Prognostic Factors and Clinical Outcomes in Patients with Blast Phase Chronic Myeloid Leukemia.

BACKGROUND: Given the low incidence of patients with advanced chronic myeloid leukemia (CML), comprehensive clinical characteristics and outcomes of cohort studies of patients diagnosed with blast phase chronic myeloid leukemia (BP-CML) are limited. We examined the clinical features of blast phase CML, including the TKI selection, treatment response, and whether they have had hematopoietic stem cell transplantation (HSCT) or not. METHODS: We performed a retrospective cohort study, including BP-CML patients diagnosed in our center from January 2013 to December 2022. Clinical features, treatment therapy, and overall survival (OS) were investigated. RESULTS: Out of the 11 patients, 2 were myeloid type, eight patients were B-lymphoid, and one was T-lymphoid. Four patients suffered from chromosome abnormalities. Four patients were identified with BCR-ABL1 kinase domain mutation, including T315I, E255K, M244v, and E279K. The overall CR, CRi, PR, and MLFS rates were 9%, 54%, 27%, and 9%, respectively. The median follow-up was 21 months (9.5 - 33 months). At the end of the follow-up time, seven patients died. CML patients with lymphoids tended to get a better OS than patients with a type of myeloid, but the difference was not statistically significant (p > 0.05). Patients who received HSCT had an improved OS by two years compared to those who had not received HSCT. CONCLUSIONS: The prognosis of BP-CML patients was poor. Given the rarity of BP-CML and the limitation of clinical trial data, large-scale multi-center prospective studies are urgently needed to confirm and improve the treatment of patients with BP-CML in the future.

Comparison of efficacy and safety of tofacitinib and azathioprine in patients with alopecia areata and variants: a double-blind, randomized controlled trial.

BACKGROUND: Alopecia areata (AA) is an autoimmune pathology manifested by loss of hair. OBJECTIVE: To evaluate and compare the efficacy and safety of tofacitinib and azathioprine in patients with AA and variants. METHODS: In this double-blind randomized controlled trail (RCT) carried out at the Department of Dermatology, Medical Teaching Institute-Lady Reading Hospital (MTI-LRH), Peshawar, Pakistan, patients aged ≥ 12 years diagnosed with AA, alopecia totalis (AT) or alopecia universalis (AU) with minimum 50% scalp hair loss for a period ≥ 06 years were included. Patients were randomly assigned to receive oral tofacitinib 5 mg twice daily (Group I) or oral azathioprine 2 mg/kg body weight once daily (Group II). The primary endpoint was Severity of Alopecia Tool (SALT) score, evaluated at baseline and 06 months follow-up. Safety was consistently assessed during the study. RESULTS: A total of 104 patients underwent random allocation into either the tofacitinib group (n = 52) or the azathioprine group (n = 52). The mean (SD) age of patients was 20.23 (7.14) years and 22.26 (8.07) years, while the mean (SD) disease duration was 6.59 (4.01) years and 7.98 (4.40) years in in Group I and II, respectively. Overall, 40 (38.5%) patients were adolescents while 70 (67.3%) were male. 52 (50%) had AA, 37 (35.5%) had AT and 15 (14.5%) had AU. Mean baseline SALT score in tofacitinib group was 91.02 ± 10.21 and azathioprine group was 91.02 ± 10.63, which at 06 months follow-up improved to 14.1 ± 24.6 and 63.9 ± 33.9, respectively (difference, 11.5 points; 95% confidence interval, 38.3-61.3, p < 0.0001). Overall, no major adverse effects and no difference among the minor adverse effects in the two groups (04 adverse events for tofacitinib group and 08 for azathioprine group: p = 0.23) was observed. CONCLUSIONS: Efficacy of tofacitinib was significantly higher than azathioprine, whilst both drugs were well-tolerated in patients with AA and variants.

Advanced Delivery Strategies of Nintedanib for Lung Disorders and Beyond: A Comprehensive Review.

Nintedanib, a primary treatment for lung fibrosis, has gathered substantial attention due to its multifaceted potential. A tyrosine kinase inhibitor, nintedanib, inhibits multiple signalling receptors, including endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) and ultimately inhibits fibroblast proliferation and differentiation. Therefore, nintedanib has been studied widely for other ailments like cancers and hepatic fibrosis, apart from lung disorders. Commercially, nintedanib is available as soft gelatin capsules for treatment against idiopathic pulmonary fibrosis. Since it has very low oral bioavailability (4.7%), high doses of a drug, such as 100-150 mg, are administered, which can cause problems of gastrointestinal irritation and hepatotoxicity. The article begins with exploring the mechanism of action of nintedanib, elucidating its complex interactions within cellular pathways that govern fibrotic processes. It also emphasizes the pharmacokinetics of nintedanib, clinical trial insights, and the limitations of conventional formulations. The article mainly focuses on the emerging landscape of nanoparticle-based carriers such as hybrid liposome-exosome, nano liquid crystals, discoidal polymeric, and magnetic systems, offering promising avenues to optimize drug targeting, address its efficacy issues and minimise adverse effects. However, none of these delivery systems are commercialised, and further research is required to ensure safety and effectiveness in clinical settings. Yet, as research progresses, these advanced delivery systems promise to revolutionise the treatment landscape for various fibrotic disorders and cancers, potentially improving patient outcomes and quality of life.

Erlotinib or Gefitinib for Treating Advanced Epidermal Growth Factor Receptor Mutation-Positive Lung Cancer in Aotearoa New Zealand: Protocol for a National Whole-of-Patient-Population Retrospective Cohort Study and Results of a Validation Substudy.

BACKGROUND: Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown. OBJECTIVE: The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables. METHODS: This study will include all NZ patients with advanced EGFR mutation-positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data. RESULTS: In the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing. CONCLUSIONS: A protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation-positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51381.

Novel 1,3,4-oxadiazole derivatives of naproxen targeting EGFR: Synthesis, molecular docking studies, and cytotoxic evaluation.

The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds H4-A-F) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4-A, H4-B, H4-C, and H4-E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4-A, H4-C, and H4-F are nontoxic. Compound H4-A showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4-C was the most cytotoxic. Compound H4-C caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4-D, H4-C, and H4-B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research.

Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition.

BACKGROUND: Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition. METHODS: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton's tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS. RESULTS: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth. CONCLUSIONS: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.

Polyamine and EIF5A hypusination downstream of c-Myc confers targeted therapy resistance in BRAF mutant melanoma.

BACKGROUND: BRAF inhibitors are widely employed in the treatment of melanoma with the BRAF V600E mutation. However, the development of resistance compromises their therapeutic efficacy. Diverse genomic and transcriptomic alterations are found in BRAF inhibitor resistant melanoma, posing a pressing need for convergent, druggable target that reverse therapy resistant tumor with different resistance mechanisms. METHODS: CRISPR-Cas9 screens were performed to identify novel target gene whose inhibition selectively targets A375VR, a BRAF V600E mutant cell line with acquired resistance to vemurafenib. Various in vitro and in vivo assays, including cell competition assay, water soluble tetrazolium (WST) assay, live-dead assay and xenograft assay were performed to confirm synergistic cell death. Liquid Chromatography-Mass Spectrometry analyses quantified polyamine biosynthesis and changes in proteome in vemurafenib resistant melanoma. EIF5A hypusination dependent protein translation and subsequent changes in mitochondrial biogenesis and activity were assayed by O-propargyl-puromycin labeling assay, mitotracker, mitoSOX labeling and seahorse assay. Bioinformatics analyses were used to identify the association of polyamine biosynthesis with BRAF inhibitor resistance and poor prognosis in melanoma patient cohorts. RESULTS: We elucidate the role of polyamine biosynthesis and its regulatory mechanisms in promoting BRAF inhibitor resistance. Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reduces vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro cell line models and in vivo in a xenograft model. Polyamine biosynthesis signature is associated with poor prognosis and shorter progression free survival after BRAF/MAPK inhibitor treatment in melanoma cohorts, highlighting the clinical relevance of our findings. CONCLUSIONS: Our findings delineate the molecular mechanisms involving polyamine-EIF5A hypusination-mitochondrial respiration pathway conferring BRAF inhibitor resistance in melanoma. These targets will serve as effective therapeutic targets that can maximize the therapeutic efficacy of existing BRAF inhibitors.

Pharmacotherapy and cardiovascular challenges: a case report of olverembatinib-induced myocardial infarction with non-obstructive coronary arteries.

The anticancer drug of tyrosine kinase-inhibitors (TKIs) has significantly improved the prognosis of patients with specific leukemia but has also increased the risk of organ adverse reactions. Herein, we present a case of a patient diagnosed with myeloproliferative neoplasms who experienced recurrent chest pain after receiving treatment with Olverembatinib. Electrocardiography and coronary angiography confirmed the diagnosis of myocardial infarction with non-obstructive coronary arteries. This case serves as a reminder for clinicians to pay more attention and actively prevent the cardiac adverse reactions of TKIs when using such medications.

CDK4/6 Inhibitor-Associated Mean Corpuscular Volume Change: A Potential Parameter for Predicting Survival in Metastatic Breast Cancer?

OBJECTIVE: To evaluate the impact of CDK4/6 inhibitors on erythrocyte mean corpuscular volume (MCV) change and its possible correlation with progression-free survival (PFS) and overall survival (OS). STUDY DESIGN: Observational study. Place and Duration of the Study: Department of Medical Oncology, Kahramanmaras Necip Fazil City Hospital, Kahramanmaras, Turkiye, between January 2020 and 2023. METHODOLOGY: The data of 74 patients with HR (+) HER2 (-) metastatic breast cancer were analysed retrospectively. MCV and other complete blood count metrics were noted before and after the treatment. The first post-treatment evaluation was performed at three months. The median ΔMCV values at the third month after treatment-baseline were calculated. RESULTS: The patients were all females, with a median age of 55 years (between 35 and 80). Prior to the therapy, the baseline median MCV level was 90.4 (min-max: 77.3-113.2). After three months, the median MCV level was 95 (min-max: 84.3-115.3). Moreover, 7.15 was the median ΔMCV level. Regarding PFS (16.53 vs. 15.26 months) (p = 0.13) and OS (21.46 vs. 17.83 months) (p = 0.08), there was no statistically significant difference seen between the group with ΔMCV ≥7.15 and the group with ΔMCV <7.15. CONCLUSION: CDK4/6 inhibitors led to an increase in MCV but there was no significant difference between PFS or OS and the increase in MCV. To figure out whether the rise in MCV represents a prognostic or predictive marker, further research is required. KEY WORDS: Breast cancer, CDK4/6 inhibitors, Mean corpuscular volume, Prognosis.

MEK-inhibitor treatment reduces the induction of regulatory T cells in mice after influenza A virus infection.

Regulatory T cells (Tregs) play a crucial and complex role in balancing the immune response to viral infection. Primarily, they serve to regulate the immune response by limiting the expression of proinflammatory cytokines, reducing inflammation in infected tissue, and limiting virus-specific T cell responses. But excessive activity of Tregs can also be detrimental and hinder the ability to effectively clear viral infection, leading to prolonged disease and potential worsening of disease severity. Not much is known about the impact of Tregs during severe influenza. In the present study, we show that CD4+/CD25+FoxP3+ Tregs are strongly involved in disease progression during influenza A virus (IAV) infection in mice. By comparing sublethal with lethal dose infection in vivo, we found that not the viral load but an increased number of CD4+/CD25+FoxP3+ Tregs may impair the immune response by suppressing virus specific CD8+ T cells and favors disease progression. Moreover, the transfer of induced Tregs into mice with mild disease symptoms had a negative and prolonged effect on disease outcome, emphasizing their importance for pathogenesis. Furthermore, treatment with MEK-inhibitors resulted in a significant reduction of induced Tregs in vitro and in vivo and positively influenced the progression of the disease. Our results demonstrate that CD4+/CD25+FoxP3+ Tregs are involved in the pathogenesis of severe influenza and indicate the potential of the MEK-inhibitor zapnometinib to modulate CD4+/CD25+FoxP3+ Tregs. Thus, making MEK-inhibitors even more promising for the treatment of severe influenza virus infections.

Design, in silico Evaluation, and Determination of Antitumor Activity of Potential Inhibitors Against Protein Kinases: Application to BCR-ABL Tyrosine Kinase.

Despite significant progress made over the past two decades in the treatment of chronic myeloid leukemia (CML), there is still an unmet need for effective and safe agents to treat patients with resistance and intolerance to the drugs used in clinic. In this work, we designed 2-arylaminopyrimidine amides of isoxazole-3-carboxylic acid, assessed in silico their inhibitory potential against Bcr-Abl tyrosine kinase, and determined their antitumor activity in K562 (CML), HL-60 (acute promyelocytic leukemia), and HeLa (cervical cancer) cells. Based on the analysis of computational and experimental data, three compounds with the antitumor activity against K562 and HL-60 cells were identified. The lead compound efficiently suppressed the growth of these cells, as evidenced by the low IC50 values of 2.8 ± 0.8 µM (K562) and 3.5 ± 0.2 µM (HL-60). The obtained compounds represent promising basic structures for the design of novel, effective, and safe anticancer drugs able to inhibit the catalytic activity of Bcr-Abl kinase by blocking the ATP-binding site of the enzyme.

Molecular docking aided machine learning for the identification of potential VEGFR inhibitors against renal cell carcinoma.

Renal cell carcinoma is a highly vascular tumor associated with vascular endothelial growth factor (VEGF) expression. The Vascular Endothelial Growth Factor -2 (VEGF-2) and its receptor was identified as a potential anti-cancer target, and it plays a crucial role in physiology as well as pathology. Inhibition of angiogenesis via blocking the signaling pathway is considered an attractive target. In the present study, 150 FDA-approved drugs have been screened using the concept of drug repurposing against VEGFR-2 by employing the molecular docking, molecular dynamics, grouping data with Machine Learning algorithms, and density functional theory (DFT) approaches. The identified compounds such as Pazopanib, Atogepant, Drosperinone, Revefenacin and Zanubrutinib shown the binding energy - 7.0 to - 9.5 kcal/mol against VEGF receptor in the molecular docking studies and have been observed as stable in the molecular dynamic simulations performed for the period of 500 ns. The MM/GBSA analysis shows that the value ranging from - 44.816 to - 82.582 kcal/mol. Harnessing the machine learning approaches revealed that clustering with K = 10 exhibits the relevance through high binding energy and satisfactory logP values, setting them apart from compounds in distinct clusters. Therefore, the identified compounds are found to be potential to inhibit the VEGFR-2 and the present study will be a benchmark to validate the compounds experimentally.

Risk of hepatitis B virus reactivation in cancer patients undergoing treatment with tyrosine kinase-inhibitors.

This editorial commented on an article in the World Journal of Gastroenterology titled "Risks of Reactivation of Hepatitis B Virus in Oncological Patients Using Tyrosine Kinase-Inhibitors: Case Report and Literature Analysis" by Colapietro et al. In this editorial, we focused on providing a more comprehensive exploration of hepatitis B virus reactivation (HBVr) associated with the usage of tyrosine kinase inhibitors (TKIs). It includes insights into the mechanisms underlying HBV reactivation, the temporal relationship between TKIs and HBV reactivation, and preventive measures. The aim is to understand the need for nucleos(t)ide analogs (NAT) and serial blood tests for early recognition of reactivation and acute liver injury, along with management strategies. TKIs are considered to be an intermediate (1%-10%) of HBVr. Current guidelines stipulate that patients receiving therapy with high or moderate risks of reactivation or recent cancer diagnosis must have at least tested hepatitis B surface antigen, anti-hepatitis B core antigen (HBc), and anti-hepatitis B surface antibody. Anti-HBc screening in highly endemic areas means people with negative tests should be vaccinated against HBV. Nucleoside or nucleotide analogs (NAs) like entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) form the basis of HBV reactivation prophylaxis and treatment during immunosuppression. Conversely, lamivudine, telbivudine, and adefovir are generally discouraged due to their reduced antiviral efficacy and higher risk of fostering drug-resistant viral strains. However, these less effective NAs may still be utilized in cases where ETV, TDF, and TAF are not feasible treatment options.

Application of a Fluorescence Recovery-Based Polo-Like Kinase 1 Binding Assay to Polo-Like Kinase 2 and Polo-Like Kinase 3.

Assay systems for evaluating compound protein-binding affinities are essential for developing agonists and/or antagonists. Targeting individual members of a protein family can be extremely important and for this reason it is critical to have methods for evaluating selectivity. We have previously reported a fluorescence recovery assay that employs a fluorescein-labelled probe to determine IC50 values of ATP-competitive type 1 inhibitors of polo-like kinase 1 (Plk1). This probe is based on the potent Plk1 inhibitor BI2536 [fluorescein isothiocyanate (FITC)-polyethylene glycol (PEG)-lysine (Lys) (BI2536) 1]. Herein, we extend this approach to the highly homologous Plk2 and Plk3 members of this kinase family. Our results suggest that this assay system is suitable for evaluating binding affinities against Plk2 and Plk3 as well as Plk1. The new methodology represents the first example of evaluating N-terminal catalytic kinase domain (KD) affinities of Plk2 and Plk3. It represents a simple and cost-effective alternative to traditional kinase assays to explore the KD-binding compounds against Plk2 and Plk3 as well as Plk1.

An overview of RAF kinases and their inhibitors (2019-2023).

Protein kinases (PKs) including RAF, perform a principal role in regulating countless cellular events such as cell growth, differentiation, and angiogenesis. Overexpression and mutation of RAF kinases are significant contributors to the development and spread of cancer. Therefore, RAF kinase inhibitors show promising outcomes as anti-cancer small molecules by suppressing the expression of RAF protein, blocking RAS/RAF interaction, or inhibiting RAF enzymes. Currently, there are insufficient reports about approving drugs with minimal degree of toxicity. Therefore, it is an urgent need to develop new RAF kinase inhibitors correlated with increased anticancer activity and lower cytotoxicity. This review outlines reported RAF kinase inhibitors for cancer treatment in patents and literature from 2019 to 2023. It highlights the available inhibitors by shedding light on their chemical structures, biochemical profiles, and current status. Additionally, we highlighted the hinge region-binding moiety of the reported compounds by showing the hydrogen bond patterns of representative inhibitors with the hinge region for each class. In recent years, RAF kinase inhibitors have gained considerable attention in cancer research and drug development due to their potential to be studied under clinical trials and their demonstration of various degrees of efficacy and safety profiles across different cancer types. However, addressing challenges related to drug resistance and safety represents a major avenue for the optimization and enhancement of RAF kinase inhibitors. Strategies to overcome such obstacles were discussed such as developing novel pan-RAF inhibitors, RAF dimer inhibitors, and combination treatments.

A phase 2a study investigating the effects of ritlecitinib on brainstem auditory evoked potentials and intraepidermal nerve fiber histology in adults with alopecia areata.

Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9-month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50-mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double-blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4-week loading dose of 200 mg QD or placebo for 9 months (placebo-controlled phase); they then entered the active-therapy extension and received ritlecitinib 50 mg QD (with a 4-week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I-V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans.

Clinical outcome predictors for metastatic renal cell carcinoma: a retrospective multicenter real-life case series.

Over the last decades, the therapeutic armamentarium of metastatic renal cell carcinoma (mRCC) has been revolutionized by the advent of tyrosin-kinase inhibitors (TKI), immune-checkpoint inhibitors (ICI), and immune-combinations. RCC is heterogeneous, and even the most used validated prognostic systems, fail to describe its evolution in real-life scenarios. Our aim is to identify potential easily-accessible clinical factors and design a disease course prediction system. Medical records of 453 patients with mRCC receiving sequential systemic therapy in two high-volume oncological centres were reviewed. The Kaplan-Meier method and Cox proportional hazard model were used to estimate and compare survival between groups. As first-line treatment 366 patients received TKI monotherapy and 64 patients received ICI, alone or in combination. The mean number of therapy lines was 2.5. A high Systemic Inflammation Index, a BMI under 25 Kg/m2, the presence of bone metastases before systemic therapy start, age over 65 years at the first diagnosis, non-clear-cell histology and sarcomatoid component were correlated with a worse OS. No significant OS difference was observed between patients receiving combination therapies and those receiving exclusively monotherapies in the treatment sequence. Our relapse prediction system based on pathological stage and histological grade was effective in predicting the time between nephrectomy and systemic treatment. Our multicentric retrospective analysis reveals additional potential prognostic factors for mRCC, not included in current validated prognostic systems, suggests a model for disease course prediction and describes the outcomes of the most common therapeutic strategies currently available.

Pan-RAF:MEK Molecular Glues Take Center Stage.

In this issue, Ryan and colleagues describe the preclinical development of a pan-RAF:MEK molecular glue with superior efficacy, brain penetrance, and tolerability in xenograft models of Ras/Raf/MAPK pathway-driven tumors. See related article by Ryan et al., p. 1190 (1).