Multitargeted Tyrosine Kinase Inhibitor Research Articles

Cabozantinib in the Treatment of Neuroendocrine Neoplasms: Insights Across Different Tumor Origins.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from neuroendocrine cells, exhibiting a wide range of behaviours from indolent to highly aggressive forms. Treatment options remain limited, particularly for progressive cases. Cabozantinib, a multitarget tyrosine kinase inhibitor, has demonstrated potential in targeting key pathways related to tumor growth, angiogenesis, and metastasis. This review provides a comprehensive analysis of cabozantinib's therapeutic role across various NEN subtypes, including gastroenteropancreatic NENs, lung NENs, pheochromocytomas/paragangliomas, Merkel cell carcinoma, presacral NENs, pituitary neuroendocrine tumors, and neuroendocrine prostate cancer. The paper discusses several preclinical and clinical studies that demonstrate the efficacy of cabozantinib in slowing tumor progression and improving progression-free survival, particularly in patients with progressive, well-differentiated NENs. However, cabozantinib's complex toxicity profile limits its broad application, necessitating further research to optimize dosing, particularly in syndromic NENs. Ongoing trials are investigating cabozantinib in combination with somatostatin analogues, peptide receptor radionuclide therapy, temozolomide and immunotherapies in order to overcome treatment resistance and expanding therapeutic strategies for advanced NENs.

Off-label use of anlotinib in malignancies' treatment: efficacy and management of adverse reactions.

Anlotinib is a novel small-molecule multi-target tyrosine kinase inhibitor (TKIs) independently developed in China, it possesses the functions of inhibiting tumor angiogenesis and suppressing tumor growth. Anlotinib has achieved notable therapeutic effects in approved indications for advanced non-small cell lung cancer, soft tissue sarcoma, small cell lung cancer, and medullary thyroid carcinoma. Additionally, with unanimous expert consensus, it has been used off-label in various other tumors, yielding favorable outcomes. This article reviews the efficacy and common adverse reactions, as well as their management, of off-label use of anlotinib in various malignant tumors.

Efficacy and safety of anlotinib as a later-line treatment for advanced colorectal cancer.

194 Background: Colorectal cancer (CRC) is increasingly prevalent in China, with rising incidence and mortality rates. Often, early-stage CRC presents with no symptoms, leading to most patients being diagnosed at an advanced stage, where prognosis is poor. First- and second-line treatments for advanced CRC typically include chemotherapy combined with cetuximab or bevacizumab. However, third-line therapies such as regorafenib, furosemide, and TAS102 have shown limited efficacy. Anlotinib, a multi-targeted tyrosine kinase inhibitor (TKI), has demonstrated improved progression-free survival (PFS) in refractory metastatic CRC (mCRC) in a phase III trial (NCT02332499), showing both efficacy and manageable toxicity. This report provides updated results from extended follow-up. Methods: This study enrolled 73 patients with advanced colorectal cancer who had undergone at least two prior standard treatments and were treated with oral anlotinib hydrochloride (8-12 mg daily, days 1-14 of a 21-day cycle) between November 2021 and March 2024 at Tangdu Hospital. Patients were treated until disease progression or intolerable adverse events. Efficacy was assessed using RECIST version 1.1, and adverse reactions were evaluated using CTCAE version 5.0. The primary endpoints were PFS, disease control rate (DCR), and adverse events (AEs), while secondary endpoints included overall survival (OS). Results: Of the 73 patients included, 38 had an ECOG performance status (PS) of 0-1, and 35 had a PS of 2. Clinical staging identified 18 patients with stage IIIB/IIIC and 55 with stage IV disease. Patients received anlotinib doses of 8 mg (n=11), 10 mg (n=44), or 12 mg (n=18), with 48 patients also receiving chemotherapy and 25 receiving anlotinib alone. The median PFS was 4.0 months (95% CI: 3.4-4.6), and the median OS was 7.0 months (95% CI: 5.7-8.3). Subgroup analysis indicated that patients under 60 years of age, those without liver metastases, and those with ECOG PS 0-1 derived greater benefit from anlotinib. The most common treatment-related adverse event was hypertension (19.2%). Other notable adverse events included elevated AST (11.0%), proteinuria (6.8%), and jaundice (6.8%). Most adverse reactions were grade 1-2, although 1 patient experienced grade ≥3 gastrointestinal bleeding. Conclusions: Anlotinib showed promising efficacy and a favorable safety profile as a later-line treatment for advanced colorectal cancer. These findings suggest that anlotinib may be a viable clinical option for advanced CRC, though larger-scale clinical trials are necessary to confirm these results and further define its role in treatment.

Zanzalintinib (XL092) alone or in combination with atezolizumab in patients (pts) with refractory metastatic colorectal cancer (mCRC): Results from an expansion cohort of the phase 1 STELLAR-001 study.

127 Background: VEGFR tyrosine kinase inhibitors (TKIs) in combination with immune checkpoint inhibitors (ICIs) have demonstrated clinical activity in pts with previously treated mCRC, particularly in pts without liver metastases (LM). Zanzalintinib (zanza) is a novel, oral, multitargeted TKI with activity against VEGFR, MET, and TAM kinases. Here, we present results from the randomized expansion cohort of pts with previously treated non-MSI-H/dMMR mCRC receiving zanza ± atezolizumab (atezo) in the phase 1 STELLAR-001 study (NCT03845166). Methods: Adults (aged ≥18 y) with locally advanced or metastatic CRC that was RAS -wildtype, who were refractory/intolerant to prior standard of care (5-FU–based treatment ± targeted therapies) and had an ECOG PS of 0/1, were enrolled. Pts with MSI-high or dMMR CRC, or who had received prior treatment with a PD-L1/PD-1 targeting ICI, regorafenib, and/or TAS-102, were excluded. Pts were randomized 1:1 to receive zanza+atezo (100 mg QD + 1200 mg Q3W) or single-agent zanza (100 mg QD). Objectives were to evaluate median (m)OS, investigator-assessed ORR, and mPFS per RECIST 1.1, and safety. Results: As of May 6, 2024, 107 pts were enrolled (zanza+atezo, n=54; zanza, n=53). In the zanza+atezo/zanza groups, median age was 61/60 years, 39%/51% had an ECOG PS of 1, pts had a median 2.5/3.0 (range, 1–5) prior lines of therapy, and 31%/32% did not have LM. With a median follow-up of 15 months across both arms, the mOS was 14.3 and 11.1 months for zanza+atezo and zanza, respectively (HR 0.75, 95% CI 0.45–1.26), confirmed ORR was 7.4% and 1.9% (all partial responses), mPFS was 4.0 and 3.0 months (HR 0.68, 0.44–1.04), and DCR was 59% and 55%. In pts without LM, mOS was not reached and 12.5 months (HR 0.46, 0.15–1.36) with 6-month survival rates of 88% and 65%, confirmed ORR was 18.0% and 5.9%, mPFS was 8.2 and 3.3 months (HR 0.40, 0.16–1.0), and DCR was 76% and 59%. The most common treatment-related adverse events (TRAEs) were diarrhea (zanza+atezo, 52%; zanza, 49%), nausea (54%, 36%), and decreased appetite (41%, 36%). Grade 3/4 TRAEs occurred in 48% of pts with zanza+atezo and 40% with zanza (Grade 4 in 3.7% and 0); a Grade 5 TRAE occurred in 1 pt (2%) in each group. 89% and 94% of pts had discontinued study treatment. Zanza was discontinued due to TRAEs in 11% and 8% of pts; atezo was discontinued due to TRAEs in 9% (zanza+atezo). Biomarker analysis is ongoing and results will be presented. Conclusions: Clinical activity was observed with zanza both as a single agent and in combination with atezo in this cohort of heavily pretreated pts with mCRC. Greater activity was seen with zanza+atezo versus zanza alone, particularly in pts without LM. Both treatments were generally well tolerated. Evaluation of zanza+atezo versus regorafenib is ongoing in the phase 3 STELLAR-303 study in non-MSI-H/dMMR mCRC (NCT05425940). Clinical trial information: NCT03845166 .

Kinomic profiling to predict sunitinib response of patients with metastasized clear cell Renal Cell Carcinoma.

Treatment with Sunitinib, a potent multitargeted receptor tyrosine kinase inhibitor (TKI) has increased the progression-free survival (PFS) and overall-survival (OS) of patients with metastasized renal cell carcinoma (mRCC). With modest OS improvement and variable response and toxicity predictive and/or prognostic biomarkers are needed to personalize patient management: Prediction of individual TKI therapy response and resistance will increase successful treatment outcome while reducing unnecessary drug use and expense. The aim of this study was to investigate whether kinase activity analysis can predict sunitinib response and/or toxicity using tissue samples obtained from primary clear cell RCC (ccRCC) from a cohort of clinically annotated patients with mRCC receiving sunitinib as first-line treatment. EuroTARGET partners collected ccRCC and matched normal kidney tissue samples immediately after surgery, snap-frozen and stored at -80°C until use. Phosphotyrosine-activity profiling was performed using PamChip® peptide microarrays (144 peptides derived from known phosphorylation sites in Protein Tyrosine Kinase substrates) of lysed tissue samples (5 µg protein input) of 163 mRCC patients. Evolve software Was used to analyze kinome profiles and Bionavigator was used for unsupervised and supervised clustering. The kinexus kinase predictor (www.phosphonet.ca) was used to analyze the peptide lists within the clusters. Kinome data was available from 94 patients who received sunitinib as 1st-line treatment and had complete follow-up of their clinical data (PFS, OS and toxicity) for at least 6 months. Matched normal tissue was available from 14 mRCC patients. Supervised clustering of basal kinome activity could correctly classify mRCC patients with PFS >9 months versus PFS<9 months with an accuracy of 61 %. Unsupervised hierarchical clustering revealed 3 major clusters related to immune signaling, VEGF pathway, and immune signaling/cell adhesion. Basal kinase activity levels of patients with short PFS were substantially higher compared to patients who experienced extended PFS. Based on kinase levels ccRCC tumors can be subdivided into 3 clusters which may reflect the aggressiveness of these tumors. The accuracy of response prediction of 61 % based on basal kinase levels is too low to justify implementation. STK assays may help to predict sunitinib toxicity and guide clinical management. Additionally, it is possible that mRCC patients with an immune kinase signature are better checkpoint inhibitor candidates, but this needs to be studied.

Anlotinib combined with penpulimab and nab-paclitaxel as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.

367 Background: Recently, PD-1 blockades combined with dual chemotherapy regimens in first-line setting exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remained unsatisfactory. Therefore, PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy regimen might offer a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as first-line combination therapy or second-line monotherapy for ESCC patients in China clinically. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with penpulimab (PD-1 blockade) and nab-paclitaxel as first-line therapy in advanced ESCC. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and treated with anlotinib (12mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m 2 , iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 30. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and OS. Results: From Jul 2022 to Sep 2024, a total of 30 patients were enrolled, with 29 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 1 CR (3.4%), 23 PR (79.3%), 2 SD (6.9%) and 3 NE (10.3%). Therefore, the preliminary ORR was 82.8% (95%CI: 64.2%-94.2%), DCR was 89.7% (95%CI: 72.6%-97.8%). The primary median PFS of the 29 patients was 10.84 months (95%CI: 7.57-14.11). Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 29 patients with the incidence &gt;20% were anemia (62%), leukopenia (31%), peripheral neurotoxicity (28%) and rash (21%). Common grade ≥3 treatment-emergent adverse events were leukopenia (7%), glutamic-pyruvic transaminase was elevated (3%), glutamic oxalacetic transaminase increased (3%), hypertension (3%), diarrhea (3%) and rash (3%). Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy for advanced ESCC demonstrated promising efficacy and manageable safety profile. And the conclusions needed to be confirmed in subsequent trials. Clinical trial information: ChiCTR2400089133 .

Prolonged Β-Hydroxybutyrate-Mediated Ketosis Enhances Ponatinib Response of K562 Chronic Myeloid Leukaemia Cells

Purpose: Ketosis is a metabolic state characterized by production of ketone bodies, including acetoacetate, β-hydroxybutyrate (BHB), and acetone, in response to reduced blood glucose levels. BHB stands out as the principal ketone body in nutritional ketosis which has diverse therapeutic implications for metabolic, nondegenerative and neoplastic disorders. In current study we investigated the impact of ketosis on chronic myeloid leukaemia (CML) cell viability and drug response. Materials and Methods: We investigated the impact of BHB-mediated ketosis on the viability of K562 cells, an in vitro model of CML, and explored the influence of BHB on the sensitivity of these cells to ponatinib, a multi-targeted tyrosine kinase inhibitor used in CML treatment. We used MTT assay to measure cell viability and Hoechst/PI assay to measure cell death. Results: Our findings reveal that BHB concentrations ranging from 1 mM to 5 mM, which fall within the physiological range of ketosis, elicit a minimal yet concentration-dependent reduction in cell viability. We also observed that while a 24-hour pre-treatment with BHB did not enhance the response of K562 cells to ponatinib, prolonged ketosis (4 days) improved response of cells to the drug by decreasing final cell viability from 25.15% to 13.12%. The primary mode of viability inhibition by ponatinib was cell death which was further intensified by exposure to prolonged ketosis. Conclusion: Ketosis induced by ketogenic diet of ketone body supplementation is considered as safe and effective adjuvant cancer therapy options and here, we report its potential effectiveness in the context of CML.

Combination therapy of multi-targeted tyrosine kinase inhibitors and immune checkpoint inhibitors for advanced adrenocortical carcinoma

Combination therapy of multi-targeted tyrosine kinase inhibitors and immune checkpoint inhibitors for advanced adrenocortical carcinoma

Effects of Food on the Pharmacokinetics and Safety of HA121-28 Tablet, a Novel Multi-Targeting Tyrosine Kinase Inhibitor, in Healthy Chinese Subjects: A Phase I Clinical Trial.

HA121-28, a novel multi-targeting tyrosine kinase inhibitor, has dual efficacy against tumor growth and neovascularization. The objectives of this study were to assess the effect of high-fat and high-calorie food on thepharmacokinetic(PK) profile and safety of HA121-28 tablet in healthy subjects. A single-dose, randomized, open-label, two-period, crossover-designed phase I clinical trial was conducted. Subjects received 200 mg HA121-28 in the fasted state or with high-fat and high-calorie breakfast. The effects of high-fat and high-calorie food on the PK profile and safety of HA121-28 were evaluated by using noncompartmental analysis and whole-process safety assessment. Twenty subjects were successfully completed the trial. The geometric mean ratios (GMRs) for the peak concentration in plasma (Cmax), area under the curve from zero to the time point (AUClast), and area under the curve from zero to infinite (AUCinf) postprandially versus fasted were 108.45% (98.51% - 119.40%), 105.23% (100.25% - 110.47%), and 104.14% (97.41% - 111.34%), respectively. The majority of reported adverse events were graded as either level 1 or 2 in severity and recovered spontaneously without any interventions. The exposure of HA121-28 was not significantly affected by the high-fat and high-calorie food. The clinical application of HA121-28 tablet can be recommended for use in both fasted and postprandial states.

Sorafenib-induced cardiovascular toxicity: a cause for concern.

Sorafenib, a multi-target tyrosine kinase inhibitor, is primarily used to manage hepatocellular carcinoma, advanced renal cell carcinoma, and differentiated thyroid cancer. Although this drug extends patient survival and slows tumor progression, its cardiovascular toxicity substantially impacts of quality of life. Effective the prevention and treatment of the resulting complications are needed. The mechanisms underlying of sorafenib-induced cardiovascular toxicity are complex, and remain incompletely understood despite extensive research. In this review, we discuss the incidence of sorafenib-induced cardiovascular toxicity, including hypertension, thromboembolism, and heart failure in clinical settings. We also summarize current research on the underlying mechanisms, such as ferroptosis, necroptosis, autophagy, mitochondrial damage, and endoplasmic reticulum stress. Additionally, we explore studies regarding the protective effects of various drugs against sorafenib-induced cardiovascular toxicity. This in-depth synthesis of data regarding the clinical manifestations and mechanisms of sorafenib-induced cardiotoxicity provides a valuable scientific foundation for developing therapeutic drugs to combat these adverse effects.

Clinical and biomarker analyses of SHR-1701 combined with famitinib in patients with previously treated advanced biliary tract cancer or pancreatic ductal adenocarcinoma: a phase II trial

Advanced biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC) have poor prognoses and limited treatment options. Here, we conducted this first-in-class phase II study to evaluate the efficacy and safety of SHR-1701, a bifunctional fusion protein targeting programmed death-ligand 1 (PD-L1) and transforming growth factor-beta (TGF-β), combined with famitinib, a multi-targeted receptor tyrosine kinase inhibitor, in patients with advanced BTC or PDAC who failed previous standard treatment (trial registration: ChiCTR2000037927). Among 51 enrolled patients, the BTC cohort showed an objective response rate (ORR) of 28% (including 2 complete responses) and a disease control rate (DCR) of 80%, with a median progression-free survival (mPFS) of 5.1 months and a median overall survival (mOS) of 16.0 months. In the PDAC cohort, the ORR was 15% (2 complete responses), with a DCR of 60%, and the mPFS and mOS were 2.1 months and 5.3 months, respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 29.4% of patients, with no grade 5 TRAEs reported. Exploratory analyses revealed that primary tumor resection history, peripheral blood immunophenotype changes, and distinct immune-metabolic profiles were associated with treatment benefits. An immune/metabolism score integrating the features of six genes was developed as a predictive biomarker for immunotherapy response in multiple cohorts, allowing for the selection of patients most likely to experience positive outcomes from this therapy regimen. In conclusion, our study provides proof-of-concept data supporting the potential of SHR-1701 plus famitinib as an effective and safe subsequent-line therapy for refractory BTC and PDAC, highlighting the promise of targeting PD-L1, TGF-β, and angiogenesis pathways simultaneously.

Efficacy and Safety of Pazopanib in the Treatment of Thyroid Cancer: A Systematic Review.

Pazopanib, a multi-targeted tyrosine kinase inhibitor, has been explored for its efficacy in treating various subtypes of thyroid cancer, including differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC). This systematic review assesses the efficacy and safety of pazopanib, focusing on the progression-free survival (PFS), overall survival (OS), and response rates and adverse events. A comprehensive search was conducted in databases including PubMed, Scopus, and Web of Science up to October 2024 to identify randomized controlled trials and phase II clinical trials that investigated the use of pazopanib in thyroid cancer. The PRISMA guidelines were followed for data extraction and quality assessment. The review included six studies encompassing 289 patients, presenting a comprehensive overview of pazopanib's application across different thyroid cancer subtypes. The studies reported median PFS rates ranging from 2.1 to 11.7 months and median OS rates ranging from 5.7 months to not reached. The partial response rates varied from 5% to 49%. Adverse events were common, with hypertension occurring in up to 71.7% of patients, and fatigue and diarrhea were also frequently reported. Grade 3-5 adverse events led to treatment discontinuations in up to 14% of patients. Pazopanib shows variable efficacy across thyroid cancer types, offering significant benefits in MTC and refractory DTC in terms of PFS and OS but limited impact in ATC. The adverse event profile necessitates careful management, particularly regarding hypertension and other treatment-related toxicities. Further studies are required to refine the therapeutic protocols for pazopanib, exploring combination therapies that may enhance its efficacy and reduce the adverse outcomes.

In vitro assessment of the role of endoplasmic reticulum stress in sunitinib-induced liver and kidney toxicity

Sunitinib, a multi-targeted tyrosine kinase inhibitor, is prescribed for the treatment of metastatic gastrointestinal stromal tumors, advanced metastatic renal cell carcinoma, and pancreatic neuroendocrine tumors. Hepatotoxicity and nephrotoxicity are significant adverse effects of sunitinib administration; however, there is limited information regarding the molecular mechanisms of these adverse effects. The aim of the present study was to elucidate the role of endoplasmic reticulum stress in hepatotoxicity and nephrotoxicity induced by sunitinib. In addition to endoplasmic reticulum stress, oxidative stress and mitochondrial membrane potential were evaluated to investigate the molecular mechanism more comprehensively. Findings revealed that sunitinib exposure significantly increased the reactive oxygen species levels and decreased the Nrf2 gene expression and GSH/GSSG ratio, suggesting oxidative stress induction in normal hepatocyte (AML12) and normal kidney (HK-2) cell lines. Endoplasmic reticulum stress markers, including ATF4, CHOP, IRE1α, XBP1s and ATF6 mRNA expressions, were upregulated in AML12 cells. Furthermore, enhanced intracellular calcium levels also indicate endoplasmic reticulum stress in hepatocytes. In contrast, sunitinib exposure did not alter endoplasmic reticulum-related gene expression levels and intracellular calcium levels in HK-2 cells. In terms of mitochondrial membrane potential and caspase-3 activity, sunitinib induced mitochondrial membrane damage and increased caspase-3 activation not only in AML12 cells but also in HK-2 cells. The research findings indicate that sunitinib may induce cytotoxic effects in hepatocytes through mechanisms involving oxidative stress, endoplasmic reticulum stress, and mitochondrial damage. However, in the kidney, the toxicity mechanism is different from that of liver, and the endoplasmic reticulum stress does not seem to be involved in this mechanism.

Nintedanib attenuates NLRP3 inflammasome-driven liver fibrosis by targeting Src signaling

Liver injury induces an inflammatory response that activates hepatic stellate cells, which is the initial factor of liver fibrosis. Nintedanib, a multi-targeted tyrosine kinase inhibitor targeting the Src signalling pathway, has been approved for the treatment of idiopathic pulmonary fibrosis. However, it is still not known whether nintedanib ameliorates liver fibrosis by inhibiting inflammasome activation. Here, a carbon tetrachloride (CCl4)-induced liver fibrosis model was used to assess the anti-fibrotic efficacy of nintedanib in vivo. Lipopolysaccharide and ATP were used to activate nucleotide oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in LX-2 cells, and the efficacy of nintedanib on NLRP3 inflammasome activation was evaluated. Moreover, we used Src-overexpressing and Src-downregulating lentiviruses to transfect LX-2 cells to explore the targets of nintedanib. Nintedanib attenuated inflammation and extracellular matrix accumulation in CCl4-induced fibrotic livers and reduced the expression of NLRP3, fibrotic makers, and the phosphorylation of Src, epidermal growth factor receptor (EGFR), AKT, ERK1/2 in LX-2 cells. Furthermore, nintedanib thwarted NLRP3 inflammasome activation by suppressing the phosphorylation of Src and its downstream signalling pathway and reducing reactive oxygen species production. Our study indicates that nintedanib effectively suppresses NLRP3 inflammasome activation and has the potential for the treatment of liver fibrosis.

The role of external-beam radiotherapy for differentiated thyroid cancer.

The treatment options for differentiated thyroid cancer (DTC) are surgery, thyroid stimulating hormone suppression, radioactive iodine, and multitargeted tyrosine kinase inhibitors. The role of external-beam radiotherapy (EBRT) for DTC is controversial because of the lack of randomized controlled trials, but prospective single-arm studies and propensity score matching analyses have shown its efficacy and safety. This review discusses the role of EBRT after resection of gross disease, when there is a high risk of locoregional failure, as well as its role for locoregionally gross recurrent and unresectable disease. As in other tumor sites, EBRT has an important role in the palliative management and local control of patients with metastatic DTC, especially with bone and brain metastases.

Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients.

Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.

Silk Fibroin-Based Lenvatinib Nanomedicine with Conformation Tunability for Systemic Treatment of Hepatocellular Carcinoma.

Multitarget tyrosine kinase inhibitors (TKIs) serve as first-line therapeutics in the systemic treatment of hepatocellular carcinoma (HCC), yet their clinical effectiveness is hampered by suboptimal pharmacokinetics and bioavailability. There is a critical need to enhance the circulation, tumor targeting, and infiltration of TKIs. In this context, we developed a silk fibroin (SF)-based nanomedicine that exploits the chemical versatility and conformation tunability of SF. Folic acid (FA) with affinity toward HCC cells is utilized to functionalize SF, simultaneously aiding in the pH-sensitive β-sheet transitions of SF. This dynamic conformation behavior is key to improving the nanomedicine's circulation, biological adhesion, and tumor localization. By encapsulating Lenvatinib (Leva) TKI, the nanomedicine exhibits tumor-targeted accumulation and potent inhibition on HCC cell survival and angiogenesis, thereby amplifying Leva's bioavailability and therapeutic impact. Owing to SF's low immunogenicity and high reproducibility, this SF-based approach for TKI delivery holds substantial promise for advancing HCC systemic therapy.

Dasatinib and erianin co-loaded ion-responsive in-situ hydrogel for effective treatment of corneal neovascularization

Corneal neovasularization (CNV) is one of the leading causes for visual impairment. Dasatinib is a multi-target tyrosine kinase inhibitor, which can inhibit both platelet derived growth factor receptor and Src family kinases. Erianin exhibits excellent anti-inflammatory and anti-angiogenic effects. In this study, dasatinib and erianin were found to synergically inhibit the proliferation, migration and tube formation of Ea.hy926 cells, the three most important cellular processes of CNV. Next, dasatinib and erianin were co-encapsulated in nanostructured lipid carriers (dasa-eri-NLC), which increased the solubility of dasatinib by about 1790 times, increased the solubility of erianin by about 3 times. To improve its retention time on the ocular surface, dasa-eri-NLC was mixed with gellan gum (dasa-eri-NLC-gel), which achieved a sol-gel transformation when got in contact with tears. The dasa-eri-NLC-gel exhibited good rheological properties with shear thinning properties, extended the ocular residence time by more than 6 times, sustained the drug release, improved the corneal permeability of drug and exhibited good biocompatibility. Finally, the in vivo anti-CNV effect was evaluated in an alkaline burned mouse model of CNV, in which, the dasa-eri-NLC-gel significantly impeded the development and pathological changes of CNV, inhibited the expression of TNF-α, VEGF-A, HIF-1α, Src, pSrc in the cornea. In summary, dasa-eri-NLC-gel safely and efficiently delivered dasatinib and erianin to the cornea and exhibited significantly anti-CNV effect via inhibiting various angiogenesis related cytokines or factors. Dasa-eri-NLC-gel showed a great promise for the treatment of CNV and our study laid a solid foundation for future clinical transformation.

Benmelstobart plus anlotinib in patients with EGFR-positive advanced NSCLC after failure of EGFR TKIs therapy: a phase I/II study

The effect of immune‐based therapies on patients with epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitor (TKI) therapy remains unclear. The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart, an anti-programmed cell death ligand 1 antibody, and anlotinib, a small-molecule multi-target anti-angiogenic TKI, in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy. Patients were enrolled in a phase I/II study. In phase I (dose-escalation), patients received anlotinib (8, 10, 12 mg) plus benmelstobart (1200 mg). Recommended phase II dose, determined during phase I, was used in phase II dose-expansion cohort. Primary endpoints were maximum tolerable dose in phase I and progression-free survival (PFS) in phase II. At the data cutoff date (March 10, 2024), 55 patients were enrolled in phase II dose-expansion cohort. Median PFS of patients included in phase II cohort was 9.0 months, median overall survival was 28.9 months, objective response rate was 25.5%, disease control rate was 87.3%, and median duration of response was 19.8 months. Incidence of grade ≥3 treatment-related adverse events in study population was 25.5% (14/55), whereas grade ≥3 immune-related adverse events occurred in 10.9% (6/55) of patients. Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile, supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy. Trial Registration: ChiCTR1900026273.

Determination of QLNC-3A6 in canine plasma by UHPLC-MS/MS and its application in pharmacokinetic studies

Multi-targeted tyrosine kinase inhibitor QLNC-3A6 Di-maleate, a structurally novel small molecule compound, has therapeutic efficacy for the treatment of canine cutaneous mast cell tumor (CMCT) caused by mutations in the c-Kit gene. Since pharmacokinetic (PK) information plays an important role in the development and application of new drugs, etc., a rapid, highly sensitive and selective UHPLC-MS/MS analytical method was developed and validated for the first time in this study for the quantitative detection of QLNC-3A6 in canine plasma. 100 µL of plasma was precipitated using 350 µL of acetonitrile, and Chromatographic separation was performed on a Phenomenex Kinetex C18 column (50 × 2.1 mm, 2.6 µm) at a flow rate of 0.4 mL/min, the mobile phases were set to 0.1% formic acid aqueous solution (A) and 0.1% formic acid acetonitrile (B). The calibration curve linear range was 0.5–100 ng/mL (R 2>0.99). The intraday and interday precision values (relative standard deviation, RSD) were 2.06–13.57% and 6.90–9.14%. Intraday and interday accuracies were −10.73 to 9.54% and −3.86 to 0.70% respectively. The dilution integrity RSD value and stability RSD value were less than 3.77 and 7.45%, respectively. Subsequently, the pharmacokinetics were investigated in canine after oral administration of QLNC-3A6 Di-maleate tablets at a dose of 3 mg/kg BW using this method. The results showed that QLNC-3A6 showed fast absorption rate, rapid distribution and slow metabolic elimination in canine plasma. The results of the main PK parameters including λz, T 1/2λz, C max, T max and AUC last were 0.07 ± 0.01/h, 11.00 ± 2.57 h, 50.88 ± 31.94 ng/mL, 9.08 ± 11.57 h and 836.48 ± 230.53 ng h/mL, respectively.