Small Molecule Tyrosine Kinase Inhibitors Research Articles

Application of apatinib after multifaceted therapies for metastatic breast cancer.

BackgroundApatinib is a small molecule tyrosine kinase inhibitor (TKI) that is taken orally and has high specificity for vascular endothelial growth factor receptor 2 (VEGFR-2). This study explored the efficacy and toxicity of apatinib in patients with metastatic breast cancer (MBC) who failed to respond to multifaceted therapy.MethodsA total of 61 patients with MBC who were unresponsive to previous multifaceted chemotherapy were included in this study. The treatment regimens were either a combination of apatinib and chemotherapy or apatinib administered singly with a dose range of 250 mg every second day to 500 mg per day. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity were used as outcome measures.ResultsOf the 61 patients, partial response (PR) was observed in 14 patients (23.0%), stable disease (SD) was observed in 30 patients (49.2%), and progressive disease (PD) was observed in 17 patients (27.8%). The DCR was 44/61 (72.1%), and the ORR was 14/61 (23.0%). Of the 44 patients who achieved PR or SD, the median PFS was 4 months and 15 days. Patients with intracranial metastases were found to benefit from apatinib. Furthermore, 11 patients underwent next generation sequencing (NGS) and 5 of these had a P53 mutation. Of those 5 cases, the ORR and DCR were 0% and 20.0%, respectively. Of the 6 cases with wild-type P53, the ORR was 50.0%, and the DCR was 100.0%. Multivariate regression analysis found that hypertension was an independent prognostic factor of better DCR.ConclusionsApatinib showed good efficacy and manageable toxicity in patients with MBC that had not responded to multifaceted therapy.

Tucatinib Is Active Against Brain Metastases in HER2+ Breast Cancer

The small-molecule tyrosine kinase inhibitor tucatinib outperformed placebo against brain metastases.

Rational design of EGFR dimerization-disrupting peptides: A new strategy to combat drug resistance in targeted lung cancer therapy

Although a variety of tyrosine kinase inhibitors (TKIs) have been developed to target human epidermal growth factor receptor (EGFR) for lung cancer therapy, many patients treated with first-line small-molecule TKIs are clinically observed to eventually establish drug-resistant mutations T790 M and C797S around kinase active site, which play a primary role in development of acquired drug resistance to first-generation reversible and second-generation irreversible TKIs, respectively. Here, instead of developing small-molecule drugs to directly target the active site, we attempt to derive self-inhibitory peptides (SIPs) from the EGFR:EGFR asymmetric dimerization interface, where is separated from kinase active site and has a relatively low conservation as compared to the active site. It is found that the dimerization is a typical peptide-mediated protein interaction, where the first EGFR N-lobe adopts an N-terminal binding sequence (nBS) to interact with the dimerization interface of second EGFR C-lobe. A core binding sequence (nCBS, 676NQALLRILKE68) is identified in the nBS region as hotspot segment, which is then rationally optimized to generate a number of SIPs. Consequently, three designed SIPs are determined as promising candidates; they have high affinity to EGFR kinase domain, strong competitive potency with native nBS peptide for the dimerization interface, and effective cytotoxicity on human lung cancer cell lines. It is also demonstrated that these peptides are insensitive to drug-resistant EGFR T790 M/C797S mutation at molecular and cellular levels, and exhibit a good selectivity for EGFR over HER2 at molecular level.

Pexidartinib: first approved systemic therapy for patients with tenosynovial giant cell tumor.

Pexidartinib is an orally administered small molecule tyrosine kinase inhibitor. Phase III ENLIVEN study results provided clinical evidence for US FDA approval for treatment of adult patients with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Recommended dosage is 400 mg orally twice daily on an empty stomach. Long-term follow-up in pooled analyses showed increased response rates compared with those observed in ENLIVEN. Patients on pexidartinib also experience meaningful improvements in range of motion. Side effects associated with pexidartinib are generally manageable; however, there is a risk of potentially life-threatening mixed or cholestatic hepatotoxicity and pexidartinib has a Risk Evaluation and Mitigation Strategy (REMS) program to ensure appropriate monitoring.

Apatinib attenuates phenotypic switching of arterial smooth muscle cells in vascular remodelling by targeting the PDGF Receptor-β.

Apatinib (YN968D1) is a small‐molecule tyrosine kinase inhibitor（TKI）which can inhibit the activity of vascular endothelial growth factor receptor‐2 (VEGFR‐2). It has been reported that apatinib has anti‐tumour effect of inhibiting proliferation and inducing apoptosis of a variety of solid tumour cells, whereas its effect on vascular smooth muscle cells (VSMC) remains unclear. This study investigated the effect of apatinib on phenotypic switching of arterial smooth muscle cells in vascular remodelling. Compared to the vehicle groups, mice that were performed carotid artery ligation injury and treated with apatinib produced a reduction in abnormal neointimal area. For in vitro experiment, apatinib administration inhibited VSMC proliferation, migration and reversed VSMC dedifferentiation with the stimulation of platelet‐derived growth factor type BB (PDGF‐BB).In terms of mechanism, with the preincubation of apatinib, the activations of PDGF receptor‐β (PDGFR‐β) and phosphoinositide‐specific phospholipase C‐γ1 (PLC‐γ1) induced by PDGF‐BB were inhibited in VSMCs. With the preincubation of apatinib, the phosphorylation of PDGFR‐β, extracellular signal‐related kinases (ERK1/2) and Jun amino‐terminal kinases (JNK) induced by PDGF‐BB were also inhibited in rat vascular smooth muscle cell line A7r5. Herein, we found that apatinib attenuates phenotypic switching of arterial smooth muscle cells induced by PDGF‐BB in vitro and vascular remodelling in vivo. Therefore, apatinib is a potential candidate to treat vascular proliferative diseases.

The Efficacy and Safety of Apatinib in Refractory/Relapse Advanced Pediatric Solid Tumor: A Retrospective Study.

BackgroundThe prognosis of recurrent or refractory advanced childhood solid tumor patients is very poor and new therapeutic strategies are in urgent need. This study aimed to determine the efficacy and safety of apatinib in pediatric refractory/relapse advanced solid tumor patients.Patients and MethodsThe study retrospectively reviewed recurrent or refractory advanced pediatric solid tumor patients who were treated with apatinib, an oral small-molecule tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor-2 (VEGFR2), at the Sun Yat-sen University Cancer Center (China) from January 2016 to March 2019.ResultsFifty-six patients were included in the safety evaluation and 49 patients were included in the efficacy evaluation. The objective responses rate (ORR) was 26.5% (95% CI 15–41): 0 CR (complete response) and 13 PR (partial response). Disease control rate (DCR) (CR+PR+SD) was 79.6% (95% CI 65–90). The median progression-free survival (PFS) was 4.0 months (95% CI 2.6–5.4). There was no significant difference for ORR or PFS between the A (apatinib monotherapy), A+MT (apatinib combined with oral metronomic therapy) and A+SC (apatinib combined with salvage combination chemotherapy) group (p>0.05). The most common grade 3 or 4 adverse events were neutropenia (9[16.1%]), thrombocytopenia (8[14.3%]), hand-foot syndrome (3[5.4%]), hypertension (3[5.4%]), anaemia (3[5.4%]) and mucositis (2[3.6%]). Hypertension was the most serious adverse event and one death that occurred was considered as drug-related.ConclusionApatinib showed promising clinical activity in heavily treated recurrent or refractory advanced childhood solid tumor patients. However, it is necessary to pay special attention to monitoring blood pressure when using apatinib in children. Prospective randomized controlled clinical trial is warranted.

Identification of target small molecule tyrosine kinase inhibitors that need monitoring and clinical application of protocol for early detection of cancer therapeutics-related cardiac dysfunction using signal detection: An investigation of real world data.

In order to detect cancer therapeutics-related cardiac dysfunction (CTRCD) early, we identified which drugs were to be monitored using signal detection and the package insert, and created and applied a protocol to address this. Adverse event data recorded in the Japanese Adverse Drug Event Report (JADER) database between April 2004 and January 2018 were used. Among small molecule tyrosine kinase inhibitors that are not described in the serious side-effects section of the package insert despite signal detection, tyrosine kinase inhibitors with severe side-effects in the background of cases reported by JADER database were selected to be monitored in clinical practice. We applied our findings clinically by creating a protocol to detect CTRCD early. All cases at Tosei General Hospital where the target tyrosine kinase inhibitors were administered from when they were first released in November 2019 were included. We compared the results from before and after we began the protocol to clarify its effects. We found that CTRCD was not described in the serious side-effect section of the package inserts for Bosutinib, Alectinib, and Osimertinib even though CTRCD signals were detected for them. Therefore, it is possible that we may have previously overlooked CTRCD. When we applied our protocol using Osimertinib as the target drug, we were able to detect CTRCD early in 5/21 (24%) patients. It was clarified that the drug identification method used in this study for early detection of adverse events leads to early detection of adverse events when applied clinically.

Ibrutinib in Gynecological Malignancies and Breast Cancer: A Systematic Review.

Ibrutinib is an orally available, small-molecule tyrosine kinase inhibitor. Its main purpose is to inhibit Bruton’s tyrosine kinase (BTK), an enzyme that is crucial in B cell development. It is FDA approved for the treatment of certain hematological malignancies. Several promising off-target drug effects have led to multiple, mostly preclinical investigations regarding its use in solid tumors. Unfortunately, data on its effectiveness in gynecological malignancies are limited, and (systematic) reviews are missing. The objective of this review was to summarize the existing literature and to analyze the evidence of ibrutinib as a treatment option in gynecological malignancies, including breast cancer. Studies were identified in MEDLINE and EMBASE using a defined search strategy, and preclinical or clinical research projects investigating ibrutinib in connection with these malignancies were considered eligible for inclusion. Our findings showed that preclinical studies generally confirm ibrutinib’s efficacy in cell lines and animal models of ovarian, breast, and endometrial cancer. Ibrutinib exerts multiple antineoplastic effects, such as on-target BTK inhibition, off-target kinase inhibition, and immunomodulation by interference with myeloid-derived suppressor cells (MDSCs), programmed death-ligand 1 (PD-L1), and T cell response. These mechanisms were elaborated and discussed in the context of the evidence available. Further research is needed in order to transfer the preclinical results to a broader clinical appliance.

The cytochrome P450 metabolic profiling of SMU-B in vitro, a novel small molecule tyrosine kinase inhibitor

A novel small molecule tyrosine kinase inhibitor 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1′-methylspiro[indoline-3,4′-piperidine]-2-one (SMU-B) had good activity against ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) targets in non-small-cell lung cancer. The excellent bioactivity of SMU-B highlights the importance of determining its metabolic traits, which could provide meaningful information for further pharmacokinetic studies of SMU-B. In this work, we studied the metabolism of SMU-B in human liver microsomes. Three metabolites of SMU-B were identified by a quadrupole-time of flight tandem mass spectrometer (Q-TOF-MS), and the metabolic pathways of SMU-B were demethylation, dehydrogenation and oxidation. CYP3A4/5 was the principal isoform involved in SMU-B metabolism, as shown by chemical inhibition and recombination human enzyme studies. Additionally, a predication with a molecular docking model confirmed that SMU-B could interact with the active sites of CYP3A4 and CYP3A5. This study illuminates the metabolic profile of the anti-tumor drug SMU-B, which will accelerate its clinical use.

Progress on treatment of MET signaling pathway in non-small cell lung cancer

MET activation includes gene mutation, amplification, and protein overexpression. Clinical evidence suggests that MET activation is both a primary oncogenic driver in lung cancer, and a secondary driver after acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Several small molecule TKIs have already shown to be effective in the MET pathway. However, the activation form and the diagnostic criteria of MET oncogene are still controversial, especially in patients resistant to EGFR TKIs or ALK TKIs. With the development of new MET inhibitors, a quantity of emerging trials has focused on the mechanism of acquired resistance to MET TKIs and therapeutic strategies after resistance.

A pilot study of nintedanib in molecularly selected patients with advanced non-small cell lung cancer (NSCLC) (NCT02299141).

e21694 Background: Nintedanib is a small molecule tyrosine kinase inhibitor targeting VEGFR1-3, PDGFR and FGFR. The purpose of the study was to evaluate the response rate for patients with advanced non-small cell lung cancer (NSCLC) with mutations in TP53, VEGFR1-3, PDGFR-A, PDGFR-B, and FGFR1-3 treated with nintedanib as part of an open label, single arm pilot study. Methods: Patients with advanced NSCLC previously treated with platinum-doublet chemotherapy with ECOG PS≤1 and adequate organ function were enrolled. Exclusion criteria included cavitary or necrotic tumors with invasion of major blood vessels, history of recent thromboembolic events, predisposition to bleeding or thrombosis, myocardial infarction and weight loss > 10% within past 6 months. Nintedanib was administered at a dose of 200 mg orally twice daily during each 28-day cycle until disease progression or unacceptable toxicity. Response assessments were performed every 8 weeks. The primary endpoint was overall response (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS) and correlating outcomes with specific mutations. Results: Between 5/7/2015 and 11/15/2019, 20 patients were enrolled to study. The median age was 66 years, 15/20 (75% were females), 17/20 (85%) had received prior immunotherapy and 11/20 (55%) had received at least three prior lines of systemic therapy. The ORR was 15% with 3/20 partial responses (PR), while 12 patients had stable disease (SD), with disease control (PR+SD≥16 weeks) rate of 60% (12/20). The median progression-free survival and median overall survival were 18 weeks (95% CI: 8-31) and 48 weeks (95% CI:15-56) respectively. All three responders had a TP53 mutation and had received prior immunotherapy. There were nine grade 3 events including transaminitis in 20%, while one patient each (5%) experienced hyperbilirubinemia, anorexia, fatigue, hypertension, and nausea. Grade 4 events included transaminitis (10%) and cerebral edema (5%). There was one grade 5 cardiac event, which was unrelated to nintedanib. Conclusions: In this pilot study in heavily pretreated and molecularly selected patients with metastatic NSCLC, nintedanib showed modest activity. Clinical trial information: NCT02299141.

An exploratory study of fruquintinib as second-line treatment for patients with advanced or metastatic biliary tract cancer.

TPS4657 Background: Biliary tract cancer (BTC) is a relatively uncommon but highly fatal malignancy and most patients with BTC are diagnosed at advanced stages. Currently, no standard second-line treatment has been established following recurrence from the first-line treatment. VEGF is highly expressed in more than 50% of BTC, which indicates anti-angiogenesis might be a potentially effective method to improve the outcome in BTC. Fruquintinib is a novel small molecule tyrosine kinase inhibitor targeting VEGFR1, VEGFR2, and VEGFR3 and is currently being evaluated in clinical trials for multiple cancers including lung cancer, gastric cancer and colorectal cancer, and showed strong anti-tumor activity. However, the effect and safety of fruquintinib has not been investigated in the setting of second-line treatment for BTC. Methods: The study is a multicenter, single-arm, phase 2 trial of fruquintinib (5 mg, po, for 3 weeks, followed by 1 week off, 4 weeks for a cycle) for patients with advanced or metastatic BTC who have failed to first-line chemotherapy. The primary endpoint is progression-free survival (PFS) with the null hypotheses of 8 weeks, and the median PFS≥15 weeks as evidence of the study drug activity (α=0.05, 80% power, one-sided). The number of patients required to complete the study is 27. Allowing for 20% expulsion rate, the study needs 33 patients. The secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS), safety and quality of life (QoL). Meanwhile, the study also set an exploratory objective to evaluate the mutation status of related genes in plasma (cfDNA) and tumor tissue and explore the interplay between mutation patterns with efficacy. Major eligibility requirements: Age ≥18 years; Histologically or cytologically confirmed diagnosis of advanced or metastatic biliary tract adenocarcinoma; First-line chemotherapy failed (tumor progression or intolerable adverse events); No less than 3 months of expected survival; ECOG PS≤1; At least one measurable lesion according to RECIST 1.1 criteria; Adequate organ function. Eligible patients with advanced or metastatic BTC refractory to first-line chemotherapy will be enrolled at 7 medical centers in China. The study is open and actively enrolling at time of submission. Clinical trial information: NCT04156958 .

Efficacy of DNA versus RNA NGS-based Methods in MET Exon 14 skipping mutation detection.

9036 Background: Exon 14 skipping mutations in the mesenchymal-epithelial transition ( MET) gene are reported in 2-5% of lung adenocarcinomas and are mutually exclusive of other driver mutations. Small-molecule MET tyrosine kinase inhibitors, capmatinib and tepotinib, showed durable responses in previously treated and treatment-naïve patients harboring MET-exon-14 skipping mutations. Studies suggest that for detection of MET-ex14 mutations, DNA-based assays alone may be sub-optimal when compared to RNA-based NGS assays. We compared the performance of DNA and RNA-based assays for detection of MET-ex14 variants. Methods: We examined NGS-based profiling data of lung adenocarcinomas (or when this diagnosis could not be excluded) to identify MET-ex14 mutations missed by DNA but identified by RNA analysis. The carcinomas were profiled by a DNA-based NGS panel that targets MET exons 2, 14, 16, 18 and 19. Cases without driver mutations were reflexed to an NGS-based RNA fusion panel (Archer’s Anchored Multiplex PCR). Results: Over a 21-month period, MET-ex14 skipping events were detected in 16/644 (2.5%) lung carcinomas by DNA profiling. RNA analysis on driver-negative cases identified 9 additional MET-ex14 mutations. All 16 MET-ex14 DNA variants occurred at or around the intron 14 splice donor site, as the assay did not include the intron 13 splice acceptor site. Clinical characteristics of the MET positive cohort include a male to female ratio of 0.8:1.0, an average age of 76.5 years and 52% non-smoker status. All tumors were adenocarcinomas (including one with a < 10% spindle/pleomorphic component) with the exception of 3 adenosquamous carcinomas and 1 squamous cell carcinoma. Conclusions: DNA based NGS-panels can potentially miss MET-ex14 skipping events in lung carcinomas, when the primers do not target both 3′ splice site of intron 13, and the 5′ splice site of intron 14. A reflex work flow interrogating RNA fusions can potentially capture such events. The clinical and molecular characterization of the variants detected only by RNA NGS assays warrants further exploration.

Construction and antitumor effects of antitumor micelles with cyclic RGD-modified anlotinib

Anlotinib is a new type of small-molecule multi-target tyrosine kinase inhibitor with inhibitory effects against angiogenesis and tumor growth. An effective targeted nano-delivery system is urgently needed to effectively utilize anlotinib for the treatment of melanoma and lung metastases. In this study, an anlotinib-loaded reduction-sensitive nanomicelle, cyclic RGD peptide (cRGDyk)-anlotinib-reduction sensitive micelles (cARM), was developed as a tumor microenvironment-responsive delivery platform. The micelle carrier was formed by the self-assembly of reduction-sensitive amphiphilic copolymers DSPE-SS-PEG2k and DSPE-PEG2k-cRGDyk. The disulfide bonds in the amphiphilic block of micelles are responsive to elevated GSH in tumor cells for controlled drug release. In a B16F10 tumor-bearing mouse model, cRGDyk-anlotinib-RM (cARM) showed better tumor tissue accumulation and internalization than those for non-reduction-sensitive micelles. Therefore, this reduction-sensitive drug delivery system benefits from its specificity, prolonged blood circulation time, effective absorption by tumor cells, and rapid release of intracellular drugs and is therefore a promising strategy.

Anti-FLT3 nanoparticles for acute myeloid leukemia: Preclinical pharmacology and pharmacokinetics

FLT3 receptor is an important therapeutic target in acute myeloid leukemia due to high incidence of mutations associated with poor clinical outcome. Targeted therapies against the FLT3 receptor, including small-molecule FLT3 tyrosine kinase inhibitors (TKIs) and anti-FLT3 antibodies, have demonstrated promising preclinical and even clinical efficacy. Yet, even with the current FDA approval for two FLT3 inhibitors, these modalities were unable to cure AML or significantly extend the lives of patients with a common mutation called FLT3-ITD. While FLT3 is a viable target, the approaches to inhibit its activity were inadequate. To develop a new modality for targeting FLT3, our team engineered an α-FLT3-A192 fusion protein composed of a single chain variable fragment antibody conjugated with an elastin-like polypeptide. These fusion proteins assemble into multi-valent nanoparticles with excellent stability and pharmacokinetic properties as well as in vitro and in vivo pharmacological activity in cellular and xenograft murine models of AML. In conclusion, α-FLT3-A192 fusions appear to be a viable new modality for targeting FLT3 in AML and warrant further preclinical development to bring it into the clinic.

Association of Programmed Death-Ligand 1 Expression with Fusion Variants and Clinical Outcomes in Patients with Anaplastic Lymphoma Kinase-Positive Lung Adenocarcinoma Receiving Crizotinib.

Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)-positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiving crizotinib. PD-L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase-polymerase chain reaction was used for ALK variant detection, and immunofluorescence-based multiplex staining was applied for exploring immune cells in tumor microenvironments. A total of 78 patients with ALK-positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild-type tumors, PD-L1 expression was lower in ALK-positive ADC. ALK fusion variants were identified in 32 patients, and those with variant 3 and 5 (short variants) had higher PD-L1 expression than those with other variants. The crizotinib objective response rate (ORR) and progression-free survival (PFS) was better in tumors with negative PD-L1 expression (ORR/PFS in PD-L1 0% vs. 1%-49% vs. 50%-100%: 60.7%/11.8 months vs. 38.5%/6.5 months vs. 36.4%/4.0 months, p = .007/.022). The multivariate Cox proportional hazards model revealed that PD-L1 0% (vs. ≥1%) was an independent factor for longer PFS (adjusted hazard ratio 0.322, 95% confidence interval 0.160-0.650, p = .002). Multiplex IHC in three cases showed a varied extent of immune cell infiltrations in tumors with different PD-L1 expression. Positive PD-L1 expression was associated with unfavorable clinical outcomes in patients with ALK-positive lung ADC receiving crizotinib. Not all lung adenocarcinoma with sensitizing driver mutations experienced durable responses to small-molecule tyrosine kinase inhibitors (TKIs). Similar to the negative impact of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor mutant tumors treated with TKIs, this study demonstrated that positive PD-L1 expression was also associated with worse response rate and shorter progression-free survival of anaplastic lymphoma kinase (ALK)-positive adenocarcinoma treated with crizotinib. Among different ALK fusion partners, tumors with short variants (V3 and V5) had higher PD-L1 compared with long variants (V1, V2, and V6). Testing PD-L1 before initiating crizotinib for ALK-positive lung cancer could be a simple method to provide important prognostic information.

Cutaneous adverse effects of biologic medications.

Biologic therapies have become widely used but often cause cutaneous adverse effects. The authors discuss the cutaneous adverse effects of tumor necrosis factor (TNF) alpha inhibitors, epidermal growth factor receptor (EGFR) inhibitors, small-molecule tyrosine kinase inhibitors (TKIs), and cell surface-targeted monoclonal antibodies, including how to manage these reactions and when to refer to a dermatologist.

<p>Effects of Apatinib on the Pharmacokinetics of Nifedipine and Warfarin in Patients with Advanced Solid Tumors</p>

Background and PurposeApatinib is a small-molecule tyrosine kinase inhibitor for the treatment of recurrent or progressive advanced-stage gastric adenocarcinoma or gastroesophageal junction cancer. The in vitro inhibition studies suggested that apatinib exerted potent inhibition on CYP3A4 and CYP2C9. To evaluate the potential of apatinib as a perpetrator in CYP450-based drug–drug interactions in vivo, nifedipine and warfarin were, respectively, selected in the present study as the probe substrates of CYP3A4 and CYP2C9 for clinical drug–drug interaction studies. Since hypertension and thrombus are common adverse effects of vascular targeting anticancer agents, nifedipine and warfarin are usually coadministered with apatinib in clinical practice.MethodsA single-center, open-label, single-arm, and self-controlled trial was conducted in patients with advanced solid tumors. The patients received a single dose of 30 mg nifedipine on Day 1/14 and a single dose of 3 mg warfarin on Day 3/16. On Day 9–21, the subjects received a daily dose of 750 mg apatinib, respectively. The pharmacokinetics of nifedipine and warfarin in the absence or presence of apatinib was, respectively, investigated.ResultsCompared with the single oral administration, coadministration with apatinib contributed to the significant increases of AUC0–48h and Cmax of nifedipine by 83% (90% confidence interval [CI] 1.46–2.31) and 64% (90% CI 1.34–2.01), respectively. Similarly, coadministration with apatinib contributed to the significant increases of AUC0-t and Cmax of S-warfarin by 92% (90% CI 1.68–2.18) and 24% (90% CI 1.10–1.39), respectively.ConclusionConcomitant apatinib administration resulted in significant increases in systemic exposure to nifedipine and S-warfarin. Owing to the risk of pharmacokinetic drug–drug interactions based on CYP3A4/CYP2C9 inhibition by apatinib, caution is advised in the concurrent use of apatinib with either CYP2C9 or CYP3A4 substrates.

A novel small molecule tyrosine kinase inhibitor (GUtinib) preferentially targets discoidin domain receptors and reduces toxic proteins in neurodegeneration (5398)

A novel small molecule tyrosine kinase inhibitor (GUtinib) preferentially targets discoidin domain receptors and reduces toxic proteins in neurodegeneration (5398)

Small molecule tyrosine kinase inhibitors in glioblastoma.

Glioblastoma (GBM) is the most common malignant primary brain tumor, with poor survival despite treatment with surgery, radiotherapy, and chemotherapy with temozolomide. Little progress has been made over the last two decades, and there remain unmet medical needs. Approximately 45% of patients with GBM carry EGFR mutations, and 13% of them possess altered PDGFR genes. Moreover, VEGF/VEGFR mutations are also observed in the patient population. Tyrosine kinase inhibitors (TKIs) are emerging cancer therapy drugs that inhibit signal transduction cascades affecting cell proliferation, migration, and angiogenesis. Indications for small molecule TKIs have been successfully expanded to multiple types of cancer; however, none of the TKIs have been approved for patients with GBM. In this review, we summarize clinical trials of small molecule TKIs in patients with GBM and plausible hypotheses for negative clinical study results. We also discuss the potential TKI candidates that presented significant preclinical outcomes in patients with GBM.