微球蛋白值均没有明显的变化（P＞0．05）,而治疗组则变化明显（P＜0．05）。治疗后观察组血红蛋白值和β2微球蛋白值与对照组治疗后比较,P＜0．05。结论临床上,采用中西医结合治疗老年性多发性骨髓瘤,能有效地改善患者的临床症状,提高治疗效果,降低不良反应发生率。     

精准医学时代三阴性乳腺癌治疗的研究进展

三阴性乳腺癌（triple-negative breast cancer,TNBC）是指雌激素受体、孕激素受体、人表皮生长因子受体2表达均为阴性的乳腺癌,占所有乳腺癌病理学类型的10%~20%。TNBC术后近期复发率较高,易发生内脏转移,尤其是肺和脑的转移,且晚期化疗效果欠佳。与其他亚型乳腺癌比较,TNBC恶性程度高,预后差,一直是临床研究关注的重点和难点。而在精准医学时代基因检测技术的应用,TNBC的分类更加准确,出现了针对不同靶点的靶向治疗和针对免疫检查点的免疫治疗等多种治疗手段,现就TNBC治疗的研究进展进行综述。     

Prognostic Implications of Monosomies in Patients With Multiple Myeloma

BackgroundCytogenetic analysis aides in risk stratification for patients with multiple myeloma (MM). Although several cytogenetic aberrations have been reported to be prognostic, less is known about the association between the presence of monosomies and prognosis. The present study evaluated the prevalence and prognostic implications of monosomies in patients with MM.Materials and MethodsKaryotypes were determined using conventional cytogenetics and fluorescence in situ hybridization (FISH). The prognostic effect of monosomies was evaluated by comparison with the clinical factors in MM patients with normal karyotypes.ResultsKaryotypes were successfully determined in 167 of the 170 patients with MM. Of these 167 patients, 52 (31.1%) had abnormal karyotypes. Univariable analyses showed that a normal karyotype, hypodiploidy, monosomies of chromosomes 13 and 16, deletion or monosomy of 13q14, and loss of X detected by metaphase analysis were each associated with reduced progression-free survival (P < .05 for each). Univariable analyses showed that a normal karyotype, hypodiploidy, monosomies of chromosomes 13 and 16, deletion or monosomy of 13q14 detected by metaphase analysis and FISH-determined RB1 (13q)/TP53 (17p) deletion were each associated with reduced overall survival (P < .05 for each). Multivariable analysis showed that hypodiploidy detected by metaphase analysis was independently prognostic of shorter progression-free survival (P < .05 for each) and that hypodiploidy, monosomy 16, and loss of Y chromosome and FISH-determined TP53 (17p) deletion were associated with reduced overall survival (P < .05 for each).ConclusionIn addition to known cytogenetic abnormalities, such as monosomy 13, hypodiploidy, and TP53 (17p) deletion, monosomy 16 and loss of the Y chromosome have adverse prognostic implications in patients with MM.     

Plasma Dynamics of RAS/RAF Mutations in Patients With Metastatic Colorectal Cancer Receiving Chemotherapy and Anti-EGFR Treatment

Background

RAS and RAF mutations in colorectal cancer (CRC) hold value in precision medicine. Liquid biopsy is an alternative to tumor tissue biopsy, and circulating tumor DNA (ctDNA) has been intensively investigated, but the clinical relevance of RAS and RAF mutations in plasma is yet to be determined. This study aimed to investigate the clinical aspects of RAS/RAF mutations during combination treatment.

Utilization Patterns of Single Fraction Radiation Therapy for Multiple Myeloma

BackgroundPatients with multiple myeloma (MM) are living longer than ever before thanks to new therapies. As a consequence, radiation therapy (RT) is increasingly important in the management of bone lesions from MM. Current American Society for Radiation Oncology guidelines recommend greater usage of 8 Gy in 1 fraction for treatment of these lesions. The objective of this study is to analyze utilization of 8 Gy in 1 fraction for treatment of MM bone lesions in the United States utilizing the National Cancer Data Base (NCDB).Materials and MethodsThe NCDB was used to identify patients with MM treated with palliative RT for painful bony lesions in the period between 2004 and 2014. Utilization rate of RT in this patient population as well as single-fraction (SFRT) versus multiple-fraction RT (MFRT) was compared according to demographic, socioeconomic, and logistic details.ResultsA total of 95,190 patients met our inclusion criteria. Of these, 10,261 (10.8%) patients received RT, and a total of 243 (2.4%) of these patients received SFRT over the 10-year period. There was an 11.73% annual increase (P = .0001) in SFRT utilization from 2004 to 2014. Older age, black race, longer distance from the treatment facility, lower degree of education, treatment at an academic or integrated healthcare network, worse comorbidities, and more recent diagnoses were all associated with increased usage of SFRT.ConclusionSFRT for the management of MM painful bony metastases remains underutilized. Trends show that radiation oncologists do not appear to be changing their approach to treating this disease.     

Precision medicine in gastric cancer

Gastric cancer (GC) is a complex disease linked to a series of environmental factors and unhealthy lifestyle habits, and especially to genetic alterations. GC represents the second leading cause of cancer-related deaths worldwide. Its onset is subtle, and the majority of patients are diagnosed once the cancer is already advanced. In recent years, there have been innovations in the management of advanced GC including the introduction of new classifications based on its molecular characteristics. Thanks to new technologies such as next-generation sequencing and microarray, the Cancer Genome Atlas and Asian Cancer Research Group classifications have also paved the way for precision medicine in GC, making it possible to integrate diagnostic and therapeutic methods. Among the objectives of the subdivision of GC into subtypes is to select patients in whom molecular targeted drugs can achieve the best results; many lines of research have been initiated to this end. After phase III clinical trials, trastuzumab, anti-Erb-B2 receptor tyrosine kinase 2 (commonly known as ERBB2) and ramucirumab, anti-vascular endothelial growth factor receptor 2 (commonly known as VEGFR2) monoclonal antibodies, were approved and introduced into first- and second-line therapies for patients with advanced/metastatic GC. However, the heterogeneity of this neoplasia makes the practical application of such approaches difficult. Unfortunately, scientific progress has not been matched by progress in clinical practice in terms of significant improvements in prognosis. Survival continues to be low in contrast to the reduction in deaths from many common cancers such as colorectal, lung, breast, and prostate cancers. Although several target molecules have been identified on which targeted drugs can act and novel products have been introduced into experimental therapeutic protocols, the overall approach to treating advanced stage GC has not substantially changed. Currently, surgical resection with adjuvant or neoadjuvant radiotherapy and chemotherapy are the most effective treatments for this disease. Future research should not underestimate the heterogeneity of GC when developing diagnostic and therapeutic strategies aimed toward improving patient survival.     

Graft-Versus-Host Disease in Multiple Myeloma Patients Treated With Daratumumab After Allogeneic Transplantation

IntroductionAllogeneic hematopoietic cell transplantation (allo-HCT) represents an adoptive immunotherapy strategy for eliciting a graft-versus-myeloma, the effect for high-risk or relapsed multiple myeloma (MM). Allo-HCT recipients are at risk for graft-versus-host disease (GVHD) as well as associated increases in morbidity and mortality. Daratumumab, an anti-CD38 human immunoglobulin G1 kappa humanized monoclonal antibody, is used for treatment of MM. Daratumumab also affects CD38⁺ nonmyeloma cells, including T cells, which mediate GVHD. The use of daratumumab after allo-HCT has not been well described, and its potential impact on GVHD is unknown.Patients and MethodsIn a multicenter retrospective study, we evaluated incidence of GVHD in 34 patients with relapsed MM treated with daratumumab after allo-HCT.ResultsOverall response to daratumumab (partial response or better) was 41% (95% confidence interval, 24-59). Five patients (15%) developed acute GVHD after daratumumab therapy; no chronic GVHD events were observed after daratumumab therapy. One of these 5 patients had a history of chronic GVHD and developed a flare of acute GVHD during daratumumab therapy. The remaining 4 patients did not have a history of GVHD before daratumumab.ConclusionThe incidence of GVHD after daratumumab was low and did not result in increased exacerbation of GVHD in patients with a history of GVHD.     

MicroRNA-338-3p Inhibits Proliferation and Promotes Apoptosis of Multiple Myeloma Cells Through Targeting Cyclin-Dependent Kinase 4

MicroRNA-338-3p (miR-338-3p) has been reported to be a tumor suppressor in multiple cancer types. However, the biological role of miR-338-3p and its underlying mechanism in multiple myeloma (MM) remain unclear. In the present study, we investigated the biological role and potential of miR-338-3p in MM. We found that miR-338-3p was significantly decreased in newly diagnosed and relapsed MM tissues and cell lines. Overexpression of miR-338-3p in MM cells significantly inhibited proliferation and promoted apoptosis, caspase 3, and caspase 8 activity. Bioinformatics algorithm analysis predicted that cyclin-dependent kinase 4 (CDK4) was a direct target of miR-338-3p, and this was experimentally verified by a dual-luciferase reporter assay. Furthermore, overexpression of miR-338-3p inhibited CDK4 expression on mRNA and protein levels. Of note, the restoration of CDK4 expression markedly abolished the effect of miR-338-3p overexpression on cell proliferation, apoptosis, caspase 3, and caspase 8 activities in MM cells. Taken together, the present study is the first to demonstrate that miR-338-3p functions as a tumor suppressor in MM through inhibiting CDK4. This finding implies that miR-338-3p is a potential therapeutic target for the treatment of MM.