Tyrosine kinase inhibitors in sarcoma treatment

Sarcomas are a group of rare mesenchymal malignant tumors that arise from transformed cells of the mesenchymal connective tissue, which are challenging to treat. The majority of sarcomas are soft tissue sarcomas (STSs; 75%) and this heterogeneous group of tumors is further comprised of gastrointestinal stromal tumors (~15%) and bone sarcomas (10%). Although surgery remains the current primary therapeutic approach for localized disease, recurrent, metastatic and refractory sarcomas require cytotoxic chemotherapy, which usually yields poor results. Therefore the efficiency of sarcoma treatment imposes a difficult problem. Furthermore, even though progress has been made towards understanding the underlying molecular signaling pathways of sarcoma, there are limited treatment options. The aim of the present study was therefore to perform a systematic literature review of the available clinical evidence regarding the role of tyrosine kinase inhibitors (TKIs) in patients with recurrent or refractory STSs and bone sarcomas over the last two decades. Tyrosine kinases are principal elements of several intracellular molecular signaling pathways. Deregulation of these proteins has been implicated in driving oncogenesis via the crosstalk of pivotal cellular signaling pathways and cascades, including cell proliferation, migration, angiogenesis and apoptosis. Subsequently, small molecule TKIs that target these proteins provide a novel potential therapeutic approach for several types of tumor by offering significant clinical benefits. Among the eligible articles, there were 45 prospective clinical trials, primarily multicentric, single arm, phase II and non-randomized. Numerous studies have reported promising results regarding the use of TKIs, mainly resulting in disease control in patients with STSs. The lack of randomized clinical trials demonstrates the ambiguous efficiency of various studied treatment options, which therefore currently limits the approved drugs used in clinical practice. Research both in clinical and preclinical settings is needed to shed light on the underlying molecular drivers of sarcomagenesis and will identify novel therapeutic approaches for pretreated patients.     

Meta-analysis of the Efficacy of Sorafenib for HepatocellularCarcinoma

Purpose: By carrying out a meta-analysis of randomized controlled trials that compared sorafenib or combinedchemotherapy with placebo or combined chemotherapy, the effectiveness of sorafenib in hepatocellular carcinomawas evaluated in the present study, which also provided clinical practice guidelines of evidence-based-medicine.Methods: We reviewed PubMed citations concerning sorafenib treating hepatocellular carcinoma in randomizedcontrolled trials from Jan 2000 to July 2012. All the literature was extracted by Cochrane systematic reviews andunderwent meta-analysis with RewMan 5.0 software. Results: Finally, four papers documenting randomizedcontrolled studies were included. Compared with controls, sorafenib was shown to significantly increase overallsurvival (OS), time to progression (TTP), and disease control rates (DCR), but not the time to symptom progression(TTSP) in hepatocellular carcinoma patients. The incidence of grade-III/IV adverse reactions, including handfoot-skin reactions, diarrhea, hypertension and skin rash or desquamation, in sorafenib treatment group washigher than that in controls. However, there was no significant difference in the incidence of hypodynamiabetween the two groups. Conclusions: Sorafenib exerts significant curative effects in hepatocellular carcinoma.     

Investigation of Antitumor Effects of Sorafenib and Lapatinib Alone and in Combination on MCF-7 Breast Cancer Cells

Background: Breast cancer evolution and tumor progression are controlled by complex interactions betweensteroid receptors and growth factor receptor signaling. Aberrant growth factor receptor signaling can augmentor suppress estrogen receptor function in hormone-dependent breast cancer cells. Thus, we aimed to investigateantitumor effects of sorafenib and lapatinib alone and in combination on MCF-7 breast cancer cells. Materialsand Methods: Cytotoxicity of the sorafenib and lapatinib was tested in MCF-7 cells by XTT assays. 50, 25, 12.5and 6.25μM concentrations of sorafenib and 200, 100, 50 and 25μM concentrations of lapatinib were administeredalone and in combination. Results were evaluated as absorbance at 450nM and IC50 values are calculated accordingto the absorbance data Results: Both sorafenib and lapatinib showed concentration dependent cytotoxic effectson MCF-7 cells. Sorafenib exerted cytotoxic effects with an IC50 value of 32.0μM; in contrast with lapatinib theIC50 was 136.6μM. When sorafenib and lapatinib combined, lapatinib increased cytotoxic effects of sorafenib at itsineffective concentrations. Also at the concentrations where both drugs had cytotoxic effects, combination showstrong anticancer effects and killed approximately 70 percent of breast cancer cells. Conclusions: Combinationsof tyrosine kinase inhibitors and cytotoxic agents or molecular targeted therapy has been successful for manytypes of cancer. The present study shows that both sorafenib and lapatinib alone are effective in the treatmentof breast cancer. Also a combination of these two agents may be a promising therapeutic option in treatment ofbreast cancer.     

The Prognosis of Hepatocellular Carcinoma Treated with Sorafenib in Combination with TACE

Objective: Sorafenib have been shown to be effective in the treatment of advanced HCC and has been standard therapy since its release in Japan in 2009 (Llovet et al., 2008; Cheng et al., 2009). However, due to a low response rate, more aggressive combination treatment has been utilized as a multimodal strategy. The present study aimed to determine the efficacy of sorafenib alone and in combination with transarterial chemoembolization (TACE) for the treatment of advanced HCC. Methods: All patients with unresectable advanced HCC who were prescribed sorafenib at Kanto Rosai Hospital were included in the study. Five-year overall survival (OS) rates were estimated for patients treated with sorafenib alone or in combination with TACE. Multivariate and univariate regression analyses were performed to identify factors affecting OS. Analysis using propensity score matching and inverse-probability weights were also performed. Results: A total of 46 patients were treated with sorafenib up to June 2018. The total sorafenib dose administered was higher in the TACE combination group (70900 mg vs. 24000 mg vs. with sorafenib alone), although the relative dose intensity was lower (11.7% vs. 17.6%, respectively). The 5-year survival prognosis estimated using the Kaplan-Meier method was longer in patients treated with sorafenib in combination with TACE versus sorafenib alone (36.3% vs. 7.7%). Combination with TACE was the only factor associated with improved OS in both univariate and multivariate analysis. Among cases matched by propensity scores the hazard rate for combination with TACE was 0.067 (95% CI 0.091-1.128). Conclusion: With an array of therapeutic options currently available, it is important to determine the efficacy of different multimodal strategies, such as sorafenib combined TACE, for patients with unresectable HCC.     

安罗替尼治疗四肢韧带样纤维瘤有效性和安全性的回顾性研究

目的:评估安罗替尼在四肢韧带样纤维瘤(desmoid-type fibromatosis,DF)患者治疗中的有效性和安全性.方法:回顾性分析2019年1月至2020年4月于四川大学华西医院接受安罗替尼治疗的26例四肢DF患者的临床及随访资料.结果:26例患者均定期随访,中位随访时间为14(11.75～16)个月.随访期...     

Sorafenib reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma patients

Tyrosine kinase inhibitors (TKIs) as sorafenib are known to reduce the number of immunosuppressive regulatory T cells (Tregs) in the peripheral blood and thereby shifting the immune balance to a more stimulating setting. The effect of sorafenib on intratumoural Tregs is unclear but important for future combinations of TKIs and immunotherapy. We, therefore, evaluated the accumulation of regulatory T cells (Tregs, defined as, CD4⁺FoxP3⁺CD25^highCD127^low‐cells) in blood, ascites, metastases and primary tumours of patients with renal cell carcinoma (RCC), and we explored the effect of neoadjuvant treatment with sorafenib 400 mg bid on intratumoural Tregs in 11 patients with RCC in comparison to 15 nontreated RCC patients. We found that immunosuppressive Tregs specifically accumulate in primary tumour, metastases and ascites of RCC‐patients. Tumour infiltrating Tregs were functional. Neoadjuvant sorafenib treatment significantly reduced the percentage of tumour‐infiltrating Tregs (mean 17.3% vs. 28.1%, p = 0.046). Diminished Treg accumulation at the tumour site adds to explain the clinical effectiveness of sorafenib treatment. This observation may have important implications for the use of sorafenib in combination with immunotherapy in patients with RCC, since the depletion of Tregs has been associated with enhanced responses on vaccine mediated immunotherapy.     

Sorafenib reveals efficacy in sequential treatment of metastatic renal cell cancer

Metastatic renal cell carcinoma (mRCC) is a highly vascularized tumor with a generally poor prognosis. It is largely resistant to conventional cancer treatment, including most schemes of hormonal and cytokine therapy as well as to modern chemotherapy. Although IFN-α has been the first choice in mRCC treatment strategies for more than a decade, recent recommendations of the European Association of Urology focus on so-called molecular-targeted therapies, with multikinase inhibitors, such as sorafenib and sunitinib, blocking the progression of cell proliferation and tumor angiogenesis, as preferential therapy. Sorafenib targets the VEGF receptor, the PDGF receptor β and, finally, Raf kinase, and is approved for patients who have either received cytokines or are unsuitable for such a therapy. Although targeted therapies reveal superior efficacy compared with previous cytokine-based approaches, they do not cure patients with metastatic disease. Therefore, following tumor progression, most patients require a second-line or sequential therapy during the further progress of the disease. Owing to the fact that optimal sequencing of these new agents has not been fully elucidated, some recent mainly retrospective studies compared the sequence of sorafenib and sunitinib in order to assess the best clinical benefit in mRCC patients. Apparently, no cross-resistance could be observed in any trial, and most results demonstrated a superior efficacy of a sequence strategy when sorafenib was applied as first-line treatment. Regarding current investigations, the aim of the present article is to address and critically discuss the clinical data concerning the efficacy of sorafenib as part of a sequential treatment of mRCC.     

Sorafenib relieves cell‐intrinsic and cell‐extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity

Sorafenib, a multitargeted antiangiogenic tyrosine kinase inhibitor, is the standard of care for patients with advanced hepatocellular carcinoma (HCC). Cumulating evidence suggests that sorafenib differentially affects immune cells; however, whether this immunomodulatory effect has any impact on antitumor immune responses is unknown. Using an orthotopic mouse model of HCC and tumor‐free mice, we investigated the effects of sorafenib on antitumor immunity and characterized the underlying mechanisms. Sorafenib treatment inhibited tumor growth and augmented antitumor immune responses in mice bearing established orthotopic HCC. The tumor‐specific effector T cell functions were upregulated, while the proportion of PD‐1‐expressing CD8⁺ T cells and regulatory T cells (Tregs) was reduced in tumor microenvironment of sorafenib‐treated mice. Mechanistically, the sorafenib‐mediated effects on Tregs could be independent of its direct tumor‐suppressing activities. Sorafenib treatment reduced Treg numbers by inhibiting their proliferation and inducing apoptosis. Moreover, sorafenib inhibited the function of Tregs, characterized by diminished expression of Treg‐associated molecules important for their function and by their impaired suppressive capacity. These data reveal that sorafenib treatment enhanced functions of tumor‐specific effector T cells as well as relieved PD‐1‐mediated intrinsic and Treg‐mediated non‐cell‐autonomous inhibitions in tumor microenvironment leading to effective antitumor immune responses. In addition to the well‐known tumor‐inhibiting activity of sorafenib, its enhancement of antitumor immunity may also contribute to the clinical efficacy. Our findings uncover a previously unrecognized mechanism of action of sorafenib and indicate that sorafenib represents a potential targeted agent suitable to be combined with immunotherapeutic approaches to treat cancer patients.     

Efficacy and Safety Comparison of Regorafenib and Fruquintinib in Metastatic Colorectal Cancer-An Observational Cohort Study in the Real World

BackgroundRegorafenib and fruquintinib are tyrosine kinase inhibitors that are recommended for refractory colorectal cancer (CRC) in China. However, to date, no head-to-head trials have been conducted to guide clinical practice.Methods and PatientsAn ambispective observational cohort study was conducted in Beijing Cancer Hospital. Patients with metastatic CRC who received regorafenib or fruquintinib were retrospectively collected between January 2018 and April 2020, and prospectively enrolled between May 2020 and February 2021. The primary outcome was time-to-treatment failure (TTF), and secondary outcomes were overall survival (OS) and adverse events. An additional goal of the study was to explore the appropriate sequence of regorafenib and fruquintinib treatment.ResultsA total of 366 patients with metastatic CRC were enrolled to receive regorafenib (n = 260) or fruquintinib (n = 106) between January 2018 and February 2021. No difference was observed for median TTF (regorafenib 2.7 months vs. fruquintinib 3.1 months, P = .200) or median OS (regorafenib 13.8 months vs. fruquintinib 11.3 months, P = .527). The propensity score analysis showed similar results for median TTF and median OS between the 2 groups, as did the results of subgroup analysis for prospective set (n = 146). For sequence analysis, patients with regorafenib followed by fruquintinib (n = 84) showed longer OS than that with the reverse (n = 29) (28.1 months vs. 18.4 months, P = .024). Most patients tolerated regorafenib at a reduced dose (93.1%), and most patients tolerated fruquintinib at a standard dose (68.9%). The incidences of most adverse events were similar between the two groups, while any grade of hand-foot skin reaction and hyperbilirubinemia were more frequently observed in the regorafenib group and ≥grade 3 hypertension was more common in the fruquintinib group.ConclusionRegorafenib and fruquintinib had similar efficacy and toxicity profiles with various frequency. Regorafenib followed by fruquintinib showed longer OS than the reverse, but the sequence needs to be further confirmed.     

Sorafenib in the treatment of thyroid cancer

Sorafenib has been evaluated in several Phase II and III studies in patients with locally advanced/metastatic radioactive iodine–refractory differentiated thyroid carcinomas (DTCs), reporting partial responses, stabilization of the disease and improvement of progression-free survival. Best responses were observed in lung metastases and minimal responses in bone lesions. On the basis of these studies, sorafenib was approved for the treatment of metastatic DTC in November 2013. Few studies suggested that reduction of thyroglobulin levels, or of average standardized uptake value at the fluorodeoxyglucose-PET, could be helpful for the identification of responding patients; but further studies are needed to confirm these results. Tumor genetic marker levels did not have any prognostic or predictive role in DTC patients.The most common adverse events observed included skin toxicity and gastrointestinal and constitutional symptoms. Encouraging results have also been observed in patients with medullary thyroid cancer. Many studies are ongoing to evaluate the long-term efficacy and tolerability of sorafenib in DTC patients.     

Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies

Background:

We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics.

Methods:

Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m⁻²)/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate.

Results:

Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months).

Conclusions:

Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m⁻² in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.     

酪氨酸激酶抑制剂与化疗交替联合治疗晚期肺腺癌的临床疗效

[目的]探讨酪氨酸激酶抑制剂（TKI）与化疗异时联合治疗晚期肺腺癌患者的疗效和不良反应。[方法]收集66例晚期肺腺癌患者,应用含铂2药化疗．疾病进展时予TKI吉非替尼或厄罗替尼治疗,或TKI初始治疗进展后使用化疗;交替进行。总生存时间及不良反应为主要观察指标;[结果]66例患者中,58例是化疗-TKI治疗模式,再化疗的有效率为15．5％,8例是TKI-化疗模式,再次TKI的有效率为25．0％,稍高于化疗-化疔模式患者中第二次治疗的有效率（12．7％）（χ2=2．6,,P=0．08）。化疗-TKI治疗与TKI-化疗患者的中位总体生存期（OS）无明显差异（18．3个月VS17．5个月）（P=-0．44）,但明显长于化疗-化疗患者（6．9个月）（P=0．0001）。交替治疗患者的3-4度不良反应与对照人群相似。[结论]晚期肺腺癌患者TKI与化疗交替联合治疗能提高有效率,明显延长生存时间,与交替方式（给药顺序）无关。     

FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development

FMS‐like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that plays an important role in hematopoietic cell survival, proliferation and differentiation. The most clinically important point is that mutation of the FLT3 gene is the most frequent genetic alteration and a poor prognostic factor in acute myeloid leukemia (AML) patients. There are two major types of FLT3 mutations: internal tandem duplication mutations in the juxtamembrane domain (FLT3‐ITD) and point mutations or deletion in the tyrosine kinase domain (FLT3‐TKD). Both mutant FLT3 molecules are activated through ligand‐independent dimerization and trans‐phosphorylation. Mutant FLT3 induces the activation of multiple intracellular signaling pathways, mainly STAT5, MAPK and AKT signals, leading to cell proliferation and anti–apoptosis. Because high‐dose chemotherapy and allogeneic hematopoietic stem cell transplantation cannot sufficiently improve the prognosis, clinical development of FLT3 kinase inhibitors expected. Although several FLT3 inhibitors have been developed, it takes more than 20 years from the first identification of FLT3 mutations until FLT3 inhibitors become clinically available for AML patients with FLT3 mutations. To date, three FLT3 inhibitors have been clinically approved as monotherapy or combination therapy with conventional chemotherapeutic agents in Japan and/or Europe and United states. However, several mechanisms of resistance to FLT3 inhibitors have already become apparent during their clinical trials. The resistance mechanisms are complex and emerging resistant clones are heterogenous. Further basic and clinical studies are required to establish the best therapeutic strategy for AML patients with FLT3 mutations.     

MET inhibition in tumor cells by PHA665752 impairs homologous recombination repair of DNA double strand breaks

Abnormal activation of cellular DNA repair pathways by deregulated signaling of receptor tyrosine kinase systems has broad implications for both cancer biology and treatment. Recent studies suggest a potential link between DNA repair and aberrant activation of the hepatocyte growth factor receptor Mesenchymal-Epithelial Transition (MET), an oncogene that is overexpressed in numerous types of human tumors and considered a prime target in clinical oncology. Using the homologous recombination (HR) direct-repeat direct-repeat green fluorescent protein ((DR)-GFP) system, we show that MET inhibition in tumor cells with deregulated MET activity by the small molecule PHA665752 significantly impairs in a dose-dependent manner HR. Using cells that express MET-mutated variants that respond differentially to PHA665752, we confirm that the observed HR inhibition is indeed MET-dependent. Furthermore, our data also suggest that decline in HR-dependent DNA repair activity is not a secondary effect due to cell cycle alterations caused by PHA665752. Mechanistically, we show that MET inhibition affects the formation of the RAD51-BRCA2 complex, which is crucial for error-free HR repair of double strand DNA lesions, presumably via downregulation and impaired translocation of RAD51 into the nucleus. Taken together, these findings assist to further support the role of MET in the cellular DNA damage response and highlight the potential future benefit of MET inhibitors for the sensitization of tumor cells to DNA damaging agents.     

Gastrointestinal stromal tumors: from a surgical to a molecular approach

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. These tumors span a wide clinical spectrum from benign to malignant and have long been recognized for their nearly absolute resistance to chemotherapy and radiation treatment. We reviewed the worldwide experience on GIST diagnosis, prognosis and treatment and describe our own series. PubMed was searched for references using the terms gastrointestinal stromal tumor, GIST and gastrointestinal sarcoma. Recent reports were given emphasis because GIST is a novel clinical entity and older published work on gastrointestinal sarcomas might be contaminated with other histologic tumor types. At present, surgery is the standard treatment for primary resectable GIST. To increase the activity of conventional chemotherapeutic agents, locoregional therapies are being implemented in the clinical setting. A major breakthrough is the development of a new class of anticancer agents targeting tumor-specific molecular abnormalities. Preliminary results on administration of imatinib mesylate, a signal transduction inhibitor, are particularly encouraging, showing potent activity of this drug against metastatic GIST. Molecular targeting of the critical pathogenetic mechanism underlying GIST might not only revolutionize the strategy to treat locally advanced and metastatic GIST but also improve disease control after macroscopically radical surgery.