Sunitinib-Induced Adrenal Crisis in a Patient with Pre-Existing Immunotherapy-Related Hypopituitarism

Sunitinib is a tyrosine kinase inhibitor that is frequently used in the treatment of metastatic renal cell carcinoma (mRCC). As a multikinase inhibitor, numerous off-target side effects of this medication are widely recognized. More recently, endocrine side effects, including hypoadrenalism, are becoming more apparent. We report a case in which a 71-year-old female experienced recurrent adrenal crises when managed with sunitinib for mRCC on a background of immune-related hypopituitarism and hypoadrenalism as a result of previous treatment with immunotherapy. Clinicians should be aware of this potential toxicity when using such medications and consider further investigation in the appropriate clinical setting.

Nintedanib exerts anti-pulmonary fibrosis activity via inhibiting TANK-binding kinase 1 (TBK1) phosphorylation

We described a chemoproteomics approach to identify TBK1 as a key target of the multikinase inhibitor nintedanib in IPF. This insight may facilitate a better understanding of the functional mechanism of nintedanib for antifibrosis efficacy.

MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1

As a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.

Avaliação dos efeitos do inibidor multiquinase sorafenibe sobre as células musculares lisas arteriais de Rattus norvegicus: Estudo in vitro / Evaluation of the effects of the multikinase inhibitor sorafenib on the arterial smooth muscle cells of Rattus norvegicus: An in vitro study

A reestenose arterial é um processo inflamatório que pode ocorrer após colocação de stent por cateterismo. Os stents farmacológicos surgiram para reduzir esse problema e o inibidor multiquinase sorafenibe demonstrou ser um composto com ação efetiva. Este estudo in vitro avaliou os efeitos do sorafenibe sobre a citotoxicidade, migração celular e distribuição das células nas fases do ciclo celular. A linhagem celular de músculo liso de rato A7r5 foi tratada com sorafenibe em concentrações que variaram de 0 a 5 μM. Os efeitos citotóxicos foram avaliados por dois ensaios colorimétricos, MTT e SRB após 24 horas de tratamento. A distribuição das células nas fases do ciclo celular foi avaliada por citometria de fluxo e a capacidade de cicatrização/migração celular pelo ensaio scratch wound assay. Comparado com o controle positivo paclitaxel, o sorafenibe demonstrou um efeito 1,6 vezes maior na redução da proliferação celular. Na avaliação do ciclo celular, o sorafenibe mostrou um bloqueio na fase G0/G1. Além disso, o sorafenibe aumentou o número de A7r5 células na fase sub-G1, sugerindo morte celular. No entanto, no estudo de cicatrização/migração celular, não foi observado efeito quando comparado ao controle negativo. Assim, esses resultados in vitro sugerem que o sorafenibe é eficaz para uso em stents farmacológicos, sugerindo uma continuidade na investigação desse fármaco.

Inhibition of SYK and cSrc kinases can protect bone and cartilage in preclinical models of osteoarthritis and rheumatoid arthritis

The pathophysiology of osteoarthritis (OA) includes the destruction of subchondral bone tissue and inflammation of the synovium. Thus, an effective disease-modifying treatment should act on both of these pathogenetic components. It is known that cSrc kinase is involved in bone and cartilage remodeling, and SYK kinase is associated with the inflammatory component. Thus the aim of this study was to characterize the mechanism of action and efficacy of a small molecule multikinase inhibitor MT-SYK-03 targeting SYK and cSrc kinases among others in different in vitro and in vivo arthritis models. The selectivity of MT-SYK-03 kinase inhibition was assayed on a panel of 341 kinases. The compound was evaluated in a set of in vitro models of OA and in vivo OA and RA models: surgically-induced arthritis (SIA), monosodium iodoacetate-induced arthritis (MIA), collagen-induced arthritis (CIA), adjuvant-induced arthritis (AIA). MT-SYK-03 inhibited cSrc and SYK with IC50 of 14.2 and 23 nM respectively. Only five kinases were inhibited > 90% at 500 nM of MT-SYK-03. In in vitro OA models MT-SYK-03 reduced hypertrophic changes of chondrocytes, bone resorption, and inhibited SYK-mediated inflammatory signaling. MT-SYK-03 showed preferential distribution to joint and bone tissue (in rats) and revealed disease-modifying activity in vivo by halving the depth of cartilage erosion in rat SIA model, and increasing the pain threshold in rat MIA model. Chondroprotective and antiresorptive effects were shown in a monotherapy regime and in combination with methotrexate (MTX) in murine and rat CIA models; an immune-mediated inflammation in rat AIA model was decreased. The obtained preclinical data support inhibition of cSrc and SYK as a viable strategy for disease-modifying treatment of OA. A Phase 2 clinical study of MT-SYK-03 is to be started.

NIMG-27. REGORAFENIB RESPONSE ASSESSMENT USING FET PET IN PATIENTS WITH PROGRESSIVE GLIOMA

BACKGROUND The REGOMA phase 2 trial showed an encouraging overall survival benefit of the multikinase inhibitor regorafenib in glioblastoma patients at first progression. We used O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the early assessment of response to regorafenib in patients with progressive glioma in an advanced disease stage. METHODS Thirty patients with progressive glioma were treated according to the REGOMA trial and prospectively followed. FET PET and MRI were performed at baseline and after the second cycle of regorafenib. Static PET parameters such as maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and metabolic tumor volumes (MTV) were calculated. Threshold values of FET PET parameters to predict a response were established by ROC analyses using an overall survival of ≥ 6 months as reference. The predictive value of FET PET parameters and their changes concerning overall survival was subsequently evaluated using the Kaplan-Meier test. MRI changes were evaluated according to the RANO criteria. RESULTS Up to now, 18 of 30 patients (glioblastoma, 83%; age range, 24-71 years) were eligible for data evaluation. The median number of tumor relapses before regorafenib was 2 (range, 1-4). During regorafenib (median cycles, 4; range, 2-9 cycles), CTCAE grade 3 or 4 side effects occurred in 56% and 11%, respectively. The median overall survival was 6 months (range, 3-18 months). After two cycles of regorafenib, a TBRmean reduction of 13% predicted a significantly longer overall survival (12 vs. 6 months; P=0.034). In contrast, MRI changes evaluated according to RANO criteria (i.e., Stable Disease or Partial Response vs. Progressive Disease) were not predictive (11 vs. 8 months; P=0.644). CONCLUSION Data suggest that amino acid PET using the tracer FET may be clinically valuable for identifying responders to regorafenib early after treatment initiation.

CTNI-50. REGORAFENIB IN RECURRENT GLIOBLASTOMA PATIENTS: A LARGE REAL-LIFE EXPERIENCE

INTRODUCTION Regorafenib (REG), an oral multikinase inhibitor, showed benefit in recurrent GBM (recGBM) patients in the REGOMA trial. We investigated the clinical outcome and safety of REG in a real-life population of recGBM patients treated at Veneto Institute of Oncology as off-label use. MATERIAL AND METHODS Patients receiving REG were entered prospectively on a clinical database. Data were retrospectively analyzed. The primary endpoints were overall survival (OS) and safety. The major inclusion criteria were: histologically confirmed diagnosis of GBM, disease progression by RANO criteria after Stupp protocol, ECOG PS ≤ 2. Patients received REG 160 mg per day for the first 3 weeks in a 4-week cycle. Kaplan-Meier method was used to estimate the survival, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events. RESULTS 54 patients were enrolled: median age was 56, ECOG PS 0-1 in 91%, MGMTmet in 53%, second surgery at the time of relapse in 30%. Median follow-up was 11.1ms, 30 PTS (56%) had died and 50 PTS (93%) had progressed. MedianOS was 10.2 ms (95%CI, 6.4-13.9), 12m-OS was 43%; medianPFS was 2.3 ms (95%CI, 1.3-3.3) and 6m-PFS was 18%. Disease control rate (DCR) was 46.3%; stable disease was reported in 38.8% and partial response in 7.4%. Age, MGMT and corticosteroid use at baseline were not statistically significant on multivariate analysis for OS. Grade 3 drug-related adverse events (AEs) occurred in 10 patients (18%) and the most frequent were hand-foot skin reaction, asthenia and increased lipase and transaminases; 1 PT(2%) reported a grade 4 AE (rash maculo-papular). AEs led to REG dose reductions in 37% of patients and, it was permanently discontinued in 5%. CONCLUSIONS We reported a “real-world” experience of REG in recGBM patients. Results are close to those reported in REGOMA trial; we showed a longer OS. Toxicity was manageable. Encouraging clinical benefits of REG in recGBM population were confirmed.

Targeted Therapies in Cancer: To Be or Not to Be, Selective

Development of targeted therapies in recent years revealed several nonchemotherapeutic options for patients. Chief among targeted therapies is small molecule kinase inhibitors targeting key oncogenic signaling proteins. Through competitive and noncompetitive inhibition of these kinases, and therefore the pathways they activate, cancers can be slowed or completely eradicated, leading to partial or complete remissions for many cancer types. Unfortunately, for many patients, resistance to targeted therapies, such as kinase inhibitors, ultimately develops and can necessitate multiple lines of treatment. Drug resistance can either be de novo or acquired after months or years of drug exposure. Since resistance can be due to several unique mechanisms, there is no one-size-fits-all solution to this problem. However, combinations that target complimentary pathways or potential escape mechanisms appear to be more effective than sequential therapy. Combinations of single kinase inhibitors or alternately multikinase inhibitor drugs could be used to achieve this goal. Understanding how to efficiently target cancer cells and overcome resistance to prior lines of therapy became imperative to the success of cancer treatment. Due to the complexity of cancer, effective treatment options in the future will likely require mixing and matching these approaches in different cancer types and different disease stages.