Search Results (188)

Systemic mastocytosis (SM) is a rare and heterogeneous disorder characterized by clonal proliferation and accumulation of neoplastic mast cells in one or more organs, most commonly the bone marrow, liver, spleen, and skin. Among its clinical variants, aggressive SM (ASM) presents organ damage and debilitating symptoms due to extensive mast cell infiltration. The management of ASM remains challenging, primarily because treatment must address both symptom control and disease progression. Background/Objectives: Recent therapeutic approaches have focused on tyrosine kinase inhibitors (TKIs) that target the oncogenic KIT driver mutation, predominantly the D816V mutation, which is implicated in mast cell proliferation. We report a case series of four patients diagnosed with ASM to highlight the real-world experience in the management of ASM. All patients had confirmed KIT D816V mutations and presented with signs of advanced organ dysfunction, such as marked hepatosplenomegaly, cytopenia, and significant bone marrow infiltration. First-line therapies, including cytoreductive agents or other TKIs were used. Responses varied in these patients, and ultimately, they were initiated on or transitioned to midostaurin, a multikinase TKI. Results: All four patients, after the initiation of midostaurin, presented clinical and biological improvement—at least a clinical improvement response according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment & European Competence Network on Mastocytosis (IWG-MRT-ECNM) criteria. These findings highlight the benefits of KIT inhibition in managing ASM, especially for patients with inadequate responses to traditional therapies. The impact of midostaurin on organ function, mast cell burden, and symptom control emphasizes the importance of the timely integration of TKIs into therapeutic protocols. However, optimal treatment duration, long-term safety, and the development of acquired resistance remain critical questions that warrant further studies. Larger prospective trials are needed to better delineate the prognostic factors associated with sustained response, refine patient selection, and explore combination strategies that may enhance therapeutic efficacy. Conclusions: The patients presented in this case series benefited from midostaurin therapy, showing either a clinical improvement or partial response according to the IWG-MRT-ECNM criteria. Our case series illustrates that KIT inhibitors can offer meaningful clinical benefit in ASM, reinforcing their position as an emerging cornerstone option in ASM management. Full article

Background/Objectives: RAF pathway aberrations are one of the hallmarks of lung cancer. Sorafenib is a multi-kinase inhibitor targeting the RAF pathway and is FDA-approved for several cancers, yet its efficacy in lung cancer is controversial. Previous clinical research showed that a ARAF p.S214C mutation exhibited exceptional responsiveness to sorafenib in lung adenocarcinoma. Methods: Considering this promising clinical potential, the oncogenic potential and sorafenib response of the ARAF p.S214C mutation were investigated using lung cancer models. ARAF p.S214C mutant, ARAF wild-type (WT), and EGFP control genes were ectopically expressed in lung adenocarcinoma cell lines retroviral transduction. In vitro and in vivo sorafenib sensitivity studies were performed, followed by transcriptomics and proteomics analyses. Results: Compared to the ARAF-WT and EGFP-engineered cells, the ARAF p.S214C-engineered cells activated Raf-MEK-ERK signaling and exhibited enhanced oncogenic potential in terms of in vitro cell proliferation, colony and spheroid formation, migration, and invasion abilities, as well as in vivo tumorigenicity. The ARAF p.S214C-engineered cells also displayed heightened sensitivity to sorafenib in vitro and in vivo. RNA sequencing and reverse-phase protein array analyses demonstrated elevated expression of genes and proteins associated with tumor aggressiveness in the ARAF p.S214C mutants, and its sorafenib sensitivity was likely moderated through inhibition of the cell cycle and DNA replication. The ERK and PI3K signaling pathways were also significantly deregulated in the ARAF p.S214C mutants regardless of sorafenib treatment. Conclusions: This study demonstrates the oncogenicity and sorafenib sensitivity of the ARAF p.S214C mutation in lung cancer cells, which may serve as a biomarker for predicting the sorafenib response in lung cancer patients. Importantly, investigating the gene–drug sensitivity pairs in clinically exceptional responders may guide and accelerate personalized cancer therapies based on specific tumor mutations. Full article

Background: BCR-ABL inhibitors such as imatinib and nilotinib exhibit multi-kinase activity that extends beyond oncology, offering significant potential for drug repurposing. Objectives: This study aims to systematically evaluate and prioritize the repurposing potential of BCR-ABL inhibitors, particularly imatinib and nilotinib. Methods: An integrated pharmacoinformatics framework was applied to analyze seven BCR-ABL inhibitors. Structural clustering, cheminformatics analysis, and transcriptomic profiling using the Connectivity Map were employed to evaluate structural relationships, target profiles, and gene expression signatures associated with non-oncology indications. Results: Structurally, imatinib and nilotinib clustered closely, while HY-11007 exhibited distinct features. Nilotinib’s high selectivity correlated with strong transcriptional effects in neurodegeneration-related pathways (e.g., HSP90 and LYN), whereas imatinib’s broader kinase profile (PDGFR and c-KIT) was linked to fibrosis and metabolic regulation. Connectivity Map analysis identified more than 30 non-cancer indications, including known off-target uses (e.g., imatinib for pulmonary hypertension) and novel hypotheses (e.g., nilotinib for Alzheimer’s via HSPA5 modulation). A substantial portion of these predictions aligned with the existing literature, underscoring the translational relevance of the approach. Conclusions: These findings highlight the importance of integrating structure–activity relationships and transcriptomic signatures to guide rational repurposing. We propose prioritizing nilotinib for CNS disorders and imatinib for systemic fibrotic diseases, supporting their advancement into preclinical and clinical evaluation. More broadly, this framework offers a versatile platform for uncovering hidden therapeutic potential across other drug classes with complex polypharmacology. Full article

Background: Advanced adrenocortical carcinoma (ACC) remains a challenging malignancy with limited therapeutic options. Multi-kinase inhibitors (MKIs), either alone or in combination with immuno-oncology (IO) agents, have been investigated in recent single-arm clinical trials and retrospective series. Methods: We conducted a systematic review and single-arm meta-analysis of studies evaluating MKIs in advanced ACC. Objective response rate (ORR) and disease control rate (DCR) were pooled using random-effects models for single-arm proportions. Overall survival (OS) and progression-free survival (PFS) were summarized descriptively due to limited variance data. Subgroup analyses compared MKI monotherapy versus MKI + IO combinations, and meta-regression was performed to assess the impact of prior mitotane exposure. Results: Eleven studies (n = 208 patients) were included. The pooled ORR was 21% (95%CI, 11–36%), and the DCR was approximately 57%. Subgroup analysis revealed a higher ORR with MKI + IO regimens (26%; 95%CI, 12–48%) compared to MKI monotherapy (15%; 95%CI, 3–47%). Median OS ranged from 5.4 to 30.6 months, and PFS from 2.8 to 13.3 months, both favouring MKI + IO combinations. Meta-regression identified prior mitotane exposure as a significant predictor of ORR (p = 0.0279), particularly within the MKI + IO subgroup. Conclusions: MKI-based regimens, especially when combined with IO, demonstrate promising efficacy in advanced ACC, a disease with few established second-line options. While limited by the non-comparative design of available studies, these findings support further investigation in prospective, randomized clinical trials. Full article

Thyroid cancer (TC) remains a prevalent malignancy, with over 820,000 global cases diagnosed in 2022. Differentiated thyroid carcinoma (DTC), primarily papillary and follicular types, accounts for most cases and has a favorable prognosis with total thyroidectomy and radioiodine (RAI) ablation. However, 5–15% of patients develop RAI-refractory (RAI-R) disease, leading to a significantly poorer outcome. For RAI-R patients, treatment decisions depend on disease progression. Active surveillance is suitable for indolent cases, while symptomatic or progressive disease requires systemic therapy. Multikinase inhibitors (MKIs) such as lenvatinib and sorafenib serve as first-line options, with cabozantinib recently approved for resistant cases. Additionally, novel targeted therapies, including RET and NTRK inhibitors, and immune checkpoint inhibitors, are under investigation, offering a personalized approach. A key challenge is determining the optimal timing for systemic therapy, balancing progression-free survival (PFS) benefits against MKI-related toxicities, which significantly impact quality of life (QoL). Molecular testing can identify actionable mutations, guiding therapy selection. Clinical guidelines (ATA, ESMO) recommend initiating treatment based on disease progression and patient condition, integrating strategies such as active surveillance, surgery, and radiotherapy when appropriate. Despite advances, systemic therapies carry significant adverse events (e.g., hypertension, fatigue, gastrointestinal toxicity), necessitating careful monitoring to prevent dose reductions or interruptions. A multidisciplinary approach is essential to optimize patient outcomes and maintain QoL. As targeted therapies continue to evolve, further research is needed to refine treatment sequencing and improve outcomes for RAI-R TC. This review synthesizes current evidence to guide clinical decision-making. Full article

Background: Colorectal carcinoma (CRC) is one of the most common cancer types along with breast, prostate, and lung cancer. Many patients with CRC present with metastatic disease despite receiving standard first- and second-line therapies; thus emerges the demand for implementing new therapies that could improve outcomes among CRC patients. This case series was conducted to assess the efficacy and safety of regorafenib plus 5-fluorouracil (5-FU) in patients with refractory metastatic CRC (mCRC). Methods: We conducted a retrospective analysis of data from adult patients aged 18 and above who were diagnosed with refractory mCRC and received regorafenib plus 5-FU combination therapy at Houston Methodist Hospital between November 2017 and October 2023. Our study focuses on assessing key outcomes, including Overall Survival [OS], Progression-Free Survival [PFS], and safety. Results: Among the 12 patients we included in this study who underwent regorafenib plus 5-FU combination therapy for refractory mCRC after receiving at least three prior lines of treatment, the best response for six patients (50%) was successfully achieved, with disease control within 7–12 weeks from therapy initiation. Patients had an overall good tolerance for this treatment regimen and reported only the most common adverse events, including Hand-Foot Syndrome (HFS), mucositis, and hypertension (HTN), which were mostly resolved with dose adjustment of medications. Conclusions: This study highlights that using a combination of regorafenib plus 5-FU can be a potential treatment option for patients with refractory mCRC. Additional research, including prospective clinical trials, is required to assess the effectiveness and safety of regorafenib and 5-FU combination therapy in comparison to other currently limited treatment options. Full article

Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy, with the treatment for transplant-ineligible localized disease traditionally relying on locoregional therapies, such as surgical resection, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE). Systemic therapy has historically been reserved for advanced, unresectable HCC. However, lenvatinib, an oral multikinase inhibitor, has recently gained traction as part of a multimodal approach for localized HCC in combination with locoregional treatments. An upfront TACE or TARE can induce tumor hypoxia, leading to the upregulation of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF), which promotes tumor angiogenesis and progression. The rationale for combining lenvatinib with a locoregional therapy is to enhance tumor shrinkage while preserving liver function before a definitive intervention. Clinical trials, such as TACTICS and LAUNCH, have demonstrated improved outcomes with this approach. Additionally, retrospective studies, including those incorporating immune checkpoint inhibitors, have reported further benefits. This review explores the combination of lenvatinib with various locoregional modalities, including TARE, microwave ablation (MWA), and radiofrequency ablation (RFA), highlighting their indications and clinical outcomes. Furthermore, we discuss the ongoing and upcoming clinical trials investigating the integration of systemic agents with locoregional therapies for intermediate-stage HCC, including EMERALD-1, EMERALD-3, LEAP-012, and CheckMate 74W. Full article

The adverse effects of protein kinase inhibitors (PKIs) and other anticancer therapies were compared using FDA Adverse Events Reporting System (FAERS) data. The dataset included 159 FDA-approved anticancer drugs (71 PKIs, 88 nonPKIs) and analyzed 8216 unique adverse event (AE) terms. PKIs showed fewer systemic toxicities, with an average of 230.1 distinct AEs per drug, compared to 537.7 in nonPKIs. Hematologic AEs were significantly lower in PKIs (e.g., febrile neutropenia: 1.93% vs. 5.25%; thrombocytopenia: 2.18% vs. 3.87%), coupled with a lower incidence of infections (6.87% vs. 14.2%) and immunosuppressive effects. However, gastrointestinal and skin-related AEs were more common in PKIs (e.g., diarrhea: 13.95% vs. 8.36%). A higher proportion AEs in the PKI group (14.57%) were classified under “Investigations”, compared to the nonPKI group (9.87%). The frequency of “Skin and subcutaneous tissue disorders” AEs was twice as high in the PKI group. Clustering analysis grouped drugs by AE profiles, showing that PKIs formed more homogeneous clusters, while nonPKIs had broader variability. Multi-kinase inhibitors with VEGFR activity were linked to dermatologic AEs, likely due to EGFR inhibition in basal keratinocytes. Despite PKIs’ targeted mechanisms, resistance remains a challenge, requiring biomarker-driven strategies. This study highlights PKIs’ improved tolerability but emphasizes using personalized treatment approaches to optimize efficacy and safety. Full article

Protein phosphorylation and dephosphorylation are key mechanisms that regulate cellular activities. The addition or removal of phosphate groups by specific enzymes, known as kinases and phosphatases, activates or inhibits many enzymes and receptors involved in various cell signaling pathways. Dysregulated activity of these enzymes is associated with various diseases, predominantly cancers. Synthetic and natural single- and multiple-kinase inhibitors are currently being used as targeted therapies for different tumors, including glioblastoma. Glioblastoma IDH-wild-type is the most aggressive brain tumor in adults, with a median overall survival of 15 months. The great majority of glioblastoma patients present mutations in receptor tyrosine kinase (RTK) signaling pathways responsible for tumor initiation and/or progression. Despite this, the multi-kinase inhibitor regorafenib has only recently been approved for glioblastoma patients in some countries. In this review, we analyze the history of kinase inhibitor drugs in glioblastoma therapy. Full article

A series of novel hydrazones bearing diphenylamine and 5-oxopyrrolidine moieties, along with benzene and naphthalene rings substituted with hydroxy, alkoxy, or carboxylic groups, were synthesized. Their anticancer activity was evaluated in vitro using both 2D (MTT and ‘wound healing’ assays) and 3D (cell spheroid) models against human melanoma IGR39 cells, the triple-negative breast cancer cell line MDA-MB-231, and pancreatic carcinoma Panc-1 cell line. Compounds 8 (2-hydroxybenzylidene derivative) and 12 (2-hydroxynaphthalenylmethylene derivative) demonstrated the highest cytotoxicity in both 2D and 3D assays, while compounds 4 (2,5-dimethoxybenzylidene derivative) and 6 (2,4,6-trimethoxybenzylidene derivative) were most effective at inhibiting cell migration. Notably, all compounds exhibited lower activity against the Panc-1 cancer cell line in a cell monolayer, but the effects on spheroid cell viability in 3D models were comparable across all tested cancer cell lines. Molecular docking studies of the most active hydrazones suggested that these compounds may act as multikinase inhibitors. In particular, 2-hydroxynaphthalenylmethylene derivative 12 showed high binding affinity values (−11.174 and −11.471 kcal/mol) to the active sites of two key protein kinases—a non-receptor TK (SCR) and STPK (BRAF)—simultaneously. Full article

Background and Objectives: Differentiated thyroid cancer is the predominant form of endocrine cancer, with most cases being treatable. However, some patients develop resistance to traditional treatments. This review examines the use of the new multi-kinase inhibitors surufatinib and sonafenib, which target pathways related to angiogenesis and tumor growth in these patients. Methods: An extensive search of the literature was performed to find research involving these drugs in treating differentiated thyroid cancer. Four relevant studies were found, including two each for surufatinib and donafenib. Information regarding the research design, participant details, treatment methods, results on effectiveness, and side effects was collected and analyzed. Results: Surufatinib showed encouraging results, with response rates between 23.2% and 60% and progression-free survival times as long as 11.1 months. Donafenib also demonstrated improved progression-free survival times (12.9 months) compared to a placebo (6.4 months) and had response rates as high as 23.3%. Both drugs were well tolerated, with the most frequent side effects being hypertension and hand−foot syndrome. Conclusions: Both urufatinib and donafenib offer substantial benefits for patients with advanced differentiated thyroid cancer and have acceptable safety profiles. These results support their potential inclusion in treatment strategies for resistant cases, and further investigation of their clinical application is recommended. Full article

Neovascularization is an important process in brain tumor development, invasion and metastasis. Several research studies have indicated that the VEGF signaling target has potential for reducing angiogenesis in brain tumors. However, targeting VEGF signaling has not met the expected efficacy, despite initial enthusiasm. This is partly because tumors cleverly use alternative growth factor pathways, other than VEGF signaling, to restore angiogenesis. Multi-target inhibitors have been developed to inhibit several receptor kinases that play a role in the development of angiogenesis. By simultaneously affecting various receptor kinases, these treatments can potentially obstruct various angiogenic pathways that are involved in brain cancer advancement, often offering a more holistic strategy than treatments focusing on just one kinase. Since 2009, the FDA has approved a number of multi-kinase inhibitors that target angiogenic growth factor receptors (e.g., VEGFR, PDGFR, FGFR, RET, c-KIT, MET, AXL and others) for treatment of malignant diseases, including brain cancer. Here, we present some recent results from the literature regarding the preclinical and clinical effects of these inhibitors on brain tumors. Full article

Background: In the context of modern cancer therapy, the management of adverse effects of systemic therapies can lead to the avoidance of underdosing and withdrawal and increases in the quality of the therapeutic act and the quality of life. This review offers an overview of the skin-related toxicities associated with Cabozantinib, a multikinase inhibitor (MKI) that is approved for treating advanced kidney cancer, hepatocellular carcinoma, and medullary thyroid cancer. It covers the most common dermatological side effects, such as palmar–plantar erythrodysesthesia, stomatitis, hair alterations, xerosis, scrotal erythema, and subungual splinter hemorrhages. Additionally, this review includes suggested preventive strategies and management approaches based on the severity of these adverse effects. Full article

Background and Objectives: Anlotinib, a novel multi-kinase inhibitor targeting angiogenesis and tumor proliferation pathways, has shown promising efficacy in various cancers. Its role in treating thyroid cancer, particularly radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), is of significant clinical interest. This systematic review aims to evaluate the efficacy and safety of Anlotinib in patients with thyroid cancer, analyzing outcomes such as progression-free survival (PFS), overall survival (OS), response rates, and adverse events. Methods: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases up to October 2023. The review included randomized controlled trials and prospective studies assessing Anlotinib in thyroid cancer patients. Data extraction and quality assessment were performed independently by two reviewers following PRISMA guidelines. Results: Six studies involving a total of 277 patients were included. In patients with RAIR-DTC, Anlotinib demonstrated significant improvement in median PFS and objective response rates. In advanced or metastatic MTC, Anlotinib significantly prolonged median PFS compared to placebo, with high objective response rates. Subgroup analyses showed that older patients and those with bone metastases benefited significantly from Anlotinib treatment. In patients with ATC, Anlotinib-based chemotherapy yielded a 60% objective response rate. Anlotinib was also effective as neoadjuvant therapy in locally advanced thyroid cancer, achieving an objective response rate of 76.9%. Common adverse events included hypertension, proteinuria, and palmar–plantar erythrodysesthesia syndrome, which were generally manageable. Conclusions: Anlotinib appears to be an effective and well-tolerated treatment option for patients with various types of thyroid cancer, providing significant improvements in PFS and objective response rates. Further large-scale randomized studies are warranted to confirm these findings and to explore long-term outcomes. Full article

Background: While the clinical use of radiolabeled somatostatin analogs is well established in neuroendocrine tumors, there is growing interest in expanding their application to other somatostatin receptor 2 (SSTR2)-expressing cancers. This study investigates the potential utility of SSTR2-targeted theranostics in hepatocellular carcinoma (HCC). Methods: SSTR2 expression in HCC cell lines and clinical samples was evaluated using qRT-PCR, Western blot analysis, and a public dataset. ⁶⁷Ga-DOTATATE uptake was measured, ¹⁷⁷Lu-DOTATATE cytotoxicity was assessed, and ⁶⁸Ga-DOTATATE tumor targeting was evaluated in HCC animal models and a patient via PET/CT imaging. Results: SSTR2 expression was confirmed in HCC cell lines and clinical samples. Radioligand uptake studies demonstrated SSTR2-mediated ⁶⁷Ga-DOTATATE uptake. ¹⁷⁷Lu-DOTATATE treatment reduced cell proliferation and enhanced the anti-tumor efficacy of the multikinase inhibitor sorafenib. ⁶⁸Ga-DOTATATE PET/CT scans successfully identified tumors in HCC animal models and spinal metastases in a patient with HCC. Conclusion: These findings provide evidence that SSTR2-based theranostics could have significant implications for the detection and treatment of HCC. Full article