Multiple Kinase Inhibitor Research Articles

Development of UPLC-MS/MS Method to Study the Pharmacokinetic Interaction between Sorafenib and Dapagliflozin in Rats.

Sorafenib (SOR), an inhibitor of multiple kinases, is a classic targeted drug for advanced hepatocellular carcinoma (HCC) which often coexists with type 2 diabetes mellitus (T2DM). Dapagliflozin (DAPA), a sodium–glucose cotransporter-2 inhibitor (SGLT2i), is widely used in patients with T2DM. Notably, co-administration of SOR with DAPA is common in clinical settings. Uridine diphosphate-glucuronosyltransferase family 1 member A9 (UGT1A9) is involved in the metabolism of SOR and dapagliflozin (DAPA), and SOR is the inhibitor of UGT1A1 and UGT1A9 (in vitro). Therefore, changes in UGT1A9 activity caused by SOR may lead to pharmacokinetic interactions between the two drugs. The objective of the current study was to develop an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of SOR and DAPA in plasma and to evaluate the effect of the co-administration of SOR and DAPA on their individual pharmacokinetic properties and the mechanism involved. The rats were divided into four groups: SOR (100 mg/kg) alone and co-administered with DAPA (1 mg/kg) for seven days, and DAPA (1 mg/kg) alone and co-administered with SOR (100 mg/kg) for seven days. Liquid–liquid extraction (LLE) was performed for plasma sample preparation, and the chromatographic separation was conducted on Waters XSelect HSS T3 column with a gradient elution of 0.1% formic acid and 5 mM ammonium acetate (Phase A) and acetonitrile (Phase B). The levels of Ugt1a7 messenger RNA (mRNA) were determined in rat liver and intestine using quantitative real-time polymerase chain reaction (qRT-PCR). The method was successfully applied to the study of pharmacokinetic interactions. DAPA caused a significant decrease in the maximum plasma concentrations (Cmax) and the area under the plasma concentration–time curves (AUC0–t) of SOR by 41.6% and 50.5%, respectively, while the apparent volume of distribution (Vz/F) and apparent clearance (CLz/F) significantly increased 2.85- and 1.98-fold, respectively. When co-administering DAPA with SOR, the AUC0–t and the elimination half-life (t1/2Z) of DAPA significantly increased 1.66- and 1.80-fold, respectively, whereas the CLz/F significantly decreased by 40%. Results from qRT-PCR showed that, compared with control, seven days of SOR pretreatment decreased Ugt1a7 expression in both liver and intestine tissue. In contrast, seven days of DAPA pretreatment decreased Ugt1a7 expression only in liver tissue. Therefore, pharmacokinetic interactions exist between long-term use of SOR with DAPA, and UGT1A9 may be the targets mediating the interaction. Active surveillance for the treatment outcomes and adverse reactions are required.

1659TiP A Spanish observational study for MOLecular characterization of THYroid carcinoma: MOLTHY Project – TTCC-2020-02

Thyroid cancer (TC) is the most frequent endocrine cancer. Treatment is generally based on surgery +/- radioactive iodine (RAI) and TSH suppression in Differentiated TC (DTC) and surgery and levothyroxine suppression in Medullary TC (MTC). Multiple kinase inhibitor drugs have become the standard therapy for advanced TC. New molecular-driven alterations therapies have raised such as neurotrophic tyrosine kinase receptor (NTRK) and rearranged during transfection (RET) inhibitors. The availability of molecular profiling test at cancer centers provides precision medicine in clinical routine and new treatment opportunities.

Novel protein kinase inhibitor TT-00420 inhibits gallbladder cancer by inhibiting JNK/JUN-mediated signaling pathway.

This study aimed to investigate the efficiency of our chemically synthesized TT-00420, a novel spectrum-selective multiple protein kinase inhibitor, in cultured cells and animal models of gallbladder cancer (GBC) and explore its potential mechanism. Multiple GBC models were established to assess the anti-tumor efficiency, toxicity, and pharmacokinetics of TT-00420. Integrated transcriptomic, proteomic and phosphoproteomic analysis was conducted to identify potential downstream effectors of TT-00420. Western blotting, qRT-PCR, nuclear-cytoplasm separation, and immunofluorescence were performed to confirm the multi-omic results and explore the molecular mechanism of TT-00420. Immunohistochemistry was used to detect FGFR1 and p-FGFR1 expression levels in GBC samples. Autodock software was utilized to investigate the potential binding mode between the TT-00420 and the human FGFR1. We found that TT-00420 exerted potent growth inhibition of GBC cell lines and multiple xenograft models. Treatment of mice with 15mg/kg TT-00420 via gavage displayed a half-life of 1.8h in the blood and rapid distribution to the liver, kidneys, lungs, spleen, and tumors at 0.25h, but no toxicity to these organs over 2weeks. Multi-omic analysis revealed c-Jun as a potential downstream effector after TT-00420 treatment. Mechanistically, TT-00420 showed rigorous ability to block FGFR1 and its downstream JNK-JUN (S63/S73) signaling pathway, and induce c-Jun S243-dependent MEK/ERK reactivation, leading to FASLG-dependent tumor cell death. Finally, we found that FGFR1 and p-FGFR1 expression was elevated in GBC patients and these levels correlated with decreased patient survival. TT-00420 shows potent antitumor efficacy and may serve as a novel agent to improve GBC prognosis.

First-in-human, phase I study of TT-00420, a multiple kinase inhibitor, as a single agent in advanced solid tumors.

3013 Background: TT-00420 is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B and Janus kinases (JAK) involved in cytokine signaling and receptor tyrosine kinases (FGFRs and VEGFRs) involved in the tumor microenvironment. TT-00420 has demonstrated anti-tumor activity in both in vitro and in vivo preclinical models of solid tumors, including triple-negative breast cancer (TNBC) and cholangiocarcinoma (CCA). Methods: This phase I, first-in-human, dose escalation and expansion study of TT-00420 ( NCT03654547 ) enrolled adult patients with advanced or metastatic solid tumors. Capsules in 1 mg or 5 mg formulation were administered orally once daily in 28-day cycles. Dose escalation was guided by Bayesian modeling with overdose control. The primary safety endpoints were to determine dose limiting toxicities (DLTs) and a dose recommended for dose expansion (DRDE). Secondary endpoints included pharmacokinetics (PK) and preliminary efficacy evaluated per RECIST v1.1 criterion. Results: As of February 7, 2022, 48 advanced solid tumor patients were enrolled in the study, and received at least one dose of TT-00420 in 7 dose levels: 1 mg q.d. (N = 1), 3 mg q.d. (N = 1), 5 mg q.d. (N = 4), 8 mg q.d. (N = 10), 10 mg q.d. (N = 6), 12 mg q.d. (N = 20), and 15 mg q.d. (N = 6). DLTs were observed in 3 out of 40 DLT-evaluable patients, including 1 patient at 8 mg q.d. who had Grade (Gr) 3 palmar-plantar erythrodysaesthesia syndrome and 2 patients at 15 mg q.d. who both had Gr 3 hypertension. Among the twenty (20) safety evaluable patients treated at 12 mg, the DRDE, drug-related TEAEs included hypertension (n = 11, 55.0%; Gr 3: n = 6, 30%); diarrhea (n = 7, 35%, Gr 3: n = 1, 5%); mucosal inflammation (n = 7, 35%; Gr 3: n = 1, 5%); palmar-plantar erythrodysaesthesia syndrome (n = 6, 30%; Gr 3: n = 0, 0%); and vomiting (n = 4, 20%; Gr 3: n = 0, 0%). No grade 4 suspected adverse events were reported. Out of 42 patients who had at least one post-baseline scan, 7 (16.7%) had a best response of partial response (PR) and 22 (52.4%) had stable disease (SD). Among 7 PRs, 3 were CCA patients (one for each treated at 8 mg, 10 mg, or 12 mg), 2 were TNBC patients (one for each at 10 mg, or 12 mg), 1 was HER2-negative BC patient at 12 mg, and 1 was CRPC patient at 12 mg. Sustainable stable disease for six months or longer was observed in patients with colon cancer (n = 1), head and neck cancer (n = 1), and peritoneal mesothelioma (n = 1). Conclusions: TT-00420 monotherapy was well tolerated and had favorable PK characteristics. The TEAEs observed in dose escalation and dose expansion cohorts were manageable with concomitant treatment and/or dose interruptions of TT-00420 and reversible upon the discontinuation of TT-00420 treatment. Taking safety, efficacy and clinical PK into consideration, 10 mg p.o. q.d. was recommended for phase II study of TT-00420 in patients with advanced CCA. Clinical trial information: NCT03654547.

Phase 1 study of C019199, an oral CSF-1R/DDRs/VEGFR2 multiple kinase inhibitor, to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with advanced solid tumors, including tenosynovial giant cell tumor.

TPS3177 Background: C019199 was designed to be a tumor immune microenvironment (TME) modulator in order to improve the efficacy against tumor growth when combined with immune checkpoint inhibitors, like anti-PD1 or anti-PD-L1. It was shown to have a specific inhibition profile against CSF-1R, DDR1 and VEGFR2 with IC50 of 14nM, 40nM and 79nM, respectively. CSF-1R’s inhibition may deplete Tumor-associated macrophages (TAMs) in TME, help the infiltration of T cells and enhance T cell responses. But a single modulating mechanism may not be strong enough or may be vulnerable and easily overcome by tumors. C019199 can reshape the TME by additionally inhibiting DDRs and VEGFR2, which may remove the "physical barrier" of tumor extracellular matrix and further increase T cell infiltration on top of inducing tumor blood vessels normalization. As a single agent with the appropriate combination of multiple modulation effects, it will potentially turn "cold" tumors into "hot" tumors. Preclinical studies have shown that C019199 inhibits tumor growth in multiple animal tumor models and has better antitumor efficacy when combined with immune checkpoint blockades. Methods: A first-in-human, open label, multicenter, dose-escalation/expansion study of C019199 is currently enrolling. Eligible subjects (age ≥ 18 years and <76 years) with histologically or cytologically confirmed relapsed, refractory, or progressive metastatic solid tumors will be enrolled in. In Part A, the safety and tolerability of C019199 will be assessed in about 25 subjects to identify the maximum tolerated dose and recommended phase Ⅱ dose (PR2D). In Part B, the safety and antitumor activity of the RP2D will be assessed in about 60 subjects in disease-specific expansion cohorts. Primary endpoints are adverse events, laboratory abnormalities, dose-limiting toxicities. Secondary endpoints will include pharmacokinetics, objective response rate, progression-free survival, and disease control rate. Exploratory biomarker analyses include CSF-1 and VEGF. Clinical trial information: CTR20202045.

Reducing regorafenib toxicity by combining with dual JAK-HDAC inhibitor in colorectal cancer.

e15597 Background: In the US, colorectal cancer (CRC) is the third most common cancer. Patients receiving regorafenib, a multiple-kinase inhibitor, recommended to manage metastatic CRCs (mCRCs), has a modest improvement in median overall survival but it is associated with several toxicities. Our present study addresses regorafenib-induced toxicity concerns by combining regorafenib with a novel dual JAK-HDAC inhibitor (JAK-HDACi). The rationale for the dual inhibitor drug selection is due to the facts that the JAK/STAT/SOCS pathway is modulated in CRCs, and concurrent inhibition of JAK sensitizes solid tumors to HDACi. This study focused on evaluating the efficacy and reducing regorafenib-induced toxicity with this novel therapeutic combination in CRC preclinical models. Methods: We evaluated the toxicity of the JAK-HDACi, regorafenib, and their combination in normal colonic cells (CRL-1807) and their efficacy in CRC cell lines (HCT116, RKO, HT29, and SW480) exhibiting various statuses of p53, KRAS, BRAF, EGFR, and microsatellite instability, by conducting colony formation, cell proliferation, and cell cycle arrest assays. Kinome profiling and whole transcriptomic analysis were performed. Their efficacy was assessed in vivo in a CRC patient-derived xenograft (PDX) model, and experimental metastasis was evaluated in NSG mice using luciferase-tagged HT29 cells. Non-invasive, whole-body bioluminescence imaging was performed. Tumor tissues were harvested and stored at −80°C or prepared formalin-fixed paraffin-embedded blocks for Hematoxylin and Eosin (H&E) and immunostaining. Serum analysis was performed to evaluate liver and kidney functions to assess the toxicity. Results: At 500 nM concentrations, there was no pronounced death of CRL-1807 cells, but reduced number of colonies in CRC cells. Drug treatments decreased phosphorylation of STAT3 and ERK1/2 and cell viability, wherein the reduction was robust in the combination. The combination reduced activity of various kinases, as evident through kinome profiling. In SW480 cells, the combination caused G0-G1 cell arrest and decreased the S phase. RNA-seq results revealed modulation of key pathways: apoptosis, ECM-receptor interaction, and focal adhesion. The PDX model showed that the combination treatment reduced tumor growth, as evidenced in H&E staining with higher necrosis and reduced Ki67 staining. Experimental metastasis, bioluminescence imaging, and histological examination showed pronounced reduction in metastasis in mice treated with the combination. Serum chemistry profiles showed that the treatments did not cause systemic toxicity to mice used in either model. Conclusions: The combination therapy with the JAK-HDACi and regorafenib was more effective than the single agents with no evident toxicity. These findings lend credence to a clinical trial to assess this combination for treatment of patients with advanced CRC.

P-77 A phase II study of multiple kinase inhibitor, TT-00420, in advanced, refractory cholangiocarcinoma

Fibroblast growth factor (FGFR) alterations occur in 10-15% adult patients with advanced cholangiocarcinoma (CCA). Pemigatinib and Infigratinib, the first generation FGFR1-3 kinase inhibitors approved for the treatment of the advanced CCA with FGFR2 gene fusions or other rearrangements, are associated with a median progression-free survival of about 6 months after progression on first-line chemotherapy and acquired resistance is common. A novel spectrum-selective multi-kinase inhibitor, TT-00420, has shown clinical responses in multiple CCA patients bearing the gate-keeper mutations acquired from previous FGFR inhibitor treatment(s) in prior phase I study (NCT03654547).

CLINICAL FACTORS PREDICTING RESPONSE TO REGORAFENIB IN METASTATIC COLORECTAL CANCER

Colorectal cancer (CRC) is a common disease with high mortality. Regorafenib (Stivarga ®) is an oral small molecule, multiple kinase inhibitor approved worldwide for use in metastatic colorectal cancer. In our study, clinical factors predicting response to regorafenib were investigated. Patients who applied to Gaziantep Medical Park Hospital and Sanko University Medical Faculty Hospital Medical Oncology outpatient clinic between 2010-2021 with the diagnosis of mCRC and using regorafenib were included in the study. Electronic medical records of the patients were reviewed retrospectively. Statistical analyzes were performed using SPSS version 15.0 software. A total of 20 patients with metastatic colorectal cancer using regorafenib in the third or fourth line therapy were included in the study. Overall, 15 (75%) patients had liver metastases. The median overall survival of the patients was 25.5 months (95% Confidence Interval (CI), 24.1-26.8). Overall survival was not significantly associated with sex, ECOG performance status score, de novo metastatic disease status, smoking status and weight loss history (p=0.139, p=0.240, p=0.173, p=0.911, p=0.923, respectively). A significant association was found between the presence of liver metastasis and survival (p=0.036). The median overall survival was 40.3 months (95% CI, 0-92.6) in patients without liver metastases, and 25 months (95% CI: 13.8-36.2) in patients with liver metastases. In this retrospective study investigating the factors affecting the survival of patients using regorafenib with the diagnosis of mCRC, the presence of liver metastasis was found to be associated with a poor prognosis.

E-Cadherin-Deficient Cells Are Sensitive to the Multikinase Inhibitor Dasatinib.

Simple SummaryInactivating mutations in the CDH1 gene, encoding the cell adhesion protein E-cadherin, cause hereditary diffuse gastric cancer syndrome (HDGC), as well as being a hallmark of sporadic diffuse gastric cancers and lobular breast cancers. We have previously identified AKT3 as a potential vulnerability in gastric cancers lacking CDH1 expression. This study aimed to test whether drugs which inhibit the AKT3-associated gene, discoidin domain receptor tyrosine kinase 2 (DDR2) specifically targeted cells deficient in E-cadherin. We demonstrated that cells and organoids lacking E-cadherin exhibited heightened sensitivity to dasatinib, a drug that targets multiple kinases including DDR2 and SRC.The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for the cancer syndrome hereditary diffuse gastric cancer (HDGC). CDH1-deficient gastric cancers exhibit high AKT serine/threonine kinase 3 (AKT3) expression, but specific drugs against this AKT isoform are not available. We therefore used two publicly available datasets to identify AKT3-associated genes which could be used to indirectly target AKT3. Reactome analysis identified an enrichment of extracellular matrix remodelling genes in AKT3-high gastric cancers. Of the 51 genes that were significantly correlated with AKT3 (but not AKT1), discoidin domain receptor tyrosine kinase 2 (DDR2) showed the strongest positive association. Treatment of isogenic human cells and mouse gastric and mammary organoids with dasatinib, a small molecule inhibitor of multiple kinases including SRC, BCR-ABL and DDR2, preferentially slowed the growth and induced apoptosis of E-cadherin-deficient cells. Dasatinib treatment also preferentially slowed the growth of gastric and mammary organoids harbouring both Cdh1 and Tp53 mutations. In organoid models, dasatinib treatment was associated with decreased phosphorylation of total AKT, with a stronger effect seen in Cdh1-deficient organoids. Treatment with combinations of dasatinib and an inhibitor of AKT, MK2206, enhanced the effect of dasatinib in breast MCF10A cells. In conclusion, targeting the DDR2-SRC-AKT3 axis with dasatinib represents a promising approach for the chemoprevention and chemotherapy of gastric and breast cancers lacking E-cadherin.

Follicular lymphoma-associated mutations in the V-ATPase chaperone VMA21 activate autophagy creating a targetable dependency

The discovery of recurrent mutations in subunits and regulators of the vacuolar-type H+-translocating ATPase (V-ATPase) in follicular lymphoma (FL) highlights a role for macroautophagy/autophagy, amino-acid, and nutrient-sensing pathways in the pathogenesis of this disease. Here, we report on novel mutations in the ER-resident chaperone VMA21, which is involved in V-ATPase assembly in 12% of FL. Mutations in a novel VMA21 hotspot (p.93X) result in the removal of a C-terminal non-canonical ER retrieval signal thus causing VMA21 mislocalization to lysosomes. The resulting impairment in V-ATPase function prevents full lysosomal acidification and function, including impaired pH-dependent protein degradation as shown via lysosomal metabolomics and ultimately causes a degree of amino acid depletion in the cytoplasm. These deficiencies result in compensatory autophagy activation, as measured using multiple complementary assays in human and yeast cells. Of translational significance, the compensatory activation of autophagy creates a dependency for survival for VMA21-mutated primary human FL as shown using inhibitors to ULK1, the proximal autophagy-regulating kinase. Using high-throughput microscopy-based screening assays for autophagy-inhibiting compounds, we identify multiple clinical grade cyclin-dependent kinase inhibitors as promising drugs and thus provide new rationale for innovative clinical trials in FL harboring aberrant V-ATPase.

Designing Novel Compounds for the Treatment and Management of RET-Positive Non-Small Cell Lung Cancer-Fragment Based Drug Design Strategy.

Rearranged during transfection (RET) is an oncogenic driver receptor that is overexpressed in several cancer types, including non-small cell lung cancer. To date, only multiple kinase inhibitors are widely used to treat RET-positive cancer patients. These inhibitors exhibit high toxicity, less efficacy, and specificity against RET. The development of drug-resistant mutations in RET protein further deteriorates this situation. Hence, in the present study, we aimed to design novel drug-like compounds using a fragment-based drug designing strategy to overcome these issues. About 18 known inhibitors from diverse chemical classes were fragmented and bred to form novel compounds against RET proteins. The inhibitory activity of the resultant 115 hybrid molecules was evaluated using molecular docking and RF-Score analysis. The binding free energy and chemical reactivity of the compounds were computed using MM-GBSA and density functional theory analysis, respectively. The results from our study revealed that the developed hybrid molecules except for LF21 and LF27 showed higher reactivity and stability than Pralsetinib. Ultimately, the process resulted in three hybrid molecules namely LF1, LF2, and LF88 having potent inhibitory activity against RET proteins. The scrutinized molecules were then subjected to molecular dynamics simulation for 200 ns and MM-PBSA analysis to eliminate a false positive design. The results from our analysis hypothesized that the designed compounds exhibited significant inhibitory activity against multiple RET variants. Thus, these could be considered as potential leads for further experimental studies.

Zinc supplementation ameliorates sorafenib-induced cognitive impairment through ROS/JNK signaling pathway.

Sorafenib, a multiple kinase inhibitor, is widely used in cancer patients. Recently, clinical studies highlighted the relationship between cognitive deficits and sorafenib exposure. Zinc abundant in the body has been reported to exert neuroprotective activities. However, the effects of zinc supplementation on sorafenib-induced cognitive impairment are still unknown. In the current study, we verified that mice challenged with sorafenib displayed characteristic features of cognitive impairment. However, zinc treatment effectively improved these changes. Histopathological staining also showed that zinc significantly alleviated hippocampal microstructural and ultrastructural damages induced by sorafenib. Meanwhile, zinc significantly reduced sorafenib-induced ROS production and neuronal cells apoptosis in vivo and vitro. Additionally, we also investigated whether zinc protected against sorafenib-induced neuronal cells apoptosis via ROS/JNK pathway through treating SH-SY5Y cells with the NAC or the specific JNK activator anisomycin. The results indicated that NAC performed the same protective effects as zinc in sorafenib-challenged SH-SY5Y cells and activation of JNK by anisomycin partly abolished the protective effects of zinc. Collectively, the present study suggested that inhibition of oxidative stress and the JNK pathway might contribute to the protective effects of zinc against sorafenib-caused cognitive impairment in vivo and vitro.

Real-world efficacy and safety of cabozantinib in Korean patients with advanced hepatocellular carcinoma: a multicenter retrospective analysis.

Background:Cabozantinib, a multiple kinase inhibitor, was recently approved for patients with previously treated unresectable hepatocellular carcinoma (uHCC). We investigated the real-world safety and efficacy profiles of cabozantinib.Methods:This multicenter retrospective study included 110 patients with uHCC who received cabozantinib after progression on other systemic treatments between October 2019 and May 2021.Results:The median age was 58 (range, 20–77) years, and 98 (89.1%) were male. Prior to cabozantinib, all patients were treated with other systemic therapies: sorafenib (n = 104, 94.5%) and regorafenib (n = 91, 82.7%) were the most commonly used agents. Immune checkpoint inhibitors were previously used in 93 patients (84.5%). Cabozantinib was used beyond the third-line of therapy in most patients (n = 90, 81.8%). With a median follow-up duration of 11.9 months [95% confidence interval (CI), 10.8–17.2], the median progression-free survival (PFS) was 3.7 months (95% CI, 3.1–4.9), and the median overall survival (OS) was 7.5 months (95% CI, 5.5–9.5). The disease control rate and overall response rate (ORR) were 66.3% and 3.6%, respectively. In the Child–Pugh A cohort (n = 88), the ORR was 4.5%, and the median PFS and OS were 4.3 months (95% CI, 3.6–5.8) and 9.0 months (95% CI, 7.5–11.7), respectively.Conclusion:Cabozantinib showed consistent efficacy outcomes with a prior phase III trial, although in this study, it was used as later-line therapy for patients who were refractory to multiple systemic treatments, including immune checkpoint inhibitors.

Potential synthetic lethality for breast cancer: A selective sirtuin 2 inhibitor combined with a multiple kinase inhibitor sorafenib

Sorafenib is a clinically useful multiple kinase inhibitor for the treatment of kidney cancer, liver cancer and acute myelocytic leukemia, while it has shown weak efficacy in suppressing breast cancer. Since sirtuin2 (SIRT2) is an important epigenetic regulator and associated with several cancer types including breast cancer, development and evaluation of new SIRT2 inhibitors to probe their therapeutic potentials is currently desirable. A highly selective SIRT2 inhibitor named I was previously developed by us, which showed activity to inhibit non-small cell lung cancer cell lines in vitro. We herein report expanded screening of I and its structurally similar inactive compound II against other cancer cell lines, and found that I had a wide spectrum of anticancer activity while II had no such effects. The I-sorafenib combination treatment exerted obvious synergistic reduction on cell viability of MCF-7 cells. We observed that the combination treatment could suppress cell proliferation, survival and migration, arrest cell cycle at G0/G1 phase, and induce apoptosis in MCF-7 cells, when compared with the single treatment. In vivo studies revealed that the combination treatment showed stronger tumor growth inhibition (87%), comparing with I-(42.8%) or sorafenib-solely-treated groups (61.1%) in MCF-7 xenograft model. In conclusion, this work clearly revealed a potential synthetic lethality effect for I combined with sorafenib, and will probably offer a new strategy at least for breast cancer treatment.

Advances in Biomarker-Driven Targeted Therapies in Thyroid Cancer.

Simple SummaryThis article reviews current treatment practices for thyroid cancer with a focus on novel targeted molecular therapy. Rapidly expanding knowledge of the molecular biology of these cancers coupled with the increased availability of genetic testing has led to exciting paradigm shifts in treatment strategies for these tumor types. We aim to provide up-to-date information on these state-of-the-art therapies as a guide for clinicians who specialize in the treatments of thyroid cancer.Thyroid cancer is the most common type of endocrine malignancy comprising 2–3% of all cancers, with a constant rise in the incidence rate. The standard first-line treatments for thyroid cancer include surgery and radioactive iodine ablation, and a majority of patients show a good response to these therapies. Despite a better response and outcome, approximately twenty percent of patients develop disease recurrence and distant metastasis. With improved knowledge of molecular dysregulation and biological characteristics of thyroid cancer, the development of new treatment strategies comprising novel targets has accelerated. Biomarker-driven targeted therapies have now emerged as a trend for personalized treatments in patients with advanced cancers, and several multiple receptor kinase inhibitors have entered clinical trials (phase I/II/III) to evaluate their safety and efficacy. Most extensively investigated and clinically approved targeted therapies in thyroid cancer include the tyrosine receptor kinase inhibitors that target antiangiogenic markers, BRAF mutation, PI3K/AKT, and MAPK pathway components. In this review, we focus on the current advances in targeted mono- and combination therapies for various types of thyroid cancer.

Regorafenib in metastatic colorectal cancer: more data for clinical decisions

Regorafenib is a multiple kinase inhibitor. It influences/blocks angiogenesis (VEGFR1-3, TIE2), proliferation (KIT, RET, RAF-1, BRAF), metastatic activity (VEGFR2-3, PDGFR), tumor immunogenicity (CSF1R), tumor microenvironment (PDGFR-, PDGFR-, FGFR1-2). Regorafenib has several indications including metastatic colorectal cancer. Efficacy and safety of regorafenib data from clinical trials (CORRECT, CONCUR, CONSIGN) and observational trials from real world (REBECCA, CORRELATE, RECORA, PMS, REGOTAS) are summarized and presented in this issue. State of the matter of molecular-biologic predictors (KRAS, PIK3CA ANG-2, VEGF-A, LDH, CCL5/CCR5, CA 19-9) and radiological predictors (RadioCORRECT and other trials) is highlighted. Regimens with dose modification and its influence on effectiveness and tolerability of regorafenib are described according to the data from ReDOS, RESET, REARRANGE trials. The results from retrospective trials comparing regorafenib and another approved for refractory metastatic colorectal cancer drug trifluridine/tipiracil are presented.

Ibrutinib Blocks YAP1 Activation and Reverses BRAF Inhibitor Resistance in Melanoma Cells.

Most B-Raf proto-oncogene (BRAF)-mutant melanoma tumors respond initially to BRAF inhibitor (BRAFi)/mitogen-activated protein kinase kinase 1 inhibitor (MEKi) therapy, although few patients have durable long-term responses to these agents. The goal of this study was to use an unbiased computational approach to identify inhibitors that reverse an experimentally derived BRAFi resistance gene expression signature. Using this approach, we found that ibrutinib effectively reverses this signature, and we demonstrate experimentally that ibrutinib resensitizes a subset of BRAFi-resistant melanoma cells to vemurafenib. Ibrutinib is used clinically as an inhibitor of the Src family kinase Bruton tyrosine kinase (BTK); however, neither BTK deletion nor treatment with acalabrutinib, another BTK inhibitor with reduced off-target activity, resensitized cells to vemurafenib. These data suggest that ibrutinib acts through a BTK-independent mechanism in vemurafenib resensitization. To better understand this mechanism, we analyzed the transcriptional profile of ibrutinib-treated BRAFi-resistant melanoma cells and found that the transcriptional profile of ibrutinib was highly similar to that of multiple Src proto-oncogene kinase inhibitors. Since ibrutinib, but not acalabrutinib, has appreciable off-target activity against multiple Src family kinases, it suggests that ibrutinib may be acting through this mechanism. Furthermore, genes that are differentially expressed in ibrutinib-treated cells are enriched in Yes1-associated transcriptional regulator (YAP1) target genes, and we showed that ibrutinib, but not acalabrutinib, reduces YAP1 activity in BRAFi-resistant melanoma cells. Taken together, these data suggest that ibrutinib, or other Src family kinase inhibitors, may be useful for treating some BRAFi/MEKi-refractory melanoma tumors. SIGNIFICANCE STATEMENT: MAPK-targeted therapies provide dramatic initial responses, but resistance develops rapidly; a subset of these tumors may be rendered sensitive again by treatment with an approved Src family kinase inhibitor-ibrutinub-potentially providing improved clinical outcomes.

Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes

An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which suppresses tumorigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD1, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of ‘druggable’ targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify compounds that confer synthetic lethality with LIMD1 loss in NSCLC cells. PF-477736 was shown to selectively target LIMD1-deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 was effective in treating LIMD1−/− tumours in subcutaneous xenograft models, with no significant effect in LIMD1+/+ cells. We have identified a novel drug tool with significant preclinical characterisation that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.

Discovery of a Potent Candidate for RET-Specific Non-Small-Cell Lung Cancer-A Combined In Silico and In Vitro Strategy.

Rearranged during transfection (RET) is a tyrosine kinase oncogenic receptor, activated in several cancers including non-small-cell lung cancer (NSCLC). Multiple kinase inhibitors vandetanib and cabozantinib are commonly used in the treatment of RET-positive NSCLC. However, specificity, toxicity, and reduced efficacy limit the usage of multiple kinase inhibitors in targeting RET protein. Thus, in the present investigation, we aimed to figure out novel and potent candidates for the inhibition of RET protein using combined in silico and in vitro strategies. In the present study, screening of 11,808 compounds from the DrugBank repository was accomplished by different hypotheses such as pharmacophore, e-pharmacophore, and receptor cavity-based models in the initial stage. The results from the different hypotheses were then integrated to eliminate the false positive prediction. The inhibitory activities of the screened compounds were tested by the glide docking algorithm. Moreover, RF score, Tanimoto coefficient, prime-MM/GBSA, and density functional theory calculations were utilized to re-score the binding free energy of the docked complexes with high precision. This procedure resulted in three lead molecules, namely DB07194, DB03496, and DB11982, against the RET protein. The screened lead molecules together with reference compounds were then subjected to a long molecular dynamics simulation with a 200 ns time duration to validate the inhibitory activity. Further analysis of compounds using MM-PBSA and mutation studies resulted in the identification of potent compound DB07194. In essence, a cell viability assay with RET-specific lung cancer cell line LC-2/ad was also carried out to confirm the in vitro biological activity of the resultant compound, DB07194. Indeed, the results from our study conclude that DB07194 can be effectively translated for this new therapeutic purpose, in contrast to the properties for which it was originally designed and synthesized.

The Emerging Influences of Alpha-Fetoprotein in the Tumorigenesis and Progression of Hepatocellular Carcinoma.

Simple SummaryHepatocellular carcinoma is characterized by aggressive invasion, rapid progress and poor prognosis. Since hepatocellular carcinoma is a highly heterogeneous cancer, both at the molecular and histological level, the precision medicine for patients is not very effective and the systematic targeted therapies remain unsatisfactory. The identification of new targets and molecular pathways is urgently needed for drug treatment of hepatocellular carcinoma. Alpha-fetoprotein acts as the most common tumor marker used for hepatocellular carcinoma diagnosis. Alpha-fetoprotein in serum and cytoplasm shows very different influences in the tumorigenesis and progression of hepatocellular carcinoma. The aim of this review is to summarize the current knowledge of the role of alpha-fetoprotein in hepatocellular carcinoma.Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, and its mortality rate is the third-highest, after lung cancer and colorectal cancer. Currently, systematic targeted therapies for HCC mainly include multiple kinase inhibitors and immunotherapy. However, these drugs carry a black-box warning about the potential for inducing severe toxicity, and they do not significantly prolong the survival period of patients due to the highly heterogeneous characteristics of HCC etiology. In order to improve the prediction, effective treatment and prognosis of HCC, the tools and different biomarkers in clinical practices are recommended. Alpha-fetoprotein (AFP) is the earliest and the most widely used serum marker in the detection of HCC. Interestingly, serum AFP and cytoplasmic AFP show different, even opposite, roles in the cancer progression of HCC. This review focuses on biological characteristics, regulatory mechanisms for gene expression, emerging influences of AFP in HCC and its possible implications in HCC-targeted therapy.