Mathematical models of targeted cancer therapy

Improved understanding of the molecular underpinnings of cancer initiation and progression has led to the development of targeted cancer therapies. The importance of these new methods of cancer treatment necessitates further research into the dynamic interactions between cancer cells and therapeutic agents, as well as a means of analysing their relationship quantitatively. The present review outlines the application of mathematical modelling to the dynamics of targeted cancer therapy, focusing particular attention on chronic myeloid leukaemia and its treatment with imatinib (Glivec).     

恶性胶质瘤靶向治疗研究进展

目的 恶性胶质瘤是一种最常见的原发恶性脑肿瘤,是癌症治疗中最具挑战性疾病之一.因为手术切除后肿瘤易复发和治疗抵抗性,患者预后普遍较差.胶质瘤的分子靶向治疗正逐渐引起广泛关注.本研究总结恶性胶质瘤发病相关的分子病理改变和靶向药物的临床应用与研究进展.方法 采用PubMed文献检索系统,以“恶性胶质瘤”和“分子靶向治疗”为关键词,检索2007-01-01-2015-12-31的相关文献.纳入标准:(1)与恶性胶质瘤分子靶向通路相关的文献;(2)与恶性胶质瘤抗血管生成治疗相关的文献;(3)与恶性胶质瘤分子靶向药物的Ⅰ期及Ⅱ期临床研究相关的文献;(4)与恶性胶质瘤分子靶向耐药相关的文献.根据纳入标准分析文献43篇.结果 胶质瘤靶向治疗方向主要集中在RTK/RAS/PI3K通路、促血管生成通路和一些其他重要的细胞内信号转导通路.然而,一些因素如信号通路之间的串扰、瘤内异质性和胶质瘤干细胞的治疗抵抗性限制了单一药物的活性.各种分子靶向药物单药治疗未能表现出更好的生存获益,还需与其他治疗方法联合应用.目前对于恶性胶质瘤患者多靶点激酶抑制剂治疗的研究还处于起始阶段.结论 分子靶向药物在恶性胶质瘤的治疗中具有重要临床意义和应用潜力,但由于胶质瘤的复杂的分子生物学特性,分子靶向治疗面临诸多挑战,还需进一步探索与研究.     

Hyperfractionated radiotherapy and chemotherapy for childhood ependymoma: final results of the first prospective AIEOP (Associazione Italiana di Ematologia-Oncologia Pediatrica) study

PURPOSE: A postsurgical "stage-based" protocol for ependymoma was designed. METHODS AND MATERIALS: Children were given: (1) focal hyperfractionated radiotherapy (HFRT) if with no evidence of disease (NED), or (2) 4 courses with VEC followed by HFRT for residual disease (ED). HFRT dose was 70.4 Gy (1.1 Gy/fraction b.i.d.); VEC consisted of VCR 1.5 mg/m2 1/w, VP16 100 mg/m2/day x 3, CTX 3 g/m2 d 1. When feasible, second-look surgery was recommended. RESULTS: Sixty-three consecutive children were enrolled: 46 NED, 17 ED; the tumor was infratentorial in 47 and supratentorial in 16, with spinal metastasis in 1. Of NED patients, 35 of 46 have been treated with HFRT; 8 received conventionally fractionated radiotherapy, and 3 received no treatment. Of the 17 ED patients, 9 received VEC + HFRT; violations due to postsurgical morbidity were as follows: HFRT only (2), conventionally fractionated radiotherapy (3) + VEC (2), and no therapy (1). Objective responses to VEC were seen in 54%; objective responses to RT were seen in 75%. Overall survival and progression-free survival at 5 years for all 63 children were 75% and 56%, respectively; for the NED subgroup, 82% and 65%; and for the ED subgroup, 61% and 35%, respectively. All histologies were centrally reviewed. At multivariate analysis, grading, age, and site proved significant for prognosis. CONCLUSIONS: HFRT, despite the high total dose adopted, did not change the prognosis of childhood ependymoma as compared to historical series: New radiotherapeutic approaches are needed to improve local control. Future ependymoma strategies should consider grading when stratifying treatment indications.     

Patient-derived cell models as preclinical tools for genome-directed targeted therapy

Background

In this study, we established patient-derived tumor cell (PDC) models using tissues collected from patients with metastatic cancer and assessed whether these models could be used as a tool for genome-based cancer treatment.

Methods

PDCs were isolated and cultured from malignant effusions including ascites and pleural fluid. Pathological examination, immunohistochemical analysis, and genomic profiling were performed to compare the histological and genomic features of primary tumors, PDCs. An exploratory gene expression profiling assay was performed to further characterize PDCs.

Results

From January 2012 to May 2013, 176 samples from patients with metastatic cancer were collected. PDC models were successfully established in 130 (73.6%) samples. The median time from specimen collection to passage 1 (P1) was 3 weeks (range, 0.5–4 weeks), while that from P1 to P2 was 2.5 weeks (range, 0.5–5 weeks). Sixteen paired samples of genomic alterations were highly concordant between each primary tumor and progeny PDCs, with an average variant allele frequency (VAF) correlation of 0.878. We compared genomic profiles of the primary tumor (P0), P1 cells, P2 cells, and patient-derived xenografts (PDXs) derived from P2 cells and found that three samples (P0, P1, and P2 cells) were highly correlated (0.99–1.00). Moreover, PDXs showed more than 100 variants, with correlations of only 0.6–0.8 for the other samples. Drug responses of PDCs were reflective of the clinical response to targeted agents in selected patient PDC lines.

Conclusion(s)

Our results provided evidence that our PDC model was a promising model for preclinical experiments and closely resembled the patient tumor genome and clinical response.     

A clinically relevant orthotopic xenograft model of ependymoma that maintains the genomic signature of the primary tumor and preserves cancer stem cells in vivo

Limited availability of in vitro and in vivo model systems has hampered efforts to understand tumor biology and test novel therapies for ependymoma, the third most common malignant brain tumor that occurs in children. To develop clinically relevant animal models of ependymoma, we directly injected a fresh surgical specimen from a 9-year-old patient into the right cerebrum of RAG2/severe complex immune deficiency (SCID) mice. All five mice receiving the initial transplantation of the patient tumor developed intracerebral xenografts, which have since been serially subtransplanted in vivo in mouse brains for 4 generations and can be cryopreserved for long-term maintenance of tumorigenicity. The xenograft tumors shared nearly identical histopathological features with the original tumors, harbored 8 structural chromosomal abnormalities as detected with spectral karyotyping, maintained gene expression profiles resembling that of the original patient tumor with the preservation of multiple key genetic abnormalities commonly found in human ependymomas, and contained a small population (<2.2%) of CD133⁺ stem cells that can form neurospheres and display multipotent capabilities in vitro. The permanent cell line (BXD-1425EPN), which was derived from a passage II xenograft tumor and has been passaged in vitro more than 70 times, expressed similar differentiation markers of the xenograft tumors, maintained identical chromosomal abnormalities, and formed tumors in the brains of SCID mice. In conclusion, direct injection of primary ependymoma tumor cells played an important role in the generation of a clinically relevant mouse model IC-1425EPN and a novel cell line, BXD-1425EPN. This cell line and model will facilitate the biological studies and preclinical drug screenings for pediatric ependymomas.     

胰腺癌分子靶向治疗进展

胰腺癌在胃肠道肿瘤中预后差,5年生存率不到5％,发病率呈逐渐上升趋势。治疗主要是外科手术、化疗和放疗相结合的综合治疗,但目前常规治疗效果有限,因此针对胰腺癌生物学特性进行治疗是改善预后的关键。随着靶向治疗的进展,VEGF单克隆抗体和EGFR抑制剂在临床试验中都表现出较好的前景。其他靶向药物,如沙利度胺、基质金属蛋白酶抑制剂、COX-2抑制剂和法尼基转移酶抑制剂还在研究之中。分子靶向治疗将为胰腺癌的治疗提供新的机会。     

肿瘤靶向治疗现状和发展前景

近年来,随着分子生物学技术的提高,以及从细胞受体和增殖调控的分子水平对肿瘤发病机制的进一步认识,人们开始进行以细胞受体、关键基因和调控分子为靶点的治疗,亦称之为靶向治疗（targeted therapy）。     

胰腺癌:靶向治疗的前景

Pancreatic cancer is a devastating disease characterized by almost identical incidence and mortality rates. Since this tumour is mostly diagnosed in an advanced stage there is usually no option for a curative surgical resection. In addition, pancreatic cancers known to be resistant to conventional treatment modalities such as chemotherapy and radiotherapy. Therefore, novel strategies for targeting these tumors are urgently needed. The increasing knowledge on the underlying pathogenetic mechanisms has led to the identification of surface receptor molecules that initiate intracellular signalling cascades upon ligand binding, thus leading to tumor progression. Targeting these receptors or their secreted ligands is therefore an attractive new approach for cancer therapy. The epidermal growth factor receptor （EGFR） and the vascular endothelial growth factor receptor （VEGFR） are transmembrane tyrosine kinase receptors which can be targeted by various compounds such as antibodies or small molecule inhibitors. In addition, various molecules targeting proteins secreted by pancreatic cancers such as matrix metalloproteinases （MMP＇s） or intracellular oncogenic signalling components such as the farnesyltransferase have been proposed as potential new approaches for targeted cancer therapy. The use of these agents alone or in combination with conventional therapeutic regimens is currently being evaluated and shows first promising results for pancreatic cancer therapy.     

肿瘤分子靶向治疗研究现状

分子靶向治疗药物成为近年来肿瘤治疗发展领域的研究热点，以低毒高效的特点逐步成为临床肿瘤治疗的重要部分，大量的临床试验集中于研究该类药物的疗效和毒副反应。本文拟对肿瘤分子靶向治疗药物的最新研究情况加以概述。     

Molecular targeted therapy for advanced hepatocellular carcinoma

Systemic anticancer therapy for hepatocellular carcinoma (HCC) is limited by intrinsic drug resistance and accompanying liver dysfunction. However, recent advances in molecular targeted therapy (MTT) have shed light on the treatment of advanced HCC. A recent randomized, placebo-controlled trial demonstrated that sorafenib, a multi-target tyrosine kinase inhibitor, prolonged overall survival and time-to-progression in patients with advanced HCC. This breakthrough highlights the potential of MTT targeting hepatocarcinogenic pathways, such as the Raf/MAPK/ERK pathway, angiogenic pathways and the EGFR signaling pathway. This review discusses the current status and the potential of developing novel MTTs for advanced HCC.     

晚期肝细胞癌的靶向治疗进展

目前,原发性肝细胞癌（HCC）是居全球第5位的常见肿瘤,并且在肿瘤相关性死亡中排第3位。大部分肝细胞癌患者诊断时已无法手术切除并且中位生存期很短,由于传统的细胞毒药物对晚期肝细胞癌疗效有限,本文总结目前靶向治疗领域的一些进展,希望将来在肝细胞癌系统治疗方面能够获得实质性突破。     

小肠癌化疗及分子靶向治疗

 小肠恶性肿瘤早期临床表现无特异性,总体预后较差,5年总生存率约30%,中位生存期约19个月。回顾性分析提示术后辅助化疗有可能改善无瘤生存期,但总生存期未见明显改善;对肿瘤分期相对较晚、有区域淋巴结转移的患者,可能从辅助化疗受益。姑息化疗在改善晚期患者无进展生存期和总生存期中可能发挥作用。晚期患者使用FOLFOX方案（氟尿嘧啶、亚叶酸钙和奥沙利铂）疗效优于其他方案。对于小肠癌分子靶向治疗尚处在探索中,而化疗亦有待进一步深入研究。     

肝癌靶向治疗靶点的研究进展

随着现代医学的不断发展,医疗整体水平的进一步提高,肝癌的治疗手段已经不仅仅局限于几种传统手段,如手术切除、放射治疗和化学治疗,众多医学同仁正致力于研发更加有效的治疗手段。自20世纪80年代起,靶向治疗走进了人们的视线,经过不断的探索和研究,正逐渐成为肝癌治疗的主要途径之一。据报道肝癌的靶向治疗方法多种多样,但都不同程度地提高了肝癌的治疗效果,本文主要从受体靶点、肽靶点、标志性分子靶点这三个方面进行概述。     

Chemotherapy and molecular targeted therapy for small intestine cancer

Neoplasms of the small intestine have no specific features at early stage，and the prognosis is poor. The 5 year survival rate of all the patients is about 30% and the middle survival time is 19 months. The retrospective analysis shows that adjuvant chemotherapy after surgical resection might improve the disease free survival while the overall survival is not improved obviously. The patients who are at advanced stage or have regional lymph node metastasis may obtain benefits from adjuvant chemotherapy. Palliative chemotherapy may improve progress free survival and overall survival of patients who are at advanced stage. The therapeutic effect of patients at advanced stage using FOLFOX regimen（5 fluorouracil，calcium folinate and oxaliplatin）is better compared with other regimens. The molecular targeted therapy of small intestine cancer is still in the study process and advanced studies are also needed for chemotherapy.     

Immunotherapy and targeted therapy for cervical cancer: an update

The prognosis of patients with metastatic cervical cancer is poor with a median survival of 8–13 months. Despite the potency of chemotherapeutic drugs, this treatment is rarely curative and should be considered palliative only. In the last few years, a better understanding of Human papillomavirus tumor-host immune system interactions and the development of new therapeutics targeting immune check points have renewed interest in the use of immunotherapy in cervical cancer patients. Moreover, next generation sequencing has emerged as an attractive option for the identification of actionable driver mutations and other markers. In this review, we provide background information on the molecular biology of cervical cancer and summarize immunotherapy studies, targeted therapies, including those with angiogenesis inhibitors and tyrosine kinase inhibitors recently completed or currently on-going in cervical cancer patients.     

Nanotechnology for targeted cancer therapy

Cancer nanotechnology is currently under intense development for applications in cancer imaging, molecular diagnosis and targeted therapy. The basic rationale is that nanometer-sized particles, such as biodegradable micelles, semiconductor quantum dots and iron oxide nanocrystals, have functional or structural properties that are not available from either molecular or macroscopic agents. When linked with biotargeting ligands, such as monoclonal antibodies, peptides or small molecules, these nanoparticles are used to target malignant tumors with high affinity and specificity. In the ‘mesoscopic’ size range of 5–100 nm in diameter, nanoparticles also have large surface areas and functional groups for conjugating to multiple diagnostic (e.g., optical, radioisotopic or magnetic) and therapeutic (e.g., anticancer) agents. Recent advances have led to multifunctional nanoparticle probes for molecular and cellular imaging, nanoparticle drugs for targeted therapy, and integrated nanodevices for early cancer detection and screening. These developments have opened exciting opportunities for personalized oncology in which cancer detection, diagnosis and therapy are tailored to each individual’s molecular profile, and also for predictive oncology, in which genetic/molecular information is used to predict tumor development, progression and clinical outcome.     

胶质瘤干细胞的分子靶向治疗

胶质瘤干细胞（GSC）被认为是恶性胶质瘤迁移、复发和放化疗抵抗的根源。结合分子靶向药物在其他肿瘤领域走向临床的背景，针对 GSC 的分子靶向药物有望取得成功。目前，相关研究主要集中在 Hedgehog、PI3K 等通路，代表药物主要有环巴胺及其衍生物、雷帕霉素及其衍生物，经典药物三氧化二砷、二甲双胍也有抗 GSC 作用。     

进展期胃癌分子靶向治疗

进展期胃癌化疗效果不佳。分子靶向治疗是近年来进展期胃癌综合治疗的新手段。目前这些策略主要包括针对表皮生长因子受体（EGFR）通道的靶向治疗、针对血管内皮生长因子通道的靶向治疗、口服小分子靶向药物等。近期有关HER2、EGFR、VEGF、mTOR信号通路的靶向药物曲妥珠单抗、西妥昔单抗、贝伐单抗、阿帕替尼、索拉非尼、舒尼替尼、拉帕替尼、RAD001（everolimus）等综合治疗进展期胃癌的报道结果令人鼓舞。