In neuroblastoma MYCN amplification is associated with enhanced angiogenesis and poor survival. Mutations in the anaplastic lymphoma kinase (ALK) gene can occur with MYCN amplification, conferring a very poor prognosis. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF)/c-MET signalling are implicated in neuroblastoma progression. Cabozantinib has potent activity against VEGFR2 and MET.

The efficacy of cabozantinib against tumours arising in GEM models of high-risk neuroblastoma was assessed using multiparametric MRI. Tumour-bearing Th-MYCN and Th-ALKF1174L/Th-MYCN mice were imaged prior to, 24 and 48 hrs after treatment with either 30mg/kg/day cabozantinib or vehicle. Treatment-induced changes in tumour volume, native T1, R2* and ADC were evaluated, and histological correlates sought. Additional Th-MYCN mice were treated daily for up to 28 days.

Cabozantinib elicited significant 24 and 60 % growth delay 24 and 48 hrs after treatment in tumours in Th-MYCN mice, and a significant 6-8 % reduction in native T1. Tumour R2* was significantly reduced 48 hrs post-treatment. Significantly higher tumour necrosis and apoptosis, and significantly lower Ki67, CD34 and VEGFR2 staining, was determined from the cabozantinib-treated mice. Treatment of Th-ALKF1174L/Th-MYCN mice caused significant 4 % and 21 % tumour growth delay, and a significant 5 % reduction in native T1 at 48 hrs. Daily cabozantinib treatment of Th-MYCN mice elicited significant tumour growth delay over 7 days which translated into significant survival benefit.

Cabozantinib exhibits activity against neuroblastomas arising in both Th-MYCN and Th-MYCN/ALKF1174L mice, revealed in situ using MRI. Native T1 is an early, sensitive and clinically translatable imaging biomarker of effective treatment response in neuroblastoma.

Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal cancers globally. While surgical resection and liver transplantation offer potential cures for early-stage HCC, the majority of patients are diagnosed at advanced stages where such interventions are not viable. Sorafenib, a multi-target kinase inhibitor, has been a cornerstone in the treatment of advanced HCC since its approval in 2007. Despite its significant clinical impact, less than half of the treated patients derive long-term benefits due to the emergence of resistance and associated side effects. This review focuses on the role of sorafenib, an FDA-approved multi-target kinase inhibitor, in treating advanced HCC, discusses the mechanisms underlying its therapeutic effects and associated resistance, and explores additional therapeutic strategies being investigated to improve patient outcomes.

A growing number of studies have shown that in addition to adaptive immune cells such as CD8 + T cells and CD4 + T cells, various other cellular components within prostate cancer (PCa) tumor microenvironment (TME), mainly tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs), have been increasingly recognized as important modulators of tumor progression and promising therapeutic targets.

In this review, we aim to delineate the mechanisms by which TAMs, CAFs and MDSCs interact with PCa cells in the TME, summarize the therapeutic advancements targeting these cells and discuss potential new therapeutic avenues.

We searched PubMed for relevant studies published through December 10 2023 on TAMs, CAFs and MDSCs in PCa.

TAMs, CAFs and MDSCs play a critical role in the tumorigenesis, progression, and metastasis of PCa. Moreover, they substantially mediate therapeutic resistance against conventional treatments including anti-androgen therapy, chemotherapy, and immunotherapy. Therapeutic interventions targeting these cellular components have demonstrated promising effects in preclinical models and several clinical trials for PCa, when administrated alone, or combined with other anti-cancer therapies. However, the lack of reliable biomarkers for patient selection and incomplete understanding of the mechanisms underlying the interactions between these cellular components and PCa cells hinder their clinical translation and utility.

New therapeutic strategies targeting TAMs, CAFs, and MDSCs in PCa hold promising prospects. Future research endeavors should focus on a more comprehensive exploration of the specific mechanisms by which these cells contribute to PCa, aiming to identify additional drug targets and conduct more clinical trials to validate the safety and efficacy of these treatment strategies.

With cabozantinib as the precursor, a novel small molecule inhibitors of c-Met kinase with thieno [2,3-b] pyridine as the scaffold were designed, synthesized and evaluated for their biological activity against A549, Hela and MCF-7 cell lines. The in vitro activities of 16 compounds were tested by MTT method with cabozantinib as control drug. Most compounds had moderate to strong inhibitory activities on cells. Among them, compound 10 had the strongest inhibitory activity, which was superior to the lead compound cabozantinib. Its IC50 values for A549, Hela and MCF-7 cells were 0.005, 2.833 and 13.581 μM, respectively. The colony formation assay demonstrated that compound 10 significantly inhibited the colony formation of A549 cells and suppressed their growth in a concentration-dependent manner. The wound healing assay showed that compound 10 could effectively inhibit the migration of cancer cells compared to a blank control group. The AO/EB assay demonstrated that compound 10 possesses the capability to effectively trigger apoptosis in a concentration-dependent manner. The elementary structure-activity relationship, molecular docking and pharmacokinetics studies revealed the significance of thieno [2,3-b] pyridine derivatives in anti-tumor activity.

Cabozantinib is highly effective against advanced renal cell carcinoma (RCC). However, approximately 60% of the patients require a dose reduction due to severe adverse events. Although associations between trough concentrations of cabozantinib and its efficacy and safety have been reported in other countries, reports on Japanese patients are unavailable. Therefore, we investigated the association of cabozantinib trough concentration with therapeutic efficacy and adverse events in Japanese patients with RCC and evaluated the usefulness of therapeutic drug monitoring.

In this prospective observational study, we measured the trough concentrations of cabozantinib in 10 Japanese patients with RCC enrolled between May 2022 and September 2023. The associations of trough concentration with treatment response, as determined by RECIST 1.1, and the occurrence of grade 2 or higher adverse events were assessed.

Trough concentration was higher in patients with controlled cancer than in those with progressive cancer (1024 ± 352 versus 457 ± 216 ng/mL, P = 0.035). In addition, patients with grade 2 or higher adverse events showed a significantly higher trough concentration than those without (1560 ± 513 versus 807 ± 319 ng/mL, P = 0.032). In particular, grade 2 or higher dysgeusia, anorexia, fatigue, and dyspepsia significantly correlated with trough concentrations.

This is the first clinical study to demonstrate a correlation between cabozantinib trough concentration, therapeutic efficacy, and adverse events in Japanese patients with RCC. The therapeutic drug monitoring of cabozantinib could be useful for improving therapeutic efficacy and avoiding serious adverse events.

Corneal neovascularization (CNV) is a significant risk factor for visual impairment. The efficiency and side effects of current CNV treatments, such as steroids and antivascular endothelial growth factor agents, are still debated. In addition, the bioavailability of topical drugs is usually hindered by tears, blinking, and the corneal anatomy. Therefore, finding a new therapeutic strategy is important. This study aimed to examine the function of the new therapeutic agent capmatinib (Cap), a highly selective inhibitor of MET that plays an important role in angiogenesis, in treating CNV. In this study, we first investigated the role of the HGF/c-MET axis in CNV and the therapeutic effect of Cap in a corneal alkali burn model. We synthesised a genipin-crosslinked gelatine-based hydrogel containing Cap (Cap-Gel). We observed a more significant therapeutic effect with the Cap-Gel than with Cap alone, as well as the alleviation of inflammatory infiltration and fibrosis. On day 14, the Cap-Gel group showed the most significant inhibition of corneal neovascularization, with the shortest neovessel length (0.48 ± 0.13 mm), smallest CNV area (3.77 ± 0.78 mm2), and lowest clinical assessment score (3.33 ± 0.52). Taken together, our results suggest that Cap-Gel could be a promising drug candidate for treating CNV.

AXL, a member of the TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases, controls pro-tumorigenic signaling cascades and cancer-immunological functions, and promotes drug resistance. Due to AXL's multifaceted role and therapeutic activity in preclinical studies, a variety of AXL inhibitors are being developed and tested in clinical trials for cancer treatment. Some clinical studies are showing promising results for AXL inhibitors as monotherapy and in combination with standard of care therapeutics. Currently, no selective AXL-targeting therapy has reached FDA-approval, but several compounds have entered phase II and III studies.

We elaborate on the role of AXL in cancer progression and suppressing anti-cancer immunity at both the molecular level and immune cell interaction level. Additionally, we review pre-clinical and clinical data of AXL-targeting agents.

Preclinical and several early clinical trials demonstrated the safety of AXL-targeting monotherapies with some evidence of efficacy. Additionally, multiple novel combination regimens including AXL-targeting agents to overcome resistance mechanisms are being actively examined with some promising results. However, patient selection and companion biomarkers may be critical for the success of AXL-targeting therapies.

Resistance to tyrosine kinase inhibitors (TKIs) poses a significant challenge in the treatment of hepatocellular carcinoma (HCC). Although dysregulation of mitochondrial dynamics has been implicated in the aggressive behaviors of various tumors, the specific role and underlying mechanisms by which this dysregulation contributes to cabozantinib resistance in HCC cells remains insufficiently characterized. By investigating mitochondrial dynamics as central regulators of cabozantinib resistance, this work specifically aims to discover actionable targets for restoring drug sensitivity in treatment-refractory HCC cells. We employed transmission electron microscopy (TEM) and confocal microscopy to analyze mitochondrial morphology in HCC cells resistant to TKIs. Additionally, we utilized an oncogene hydrodynamic injection-induced primary liver cancer mouse model to assess the therapeutic efficacy of combining cabozantinib with other pharmacological agents. Our results demonstrated significant increases in mitochondrial fragmentation, p62 aggregation, and mitophagy in cabozantinib-resistant HCC cells, which correlated with overexpression of c-Myc. Notably, inhibiting mitochondrial fission, p62 aggregation, or autophagy effectively reversed the resistance of HCC cells to cabozantinib. Mechanistically, cabozantinib treatment was shown to induce c-Myc expression, which significantly enhanced mitochondrial fragmentation and p62 aggregation, thereby promoting mitophagy. This mitophagic process selectively eliminated damaged mitochondria, reducing cytochrome C-induced apoptosis in cabozantinib-resistant cells. Ultimately, combining cabozantinib with either the autophagy inhibitor chloroquine or the p62 aggregation inhibitor XRK3F2 resulted in improved anticancer efficacy. In conclusion, c-Myc overexpression facilitates p62 aggregation-mediated mitophagy, leading to cabozantinib resistance in HCC cells. Inhibition of autophagy effectively restores cabozantinib sensitivity in HCC.

Angiogenesis plays an important role in tumour growth and metastasis. Targeting tumour vascular endothelial cells to inhibit tumour angiogenesis and thus block tumour blood and nutrition supply is the current research focus on anti-tumour growth and metastasis. Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR-2) signal pathway regulates the proliferation, migration, survival and angiogenesis of vascular endothelial cells, which is abnormally activated in different tumours. Studies have confirmed that inhibiting VEGF/VEGFR-2 signalling pathway can produce anti-tumour effect. Nowadays, anti-angiogenesis therapy targeting VEGF/VEGFR-2 inhibition has become the most effective clinical strategy for cancer treatment. Therefore, a variety of VEGF/VEGFR-2 inhibitors with different structures have been developed. A few selectively inhibit VEGF to block the activation of VEGFR-2 pathway, while the majority selectively inhibit VEGFR-2 as multi-target inhibitors. Based on the classification of dominant skeletons, this paper briefly analyzes the biological activity, clinical research process and structure-activity relationship of the representative small molecule inhibitors of VEGF/VEGFR-2.

Hypoxia-inducible factor 2α (HIF-2α) is a transcription factor that mediates the expression of genes critical for cell adaptation and survival in low oxygen (hypoxic) conditions. In cancer, hypoxic conditions or molecular alterations within cancer cells can lead to HIF-2α accumulation and promote tumour growth and progression. Inactivating mutations in the von Hippel-Lindau (VHL) gene disable the oxygen-dependent HIF-2α degradation pathway and cause constitutive HIF-2α activity. VHL mutations are prevalent in clear cell renal cell carcinoma (ccRCC) where HIF-2α is a known tumourigenic driver. HIF-2α inhibition was shown to improve ccRCC patient outcomes clinically, warranting development of next-generation inhibitors.

Pharmacological effects of a novel small molecule allosteric inhibitor of HIF-2α, AB521 (casdatifan), were evaluated using in vitro cell-based assays and in vivo mouse models.

AB521 inhibited HIF-2α-mediated transcription in cancer cells, endothelial cells, and M2-polarised macrophages. AB521 was selective for HIF-2α, displaying no activity against HIF-1α, and did not exhibit off-target cytotoxicity. When delivered orally to mice, AB521 caused dose-dependent decreases in HIF-2α-associated pharmacodynamic markers and significant regression of human ccRCC xenograft tumours. AB521 combined favourably with cabozantinib, a standard of care tyrosine kinase inhibitor, or zimberelimab, a clinical-stage anti-PD-1 antibody, in ccRCC xenograft studies.

AB521 is a potent, selective and orally bioavailable HIF-2α inhibitor, with favourable pharmacological properties, that is being explored clinically for the treatment of ccRCC.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor accounting for less than 5% of all thyroid cancers. An estimated 25% of cases are familial secondary to a germline mutation on the rearranged during transfection proto-oncogene (RET); this gene can be present as a somatic mutation in approximately 40%-60% of sporadic MTC tumors. There is an existing genotype-phenotype correlation in the clinical behavior of MTC, with the RET M918T variant associated with aggressive disease. The current systemic treatment profile for progressive metastatic MTC involves antiangiogenics multikinase inhibitors (MKI), specifically cabozantinib and vandetanib, and high-specific RET inhibitor therapy. Decisions on the timing of systemic therapy initiation in this population should involve multidisciplinary care and individualization on a case-by-case scenario; a comprehensive evaluation of performance status, tumor burden, progression rate, medical comorbidities, possible medication interactions, and goals of care must be considered in a patient-centered approach. This review summarizes the evidence on the safety, efficacy, and limitations of systemic therapies for MTC; the aim is to empower clinicians with the knowledge to optimally manage patients with advanced, progressive, or metastatic MTC.

The COSMIC-021 study assessed the safety and efficacy of cabozantinib plus atezolizumab in advanced solid tumors. Presented here are results from the expansion cohorts with advanced urothelial carcinoma (UC).

This phase Ib study (ClinicalTrials.gov identifier: NCT03170960) enrolled patients with inoperable locally advanced/metastatic UC into four tumor cohorts: first-line cisplatin-eligible (cis-eligible), first-line cisplatin-ineligible (cis-ineligible), previous platinum-containing chemotherapy (previous chemotherapy-treated), and previous immune checkpoint inhibitor (ICI)-treated. Patients received oral cabozantinib 40 mg once daily and intravenous atezolizumab 1,200 mg once every 3 weeks. The primary end point was objective response rate (ORR), as assessed by the investigator per RECIST v1.1 every 6 weeks for 12 months and every 12 weeks thereafter; the secondary end point was safety.

A total of 121 patients (previous ICI-treated cohort, n = 31, and each of the other cohorts, n = 30) received study treatment from March 2018 to November 2021. The ORR (95% CI) was 30% (15 to 49) for cis-eligible, 20% (8 to 39) for cis-ineligible, 27% (12 to 46) for previous chemotherapy-treated, and 10% (2 to 26) for previous ICI-treated cohorts. The median progression-free survival (95% CI) was 5.5 (1.6 to 11.6), 5.6 (3.1 to 11.1), 5.4 (1.6 to 7.6), and 3.0 (1.8 to 5.5) months, respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) were experienced by 43%, 67%, 57%, and 45% of patients, respectively. TRAEs led to discontinuation of all treatment components in 17%, 13%, 3%, and 19%, respectively. No grade 5 TRAEs were reported in any cohort.

The novel combination of cabozantinib plus atezolizumab exhibited clinical activity in advanced UC that is cis-eligible, cis-ineligible, or previously treated with platinum-containing chemotherapy; clinical activity in previous ICI-treated UC was modest. The toxicity profile was consistent with that previously reported for the combination.

Targeted therapies and immune checkpoint inhibitors (ICIs) have significantly improved survival outcomes in metastatic renal cell carcinoma (mRCC) but are often associated with high rates of adverse events, leading to dose reductions or treatment discontinuation. The FDA's recent initiative, Project OPTIMUS, emphasizes the importance of optimizing dosing regimens in oncology clinical development, and moves beyond the conventional maximum tolerated dose approach. In this study, we aimed to review and redefine the approved dosing strategies for targeted therapies and ICIs in mRCC from the Project OPTIMUS perspective, including pazopanib, axitinib, cabozantinib, sunitinib, everolimus, and nivolumab. A comprehensive summary of FDA clinical pharmacology reviews and clinical studies performed in routine clinical practice was conducted, alongside model-informed simulations of pharmacokinetic profiles with approved and alternative regimens. Results demonstrated that actual tolerated doses in clinical practice were 46.1% to 86% lower than the approved dosages, with up to 75% of patients requiring dose adjustments. Model-informed simulations suggested that for most targeted therapies, a 14%-50% dose reduction maintained comparable efficacy while improving tolerability. For nivolumab, simulations confirmed adequate drug exposure with the approved flat dose regimens, without an increase of adverse effects. In conclusion, we identified optimized dosing regimens that could improve drug tolerability while maintaining efficacy for approved targeted therapies and ICIs in mRCC. We suggest that these optimized dosing regimens should be considered for use in clinical practice and that the optimal exposure range be included in drug labels to support pharmacokinetically guided dose individualization in clinical practice.

Lenvatinib's activity after immune checkpoint inhibitors (ICI) combination therapy in renal cell carcinoma (RCC) remains unknown. We aimed to describe the real-world outcomes of patients with metastatic RCC (mRCC) treated with lenvatinib after failure of the prior standard of care.

Multicenter retrospective study including patients with mRCC treated with lenvatinib-based therapies beyond first-line therapy between 2020 and 2024. The primary endpoints were objective response rate (ORR) and time-to-treatment failure (TTF). Secondary endpoints included disease control rate (DCR), overall survival (OS), and safety.

We included 133 patients, with a median age of 61 years. Clear-cell was the main subtype (82.0 %). Before lenvatinib treatment, 15.8 %, 51.9 %, and 27.8 % of patients showed favorable, intermediate, and poor risk disease, respectively, according to the International Metastatic RCC Database Consortium (IMDC). Moreover, patients received a median of 3 previous lines of treatment, including ICIs (90.2 %) and cabozantinib (90.2 %). Lenvatinib was given alone (45.9 %) or in combination with everolimus (33.8 %), pembrolizumab (18.0 %) or investigational agents (2.3 %). The ORR and DCR were 29.1 % and 67.7 %, respectively, with no differences between regimens or lines of treatment. With a median follow-up time of 13.5 months, the median TTF and OS were 6.2 and 9.6 months. Toxicity was manageable with dose modifications required in 34.6 %. The discontinuation rate was 9.8 %, with one toxic death.

Lenvatinib-based regimens were active and safe for heavily pre-treated patients with mRCC. These findings provide evidence to support its use in daily practice.

STELLAR-305: design of an ongoing phase III #clinicaltrial, assessing the multi-targeted tyrosine kinase inhibitor, zanzalintinib, in combination with pembrolizumab in previously untreated recurrent/metastatic #HNSCC.

NCT06082167 (ClinicalTrials.gov).

Pembrolizumab monotherapy is approved for patients with platinum-ineligible metastatic urothelial carcinoma (mUC). Cabozantinib is a multireceptor tyrosine kinase inhibitor with activity against MET and VEGFR2 and is approved as monotherapy or in combination with a PD-1 inhibitor for other malignancies. The objective was to determine the safety and efficacy of pembrolizumab + cabozantinib as first-line treatment for patients with mUC.

In this open-label, single-arm, multicenter, phase 2 study, patients received pembrolizumab 200 mg every 3 wk + cabozantinib 40 mg daily. Key inclusion criteria were locally advanced UC or mUC, Eastern Cooperative Oncology Group performance status 0-2, ineligible for or refused cisplatin, and no prior PD-1/L1 inhibitor. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). According to the statistical plan, in a cohort of 35 evaluable participants, the lower bound of the 95% confidence interval (CI) would extend no more than 26% from the ORR observed, and in a scenario with ≥17 objective responses, the CI would exclude 32%.

Responses were observed in 16 of 35 evaluable patients, with an ORR of 46% (95% CI 31-62%). Median PFS and OS were 8 mo (95% CI 5-13) and 17 mo (95% CI 13-not reached), respectively. The most common treatment-emergent adverse events (any grade) were diarrhea (58%), fatigue (56%), pruritus (39%), nausea (36%), palmar-plantar erythrodysesthesia (36%), and a decrease in appetite (33%).

This phase 2 trial of pembrolizumab + cabozantinib demonstrated a manageable toxicity profile and promising efficacy as a first-line therapy combination for cisplatin-ineligible patients with mUC.

Ewing's sarcoma (ES) is a highly aggressive primary bone malignancy that primarily affects children and adolescents. Several tyrosine kinase receptors (RTKs) have been found to be overexpressed in ES samples, and it was demonstrated that some play significant roles in driving the malignant phenotype of ES. Specifically, ES with insulin-like growth factor 1 (IGF1R) or vascular endothelial growth factor (VEGFR) overexpression were correlated with more aggressive ES and worse outcomes. Other RTKs that were determined to be overexpressed in ES include platelet-derived growth factor receptor, stem cell factor receptor, and hepatocyte growth factor. Overexpression of these molecules suggests their possible tumor-driving role, making them potential targets for intervention. Various tyrosine kinase inhibitors (TKIs), including apatinib, anlotinib, and cabozantinib have shown clinical promise in patients with recurrent ES who have progressed on previous lines of therapy. The findings reported in this review emphasize the importance of assessing IGF1R-focused inhibitors and combinational therapeutic regimens in future research. Furthermore, biomarkers predictive of response are necessary to improve patient outcomes. In order to optimize ES care, considerations for patient eligibility on the basis of positivity for biomarkers predictive of response, and the inclusion of quality-of-life evaluations in studies must be addressed.

Thyroid cancer prevalence has increased in the last few decades. Whereas the majority of well-differentiated histotypes have effective therapeutic options, the most advanced cases lacked successful treatment until recent years. Genomic alterations have emerged as targets for new anti-cancer drugs. This molecular knowledge is gradually being translated into sophisticated approaches for the stratification, management, and therapies of patients with thyroid carcinomas. The genomic characterisation of tumours in clinical assistance serves as a tool for enhancing the prognostic assessment of patients with thyroid cancer and predicting their responses to the agents. The MAPK pathway is the most predominantly activated molecular route in this cancer. Several drugs have been developed to inhibit this pathway at different levels. However, the acquired resistance that emerges is the main problem in their use. Other strategies targeting not only driver mutations but also those that confer aggressive behaviour on tumours can be potential targetable options. Due to the new therapies, patients with the most aggressive histotypes have improved survival rates. Adverse events, although manageable, have a high prevalence among the current therapies. Selective inhibitors, immunotherapies, and the combination of both will play a pivotal role in the treatment and the improvements in overall survival in thyroid cancer patients.

There is a lack of real-world evidence from Taiwan on the use of cabozantinib for advanced renal cell carcinoma (aRCC). We evaluated cabozantinib treatment for aRCC after previous antiangiogenic therapy in real-world Taiwanese clinical practice.

Medical records from seven Taiwanese hospitals were retrospectively analyzed. Eligible patients were adults with aRCC who initiated cabozantinib between October 2018 and August 2021 after ≥1 antiangiogenic therapy. Patient characteristics and treatment patterns were described. Outcomes included objective response rate (ORR [complete or partial]; primary endpoint) assessed by RECIST v1.1 or local investigator assessment, progression-free survival (PFS), and tolerability.

Fifty-one patients were included: 39.2 % received cabozantinib second-line, 33.3 % third-line, and 27.5 % fourth- or later-line. Mean patient age was 61.2 years; most were male (80 %), had clear-cell (80 %), metastatic (92 %) disease, and had previous nephrectomy (78 %). Sunitinib and pazopanib were the most common previous (any line) treatments (63 % and 53 % of patients, respectively). Dose reductions occurred in 47 % of patients and were more common in patients (57 %) who initiated cabozantinib at 60 mg/day than in those (33 %) who initiated at 40 mg/day (72 % vs 12 %, respectively); discontinuation rates were similar for these groups (48 % vs 47 %, respectively). Overall, ORR was 39.2 % (95 % CI: 25.8, 53.9) and median PFS was 12.4 months (95 % CI: 8.2, 16.3). Rates of serious treatment-emergent adverse events related to cabozantinib were low (7.8 %).

This Taiwanese study found the real-world effectiveness and tolerability of cabozantinib after previous antiangiogenic therapy to be consistent with the results of the METEOR trial.

Cabozantinib (CAB) causes a high incidence of adverse events in unresectable hepatocellular carcinoma (u-HCC) and requires dose adjustments. We evaluated the efficacy and safety of the 7-on/7-off regimen composed of 7 consecutive days' administration of CAB followed by a 7-day rest period. This was a retrospective analysis of 35 patients with u-HCC, who were treated with CAB in a multicenter cohort in Japan from 2020 to 2024. The clinical outcomes of 12 patients treated with the 7-on/7-off regimen and 23 patients treated with daily dosing were compared. There were significant differences in overall survival (12.4 months vs. 6.3 months, p = 0.03), median progression-free survival (4.8 months vs. 3.2 months, p < 0.01), objective response rate (16.7% vs. 0.0%, p = 0.04), and incidence of any adverse events (75.0% vs. 100.0%, p = 0.03) between the 7-on/7-off regimen group and daily dosing group. The median duration of drug exposure (122 days vs. 42 days, p < 0.01) and median duration of dose reduction (100 days vs. 23 days, p < 0.01) were prolonged significantly in the 7-on/7-off group than in the daily dosing group. CAB in a 7-on/7-off regimen may improve the tolerability and treatment response in patients with u-HCC.

The creation of new molecules that target EGFR is essential for the progression of cancer treatment. This study synthesized and evaluated 16 quinoline-sulfonamide derivatives for their potential as anti-cancer agents. Compound 8c, which contains a methoxy group on the benzenesulfonamide tail, exhibited notable EGFR inhibitory activity (IC50 = 0.161 µM), similar to that of Erlotinib (IC50 = 0.142 µM). Compound 8c demonstrated enhanced in-vitro cytotoxicity against HCT-116, MCF-7, HeLa, and HepG2 cancer cell lines. Studies on the cell cycle and apoptosis demonstrated that compound 8c caused G1/S arrest and markedly enhanced apoptosis in HepG2 cells. In-vivo, compound 8c demonstrated comparable and/or superior efficacy compared to doxorubicin in decreasing tumor volume, weight, TNF-alpha, and COX-2 levels in the SEC model, alongside improved histopathological and immunohistochemical results. Molecular docking and dynamic simulations confirmed its stable binding to EGFR, exhibiting superior stability metrics in comparison to Erlotinib. Pharmacokinetic and toxicity evaluations indicated that compound 8c exhibits favorable drug-like properties and a safer toxicity profile. These findings identify compound 8c as a potential candidate for the development of safe and effective anti-cancer therapies, necessitating additional preclinical investigations.

After failing primary and secondary hormonal therapy, castration-resistant and neuroendocrine prostate cancer metastatic to the bone is invariably lethal, although treatment with docetaxel and carboplatin can modestly improve survival. Therefore, agents targeting biologically relevant pathways in prostate cancer and potentially synergizing with docetaxel and carboplatin in inhibiting bone metastasis growth are urgently needed.

Phosphorylated (activated) AXL expression in human prostate cancer bone metastases was assessed by IHC staining. We evaluated the effects of a novel soluble AXL signaling inhibitor, sAXL (batiraxcept or AVB-S6-500), on tumor growth and lung metastases in prostate cancer patient-derived xenograft models that were implanted intratibially. After injection of LuCaP cells into the tibiae, tumors were treated with batiraxcept and docetaxel or carboplatin alone or in combination, and tumor growth was monitored by serum prostate-specific antigen or bioluminescence. Tumor burden was quantified by human-specific Ku70 staining, and metastasis to the lungs was determined using qPCR. Transcriptomic profiling, Western blotting, and immunohistochemistry were performed to identify treatment-regulated gene and protein profile changes.

High AXL phosphorylation in human prostate cancer bone metastases correlated with shortened survival. Batiraxcept alone or in combination with docetaxel or carboplatin significantly suppressed intratibial tumor growth and suppressed metastasis to the lungs through multiple mechanisms, including repression of cancer stemness genes (CD44, ALDH1A1, TACSTD2, and ATXN1) and the PI3K, JAK, MAPK, and E2F1/NUSAP1 signaling pathways.

Our study provides a robust preclinical rationale and mechanisms of action for using batiraxcept as a single agent or in combination with docetaxel or carboplatin to treat lethal metastatic prostate cancer.

Vascular endothelial growth factor receptor (VEGFR-2) inhibitors are critical in cancer therapy due to their role in suppressing tumor angiogenesis. Herein, we report a new series of thiadiazole-based derivatives as potential VEGFR-2 inhibitors with promising anticancer activity.

The synthesized compounds were evaluated for anti-proliferative activity against human cancer cell lines (HCT-116, MCF-7, and HepG-2), and WI-38 as normal cells. Sorafenib was used as a reference drug. VEGFR-2 inhibitory activity was determined, followed by cell cycle analysis, apoptosis assays, Q-RT-PCR analysis, and wound-healing assays. In silico molecular docking was conducted to explore binding interactions.

Among the tested compounds, 13b exhibited potent anti-proliferative activity (IC50: 3.98-11.81 µM) and strong VEGFR-2 inhibition (IC50: 41.51 nM), surpassing sorafenib (IC50: 53.32 nM). Cell cycle analysis revealed that 13b induced G2/M phase arrest in MCF-7 cells. Apoptosis levels increased from 2% to 52%, accompanied by a > 12-fold rise in the Bax/Bcl-2 ratio and activation of caspase-8/9. Additionally, 13b significantly suppressed MCF-7 cell migration, with only 5.28% wound closure. In silico studies confirmed its strong VEGFR-2 binding interactions.

Thiadiazole-based derivatives, particularly compound 13b, exhibit potent VEGFR-2 inhibition, anti-proliferative effects, apoptosis induction, and anti-migratory activity, supporting their potential as promising anticancer agents.

This study was designed to conduct data mining through the Food and Drug Administration Adverse Event Reporting System (FAERS) to assess adverse events (AEs) associated with cabozantinib in the treatment of renal cell carcinoma.

Reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms were used to detect drug-related AEs signals from reporting data in FAERS database from 2016 to 2024.

A total of 32,129 AE reports identifying cabozantinib as a 'primary suspect' were retrieved from the FAERS database. Among them, there were 21,549 reports of renal cell carcinoma as an indication. AEs induced by cabozantinib were observed in 23 system organ classes (SOCs). 215 AE signals were detected in 16 SOCs after four algorithms were simultaneously met. Among them, signals related to gastrointestinal disorders, general disorders and administration site conditions, and skin and subcutaneous tissue disorders were the most common. Of note, the median time to onset of AEs was 38 days (interquartile range (IQR) 14-116 days).

This study provides new insights into the monitoring, surveillance, and management of cabozantinib-related adverse drug reactions and provides a comprehensive long-term post-marketing safety assessment of cabozantinib.

Aberrant regulation of MET receptor tyrosine kinase activity is a frequent event in non-small cell lung cancer (NSCLC), even though the frequency of oncogenic driver mutations of MET is low. Our discovery of oncogenic MET exon 14 skipping mutations, the characterization of the first prototype MET kinase inhibitor, and characterization of MET expression levels have led the way to novel therapeutic approaches with improved outcomes in NSCLC. MET exon 14 mutations are the most consequential but not the only alterations that can be targeted through small molecule tyrosine kinase inhibitors. The abundant expression of cellular MET (c-MET) in cancer cells has provided new opportunities for immuno-oncology approaches in a broader patient population, and the integration of MET-targeted personalized medicine with immunotherapy has not been fully exploited yet. Here, we highlight essential facets of MET as a therapeutic target in NSCLC and provide an outlook for future approaches.

Medullary thyroid carcinoma (MTC) is a rare cancer that originates from germline RET proto-oncogene mutations in all hereditary forms and from somatic RET mutations in most sporadic cases. Currently, highly selective RET inhibitors have been approved for clinical use in patients with RET mutations with persistent, recurrent or metastatic disease. This therapy has proven efficacy, low toxicity, and a limited impact on patients' quality of life. However, for recurrent or metastatic RET-negative disease, few systemic therapies are available. Multikinase inhibitors are used; however, tumour cells frequently develop resistance mechanisms, or treatment must be discontinued due to the high incidence of side effects. In this context, peptide receptor radionuclide therapy (PRRT) may be a treatment option, but its clinical utility remains under investigation. The aim of this review is to evaluate the evidence of PRRT in MTC and discuss its limitations in the RET inhibitor era.

Cabozantinib is an oral multikinase inhibitor approved for treatment in metastatic renal cell carcinoma (RCC). We conducted a phase 2, nonrandomized, single-arm clinical trial (NCT04022343) of cabozantinib treatment for 12 weeks in 17 patients with locally advanced, biopsy-proven, nonmetastatic clear cell RCC before surgical resection. The primary end point was the objective response rate (complete and partial responses) at week 12 and secondary end points included safety, tolerability, clinical and surgical outcomes, and quality of life. Six patients (35%) experienced a partial response and 11 patients (65%) had stable disease. The most common adverse events were diarrhea (n = 12, 70.6%), anorexia, fatigue and hypertension (n = 10, 58.8%), nausea and palmar-plantar erythrodysesthesia syndrome (n = 9, 52.9%). No treatment grade 4 or 5 adverse events related to cabozantinib or surgery occurred. The 1-year disease-free survival and overall survival were 82.4% (95% CI 54.7-93.9%) and 94.1% (95% CI 65-99.1%), respectively. Cabozantinib treatment activated CD8+ T cells in the blood, depleted myeloid populations and induced immune niches for TCF1+ stem-like CD8+ T cells. Cabozantinib was clinically active and safe in the neoadjuvant setting in patients with locally advanced nonmetastatic clear cell RCC.

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.

The emergence of targeted therapies for MET exon 14 (METex14) skipping mutations has significantly changed the treatment landscape for NSCLC and other solid tumors. The skipping of METex14 results in activating the MET-HGF pathway and promoting tumor cell proliferation, migration, and preventing apoptosis. Type Ib MET inhibitors, designed to selectively target the "DFG-in" conformation of MET, characteristically bind to the ATP-binding pocket of MET in a U-shaped conformation, extending into the solvent-accessible region and interact strongly with residue Y1230 through π-π interactions, have shown remarkable efficacy in treating METex14-altered NSCLC, including cases with brain metastases (BMs). Notably, vebreltinib and capmatinib have demonstrated superior blood-brain barrier (BBB) permeability in both computational and experimental models, highlighting their potential for treating the central nervous system (CNS) metastases. P-glycoprotein (P-gp) is highly expressed in the BBB, which limits the brain uptake of many highly lipophilic drugs. Despite challenges posed by P-gp mediated efflux, vebreltinib has emerged as a promising candidate for CNS treatment due to its favorable pharmacokinetic profile and minimal susceptibility to P-gp efflux. This study underscores the importance of molecular dynamics simulations in predicting drug efficacy and BBB penetration, providing valuable insights for the development of CNS-targeted metastases therapies.

Background: Medullary thyroid cancer (MTC) is a frequently metastatic tumor of the thyroid that develops from the malignant transformation of C-cells. These tumors most commonly have activating mutations within the RET or RAS proto-oncogenes. Germline mutations within RET result in C-cell hyperplasia, and cause the MTC pre-disposition disorder, multiple endocrine neoplasia, type 2A (MEN2A). Single-agent therapies for MTC, including vandetanib (VAN) and cabozantinib for all MTCs and selpercatinib (SEL) for RET-mutated MTC, lead to partial responses but are not curative. Methods: To identify new therapeutic targets for MTC, we conducted proteomic profiling of normal C-cells, MTC cells, pre-malignant MEN2A patient samples, and MTC tumors. Results: From this analysis, we identified CAPN1, a member of the CALPAIN (CAPN) family endopeptidases, as widely upregulated in MTC samples. We found that short hairpin RNA-mediated depletion of CAPN1 or inhibitors of CAPN1 significantly reduced MTC cell growth, colony formation, and xenograft tumor growth in vivo. In addition, we show that CAPN1 inhibitors synergize with VAN and SEL in vitro, maximizing apoptosis. Mechanistic experiments implicate CAPN1 in inhibiting neurofibromin, encoded by NF1, and CAPN1 inhibitors stabilize NF1 protein levels and diminish downstream RAS/RET activation of AKT and ERK. Conclusions: Our data suggest that increased CAPN1 levels support RET and RAS-fueled growth by reducing NF1 levels. We find that combinatorial therapies between CAPN1 inhibitors and VAN or SEL show maximal efficacy in MTC cells.

Immune-based combinations are the cornerstone of the first-line treatment of metastatic renal cell carcinoma patients, leading to outstanding outcomes. Nevertheless, primary resistance and disease progression is a critical clinical challenge. To properly address this issue, it is pivotal to understand the mechanisms of resistance to immunotherapy and tyrosine kinase inhibitors, that tumor eventually develop under treatment. In this review of the literature, we aim at exploring resistance mechanisms arising in patients treated with first-line immune-based combinations in order to understand the biological pattern that should be investigated to overcome them. In more detail, mechanisms of resistance to nivolumab and pembrolizumab are divided into intrinsic to cancer cells and extrinsic (stromal or immune cells). Regarding axitinib, the increased expression of Nuclear protein 1 (NUPR1) or decreased levels of insulin receptor (INSR) characterize resistant cells. The secretion of non-VEGF pro-angiogenic factors, such as PDGF-BB, IL-1β, MMP-9, Gro-α, IL-8, IL-6, and CCL-2, can lead to resistance to cabozantinib. The reactivation of pathways previously targeted by lenvatinib or the activation of alternative pathways, such as EGFR-PAK2-ERK pathway, underlie the development of resistance to lenvatinib. Exploring resistance mechanism that arise during first-line therapy can lead to the development of treatment strategy able to overcome them in order to improve duration of response and patients outcomes.

Neuroendocrine tumors (NET) of the lung are a slowly growing subtype of lung cancer that has a different treatment paradigm than aggressive and more common forms of lung neuroendocrine neoplasms (NEN) like small cell lung cancer (SCLC). Current guidelines for metastatic lung NET advocate a handful of treatment options, including somatostatin analogs (SSA), everolimus, temozolomide- or platin-based chemotherapy, and peptide receptor radionuclide therapy (PRRT). However, there is no clear treatment sequence, and the therapy of choice may depend on several factors such as tumor grade / growth rate, tumor burden / symptoms, disease progression status, and somatostatin receptor (SSTR) expression. In order to tailor treatment to each individual patient, the latest scientific findings and patient-specific clinical features must be considered together. This review critically evaluates the available evidence with regards to relevant patient characteristics, inclusion and exclusion criteria, and outcome metrics of clinical trials given the presumed natural disease course. Specific patient subgroups with an unmet therapeutic need are identified and discussed in the context of ongoing clinical trials.

Cabozantinib is a multi-kinase inhibitor targeting multiple tyrosine kinases. It improves overall survival and progression-free survival in patients previously treated with sorafenib for advanced hepatocellular carcinoma (HCC) compared to the placebo in the phase 3 CELESTIAL trial. A 71-year-old man presented to our hospital for treatment of HCC with chronic hepatitis C. He was refractory to sorafenib, lenvatinib, regorafenib, and ramucirumab and started atezolizumab and bevacizumab therapy in November 2020. After administering the second cycle on December 10, 2020, the patient was diagnosed with progressive disease in January 2021. Therefore, cabozantinib (60 mg/day) was initiated on January 14, 2021. As the grade 3 aspartate aminotransferase and alanine aminotransferase levels increased, grade 3 anorexia and a decline in performance status were observed in the first week, and cabozantinib was terminated. His performance status and anorexia gradually improved, and contrast-enhanced computed tomography (CT) in June 2021 showed complete remission (CR) according to the modified Response Evaluation Criteria in Solid Tumors. The patient did not show disease progression for 11 months without receiving any treatment for HCC. To the best of our knowledge, this is the first report of CR with cabozantinib in advanced HCC.