CDK11 is a cyclin-dependent kinase with a role in transcription and RNA splicing and represents a potential target for cancer treatment. We show that blocking CDK11 activity with the OTS964 inhibitor causes p53 stabilisa...CDK11 is a cyclin-dependent kinase with a role in transcription and RNA splicing and represents a potential target for cancer treatment. We show that blocking CDK11 activity with the OTS964 inhibitor causes p53 stabilisation through MDM2 downregulation. Under these conditions, p53 activates the expression of its downstream effector CDKN1A (p21), produced in two isoforms, the canonical p21 and the recently described p21. We compared the ability of both isoforms to block proliferation and showed that p21 partially lost its inhibitory potential, likely due to the missing cyclin-binding Cy2 and PCNA-interacting motifs and its cytoplasmic localisation. We identified the epitopes of four p21 antibodies using phage display to determine isoform specificity. Moreover, we show that the trigger for p21 induction is inhibition of the spliceosomal protein SF3B1. CDK11 activates SF3B1 by phosphorylation, and inhibition of either SF3B1 or CDK11 induces p21. We discovered an isoform similar to human p21 in murine cells, suggesting evolutionary conservation of CDKN1A alternative splicing. Our results uncover an unknown link between RNA splicing and proliferation control involving a novel isoform of a key cell cycle inhibitor.
The vasculature and the immune system both play roles in breast cancer progression and metastasis. In an experimental mouse model of Shb-gene deficiency in endothelial cells, breast cancer lung metastasis correlated with...The vasculature and the immune system both play roles in breast cancer progression and metastasis. In an experimental mouse model of Shb-gene deficiency in endothelial cells, breast cancer lung metastasis correlated with immune suppression rather than with vascular leakage. The present study aimed to assess underlying gene expression changes in endothelial and immune cells responsible for this phenotype and to explore their relationship to human disease. Mouse endothelial cell Shb-gene deficiency, leading to 'vessel normalization', resulted in altered expression of chemo/cytokine genes and upregulation of immune checkpoint genes in immune cells. Endothelial cells under these conditions exhibited gene expression patterns compatible with reduced angiogenesis and vascular leakage. Additionally, genes whose products relate to immune cell vascular transmigration and function were affected. In a human triple-negative breast cancer cohort, tumors with reduced vascular leakage exhibited a higher relative proportion of regulatory T cells and larger tumor size. However, these changes were not associated with increased metastasis. In conclusion, a low leakage vascular phenotype reduces tumor cell intravasation/metastasis and modifies the immune response, which in the current context becomes pro-tumoral.
The c-Myc protein is a well-known oncoprotein that plays a crucial role in regulating cell growth, proliferation, and differentiation. The overexpression or dysregulation of c-Myc is commonly associated with tumorigenesi...The c-Myc protein is a well-known oncoprotein that plays a crucial role in regulating cell growth, proliferation, and differentiation. The overexpression or dysregulation of c-Myc is commonly associated with tumorigenesis in several cancers, including colorectal cancer (CRC). c-Myc forms a heterodimer with its partner MAX to activate the expression of various genes. Here, we synthesized a novel c-Myc-targeting small molecule, 2,2'-((cyclohexylazanedyl)bis(methylene))bis(4-ethylphenol), or ECD, and demonstrate ECD's anticancer activity via interference with the c-Myc/MAX dimer to promote c-Myc degradation in CRC cells in vitro, in silico, and in vivo. This study revealed the activity of ECD toward CRC cells as a c-Myc inhibitor. Computer-aided analysis revealed that the effect of ECD was mediated through disturbance of the c-Myc/MAX complex. Moreover, ECD exhibited cytotoxic activity by inducing DNA damage, leading to apoptotic cell death. This DNA damage-inducing property was also confirmed by whole-proteome profiling of HT29 cells after ECD treatment. In the chick embryo chorioallantoic membrane (CAM) xenograft assay, we demonstrated a remarkable inhibition of the tumorigenic activity upon ECD exposure. In summary, we identified ECD as a novel potent compound targeting the oncoprotein c-Myc that may offer new opportunities for CRC treatment.
Gonzalez-Garcia P, Moares N, Yi-He W
… +7 more, Luna-Espejo R, Fernandez-Cisnal R, Ocaña-Cuesta J, Muñoz-Miranda JP, Gabucio A, Fernandez-Ponce CM, Garcia-Cozar F
Development of chimeric antigen receptor T-cell therapy has revolutionized the treatment of B-cell malignancies, although challenges such as antigen escape and tumor heterogeneity often decrease treatment success. Modula...Development of chimeric antigen receptor T-cell therapy has revolutionized the treatment of B-cell malignancies, although challenges such as antigen escape and tumor heterogeneity often decrease treatment success. Modular CARs targeting multiple antigens have been proposed as an interesting solution to address these challenges by reducing the likelihood of tumor cells evading treatment through the loss of a single antigen. In this study, we present a new modular CAR platform, termed CARtein, which takes advantage of intein interactions to jointly target CD19 and CD20 antigens. We demonstrate that the CARtein system, which features a universal CAR signaling backbone that covalently binds to specific scFv-intein recognition partners, generates fully active CARs. Functionality was validated using Raji cells and K562 cells expressing CD19 and/or CD20, observing significant T cell activation through NFAT and NFκB promoter activity and CD69 upregulation. Overall, our study lays the foundation for the establishment of a new way to target multiple antigens through a universal and inert CAR backbone with highly specific activation.
Melanoma, the deadliest form of skin cancer, poses a significant challenge due to its genetic heterogeneity and high metastatic potential. While cytotoxic T cell (CTL)-based immunotherapies have made remarkable progress...Melanoma, the deadliest form of skin cancer, poses a significant challenge due to its genetic heterogeneity and high metastatic potential. While cytotoxic T cell (CTL)-based immunotherapies have made remarkable progress in recent years, the therapeutic potential of natural killer-(NK) cells is increasingly recognized. However, resistance mechanisms to both CTL- and NK-cell-mediated immunotherapies hinder effective treatment. To evaluate the exclusive role of NK-cells in anti-melanoma immunity, we performed 2D and 3D co-culture-based cytotoxicity assays under varying conditions. Our findings revealed a protective phenotype in melanoma cells following prolonged exposure to primary NK-cells. By combining experimental data with bioinformatic analyses, we identified key genes and pathways involved in melanoma cell adaptation to NK-cell-mediated killing (NKmK). We found that cytokines such as IFNγ play a major role in suppressing NKmK with MHC II surface expression being a critical factor. Targeting the master regulator CIITA, which governs MHC II expression and is affected by IFNγ, significantly reduced melanoma cell resistance to NKmK. This study provides potential strategies to overcome resistance to NK-cell-based immunotherapies and offers novel insights into melanoma immune escape mechanisms.
The spindle assembly checkpoint (SAC) delays the metaphase-to-anaphase transition. Aurora kinase A (AURKA) inactivation has been shown to cause premature exit from mitosis in the presence of an unsatisfied SAC. We report...The spindle assembly checkpoint (SAC) delays the metaphase-to-anaphase transition. Aurora kinase A (AURKA) inactivation has been shown to cause premature exit from mitosis in the presence of an unsatisfied SAC. We report for the first time that centromeric AURKA interacts with survivin during prometaphase. Notably, depleting or inhibiting AURKA activity at this stage causes mislocalisation of the CPC and BubR1, which compromises the SAC and can lead to mitotic slippage. Furthermore, we show that AURKA binds directly to the BIR domain of survivin at a position distinct from AURKB and indirectly to it via its C terminus. We find the interaction peaks during prometaphase but persists into late mitosis. Importantly, we demonstrate that cells with high levels of survivin are particularly vulnerable to mitotic slippage induced by the AURKA inhibitor, MLN8237/ Alisertib. Alisertib enables both normal and transformed cells with high levels of survivin to activate the APC/C prematurely, as observed by the destruction of cyclin B and securin. Thus, a high expression of survivin can alter cell fate decisions at mitosis and lead to genetic instability, a key hallmark in cancer.
Casagrande GMS, de Oliveira Silva M, Dos Reis MB
… +9 more, de Oliveira Cavagna R, Sussuchi L, Alves Pinto I, Pontes NZ, Chiarantano RS, da Silva FAF, de Marchi P, Leal LF, Reis RM
The detection of actionable mutations in liquid biopsies is a crucial tool for precision oncology in patients with non-small-cell lung cancer (NSCLC). We evaluated actionable alterations using a multigene panel in circul...The detection of actionable mutations in liquid biopsies is a crucial tool for precision oncology in patients with non-small-cell lung cancer (NSCLC). We evaluated actionable alterations using a multigene panel in circulating tumor DNA (ctDNA) from Brazilian NSCLC patients. We analyzed 32 samples from 30 patients with NSCLC, including four samples from a lung cancer screening program. ctDNA isolation and library preparation were performed using the Oncomine Lung cfDNA Assay, which covers 11 actionable genes, and sequenced on an Ion S5 Sequencer. The IonReporter 5.20 software was used for variant calling. Median read coverage reached 80 967, with a detection limit of 0.1%. TP53 (40.6%), KRAS (28.1%), and EGFR (12.5%) were the most frequently mutated genes, particularly in patients who had previously received treatment. BRAF, MAP2K1, PIK3CA, and ALK mutations were observed at lower frequencies (6.2%, 3.1%, 3.1%, and 3.1%, respectively). The EGFR p.T790M mutations related to resistance were identified in a patient who had been previously treated, and the TP53 p.R248Q mutation was discovered in an asymptomatic patient before diagnosis. No variants were observed in NRAS, ROS1, and MET genes. Our data showed that this commercial NGS panel could detect actionable mutations, enabling early detection, treatment monitoring, and disease surveillance.
Hepatic fibrogenesis is characterized by the excessive accumulation of extracellular matrix proteins, ultimately predisposing to hepatocarcinogenesis. The lack of reliable models that faithfully recapitulate early stage...Hepatic fibrogenesis is characterized by the excessive accumulation of extracellular matrix proteins, ultimately predisposing to hepatocarcinogenesis. The lack of reliable models that faithfully recapitulate early stage fibrogenesis is one of the main limitations in identifying translationally relevant therapeutics. Here, we establish a model using CRISPR/Cas9-mediated TP53 knockout iPSC (endoderm)-derived human hepatic organoids (eHEPOs) to mimic human liver fibrosis. Transcriptomic profiling of TP53KO-eHEPOs revealed enrichment of pathways associated with inflammation, ECM remodeling, and fibrosis, with notable alterations in pivotal fibrotic regulators. We also find increased expression of myofibroblasts and fibrosis markers (PDGFRB, COL1A1, COL3A1, COL11A1) and early liver cancer markers (GPC3 and MUC1). Histological analysis confirmed advanced fibrotic hallmarks and exposure to an exogenous profibrotic environment (pf-ME) further enhanced these fibrotic phenotypes. This model provides a valuable platform for exploring the role of key driver genes, such as TP53, in the initiation and progression of fibrosis, enabling the study of hepatic progenitor cell transformation across diverse microenvironmental contexts. As such, it holds the potential for advancing early stage drug discovery and the identification of novel therapeutic targets for the treatment of liver fibrosis.
Pece A, Lovato G, Cela I
… +16 more, Mercatelli A, Ferro B, Nikkola J, Pagotto S, Grottola T, De Laurenzi V, Cicchetti R, Marchetti A, Schips L, Lattanzio R, Iacobelli S, Capone E, Black P, Daugaard M, Marchioni M, Sala G
Bladder cancer incidence has recently risen, making it the ninth most diagnosed cancer, highlighting an urgent need for novel and effective diagnostic and therapeutic strategies to improve patient outcomes. Here, we repo...Bladder cancer incidence has recently risen, making it the ninth most diagnosed cancer, highlighting an urgent need for novel and effective diagnostic and therapeutic strategies to improve patient outcomes. Here, we report on a secreted glycoprotein, Galectin-3-binding protein (LGALS3BP), as a potential biomarker and therapeutic target for bladder cancer. We found a significantly elevated LGALS3BP expression in bladder cancer tissues, correlating with disease progression. Moreover, urinary and serum levels of LGALS3BP were significantly higher in patients compared to healthy individuals, with a strong correlation observed between elevated urinary protein levels and tumor grade. Of note, LGALS3BP produced by tumor cells treated with a mannosidase I inhibitor, Kifunensine, exhibited increased reactivity to a therapeutic antibody (denoted as "1959"), suggesting that glycosylation of LGALS3BP may influence antibody recognition and protein function. Furthermore, administration of 1959-sss/DM4 antibody-drug conjugate in two xenograft mouse models of human bladder cancer resulted in complete inhibition of tumor growth. In summary, findings presented here highlight LGALS3BP as a promising candidate for further investigation into its potential as a urinary biomarker and a therapeutic target for bladder cancer.
Mitochondria are essential organelles that regulate various biological processes including metabolism. Beyond their intracellular functions, intercellular mitochondrial transfer has emerged as a novel mechanism of interc...Mitochondria are essential organelles that regulate various biological processes including metabolism. Beyond their intracellular functions, intercellular mitochondrial transfer has emerged as a novel mechanism of intercellular communication. Notably, an increasing number of studies have reported its occurrence in the tumor microenvironment (TME), where it contributes to tumor progression. While previous studies largely characterized cancer cells as recipients of mitochondria, Cangkrama et al. demonstrated that cancer cells donate their mitochondria to fibroblasts via tunneling nanotubes. The mitochondrial transfer to fibroblasts reprogrammed them into cancer-associated fibroblasts exhibiting combined myofibroblastic and inflammatory characteristics, with enhanced oxidative metabolism and pro-tumorigenic activity. Our group has identified mitochondrial 'hijack' from cancer cells to tumor-infiltrating lymphocytes, leading to an impaired antitumor immunity. These insights underscore the need to recognize cancer cells as mitochondrial donors in the TME capable of reshaping the TME to their own advantage, resembling a dynastic expansion strategy that exerts influence by strategically placing lineages.
Genetic testing in epithelial ovarian cancer (EOC) in Ontario includes germline next-generation sequencing (NGS) for 19 genes. Additionally, tumor tissue undergoes reflex NGS testing for BRCA1/2 to assess eligibility for...Genetic testing in epithelial ovarian cancer (EOC) in Ontario includes germline next-generation sequencing (NGS) for 19 genes. Additionally, tumor tissue undergoes reflex NGS testing for BRCA1/2 to assess eligibility for PARPi. Although parallel testing confers advantages, this model duplicates healthcare resources. Here, we prospectively assessed the feasibility of tumor-first multigene testing by comparing tumor tissue with germline testing of peripheral blood. An 18-gene NGS panel was used to test tumor and germline DNA (n = 106 patients). In 26 patients, 27 tumor Tier I or II variants were identified, with 16/27 (59%) being germline pathogenic variants (PV) (13 BRCA1/2; 3 other genes) and 11/27 (41%) somatic variants (9 BRCA1/2; 2 other). In 51/106 patients, there were no tumor variants (excluding TP53), of which one patient had a germline BRCA1 copy number variant deletion in exon 12. Tumor-first testing detected variant-positive and variant-negative germline cases in 105/106 patients (99.1%). Among 50 BRCA-negative patients, 14/50 (28%) were homologous recombination deficiency (HRD)-positive. Therefore, we demonstrate that multigene NGS tumor-testing is effective in identifying germline variants in EOC with a < 1% false-negative rate.
Topa J, Richert J, Stokowy T
… +12 more, Staśczak A, Szajewski M, Ciesielski M, Grešner PM, Tomasik B, Arcimowicz Ł, Stankiewicz A, Suchodolska G, Senkus E, Kruszewski W, Żaczek AJ, Markiewicz A
Epithelial-mesenchymal transition (EMT) generates heterogeneity in circulating tumor cells (CTCs), affecting their biological properties and hampering their detection. This limits our understanding of the mechanisms unde...Epithelial-mesenchymal transition (EMT) generates heterogeneity in circulating tumor cells (CTCs), affecting their biological properties and hampering their detection. This limits our understanding of the mechanisms underlying hematogenous dissemination, especially in early breast cancer (BC), where CTCs are rare. Here, we aimed to detect CTCs with different EMT statuses from BC patients. CTCs in blood samples from 107 BC patients were evaluated using immunomagnetic depletion and multi-marker immunofluorescence (EpCAM, E-cadherin, MCAM, cell surface vimentin, CD31, CD45), followed by single-cell transcriptomics. CTCs were detected in 51.9% of therapy-naïve early BC cases, with 3.8% showing only epithelial CTCs (eCTCs), 5.8% epithelial-mesenchymal (emCTCs), 26.0% mesenchymal (mCTCs), and 16.3% mixed phenotypes. CTC heterogeneity was more frequent in triple-negative (86%) than in luminal BC (17%, P = 0.008). Lymph node involvement strongly predicted dissemination of all CTC phenotypes, while tumor size correlated with mCTC abundance. Single-cell RNA sequencing revealed downregulation of ribosomal genes and translation inhibition in CTCs with mesenchymal features, linked to mTORC1 signaling. Findings were also validated in an independent dataset, highlighting vulnerabilities in CTCs during dissemination.
Targeted therapy has been established as a therapeutic option for the treatment of metastatic melanoma. Despite initially being very efficient, many tumors develop resistance to targeted therapy, leading to its failure....Targeted therapy has been established as a therapeutic option for the treatment of metastatic melanoma. Despite initially being very efficient, many tumors develop resistance to targeted therapy, leading to its failure. We previously demonstrated that the neural crest (NC)-associated gene ERRFI1 is highly expressed in metastatic melanoma and correlates with a bad prognosis. Here, we show that the expression of ERRFI1 was upregulated in melanoma and negatively correlated with the expression of melanocytic differentiation markers, such as MITF and TYR. Downregulation of ERRFI1 with the help of siRNA increased the susceptibility of melanoma cells toward BRAF inhibition (BRAFi) and resensitized BRAFi-resistant melanoma cells to BRAFi. Mass spectrometry-based proteomic analysis revealed that ERRFI1 silencing diminished the activation of the mitogen-activated protein kinase (MAPK) and AKT signaling pathways, which usually contribute to drug resistance. Furthermore, we show that miR-200c targeted the 3'UTR of ERRFI1 and reduced its expression, resulting in the resensitization of BRAFi-resistant melanoma cells to BRAFi. Our study results suggest that ERRFI1 could be a potential therapeutic target for the treatment of metastatic melanoma.
Excised signal circles (ESC) are circular DNA molecules generated during T- and B-cell maturation. Previously considered biologically inert, recent work by Gao et al. now show that ESCs can replicate and accumulate in he...Excised signal circles (ESC) are circular DNA molecules generated during T- and B-cell maturation. Previously considered biologically inert, recent work by Gao et al. now show that ESCs can replicate and accumulate in healthy lymphocytes. Moreover, the authors link higher levels of ESCs to an increased risk of relapse in B-cell leukemia patients and propose that this phenomenon is due to the unique ability of ESCs to induce genome instability.
Strecker M, Zohar K, Böttcher M
… +14 more, Wartmann T, Freudenstein H, Doelling M, Andric M, Shi W, Kakhlon O, Hippe K, Jahnke B, Mougiakakos D, Baenke F, Stange D, Croner RS, Linial M, Kahlert UD
Colorectal cancer (CRC) represents the third leading cause of cancer-related deaths. Integrating cellular and molecular data from individual patients has become valuable for diagnosis, prognosis, and treatment selection....Colorectal cancer (CRC) represents the third leading cause of cancer-related deaths. Integrating cellular and molecular data from individual patients has become valuable for diagnosis, prognosis, and treatment selection. Here, we present a comparative mRNA-seq analysis of tissue samples from 32 CRC patients, pairing tumors with adjacent healthy tissues. Differential expression gene (DEG) analysis revealed dysregulated metabolic programs. We focused on the impact of overexpressed SLC7A11 (xCT) and SLC3A2, which compose the cystine/glutamate transporter (Xc-) system. To assess the oncogenic potential of the Xc- system, we analyzed gene perturbations from CRISPR screens across various cell types and used functional assays in five primary patient-derived organoid models. We identified a previously uncharacterized cell surface protein signature predicting chemotherapy resistance and highlighted the causality and potential of pharmacological blockage of ferroptosis as a promising avenue for cancer therapy. Redox homeostasis, ion/amino acid transporters, and regulators of neuronal survival and differentiation were pathways associated with these co-dependent genes in patient specimens. This study highlights several potential clinical targets for CRC therapy and promotes the use of patient-derived organoids oids to functionally validate in silico predictions.
Saad J, Newman R, Khabusheva E
… +15 more, Aakko S, Durand E, Tambe M, Kuusanmäki H, Parsons A, Miettinen JJ, Javarappa KK, Olgac EJ, Ikonen N, Kontro M, Porkka K, Maacke H, Woo J, Halilovic E, Heckman CA
Despite promising anti-leukemic activity of MCL-1 inhibitors in preclinical studies of acute myeloid leukemia (AML), clinical progress has been hindered by limited knowledge of target patient subgroups. To stratify patie...Despite promising anti-leukemic activity of MCL-1 inhibitors in preclinical studies of acute myeloid leukemia (AML), clinical progress has been hindered by limited knowledge of target patient subgroups. To stratify patients for MCL-1 inhibitor treatment, we evaluated the sensitivity of 42 primary AML samples to MCL-1 inhibitor MIK665 (S64315) and analyzed their molecular profiles. We observed that MIK665-sensitive samples had a more differentiated phenotype, whereas resistant samples displayed higher levels of ABCB1 (MDR1) and the anti-apoptotic protein BCL-XL. Moreover, ABCB1 expression had good predictive performance in identifying resistant samples. To induce sensitivity, we treated MIK665-resistant samples with ABCB1 inhibitors elacridar or tariquidar, BCL-XL inhibitor A1331852, or BCL-2 inhibitor venetoclax in combination with MIK665. The combination of MIK665 with each of elacridar, tariquidar, or venetoclax effectively eliminated AML blasts compared to the agents alone, while the combination with A1331852 showed limited efficacy for this patient subgroup. Additionally, the combination of MIK665 with venetoclax restored sensitivity in samples with primary venetoclax resistance. Overall, this study indicates that elevated ABCB1 expression is a potentially targetable resistance mechanism in the context of MIK665 resistance, and that a combination of MIK665 with venetoclax may be effective for overcoming resistance to either MCL-1 or BCL-2 inhibition.
Glioma stem cells (GSCs) from this aggressive brain cancer have been subject to nononcogene addiction therapeutic strategies, in particular targeting iron and cholesterol metabolic pathways. In this study, we show the sm...Glioma stem cells (GSCs) from this aggressive brain cancer have been subject to nononcogene addiction therapeutic strategies, in particular targeting iron and cholesterol metabolic pathways. In this study, we show the small molecule Adaptaquin (AQ) has anti-GSC effects while sparing neurons, mature oligodendrocytes and astrocytes. Transcriptomic analysis of AQ-treated GSCs showed dramatic upregulation of iron transport genes and downregulation of genes involved in cholesterol biosynthesis. Indeed, we found cytotoxic effects of AQ on GSCs were potentiated when combined with the iron chelator deferoxamine (DFO). Notably, these effects were independent of PHD2 and HIF1α regulation, indicating a distinct pathway of action. Furthermore, we observed that the heme analogue, hemin, protects GSCs from AQ-mediated cell death, suggesting the presence of a functional heme transporter in GSCs, an observation confirmed by uptake of heme analogues. Importantly, we found that AQ treatment alone or in combination with iron chelators impaired cholesterol homeostasis in GSCs, leading to mitochondrial fragmentation and cell death. These findings suggest AQ in combination with iron chelators results in lethal disruption of cholesterol metabolism in glioma stem cells.
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with metastatic CRC (mCRC) posing significant challenges due to tumor heterogeneity and resistance to therapy. Circulating tumor cells (CTC) an...Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with metastatic CRC (mCRC) posing significant challenges due to tumor heterogeneity and resistance to therapy. Circulating tumor cells (CTC) and circulating hybrid cells (CHC) detected via liquid biopsies have emerged as promising biomarkers for monitoring disease progression. This study aimed to evaluate the prognostic utility of automated CTC enumeration using the ACCEPT software compared to a manual method and assess the potential clinical relevance of CHC in mCRC. A retrospective analysis of CellSearch images from 67 mCRC patients was conducted, correlating CTC and CHC counts with progression-free survival and overall survival (OS). Automated enumeration demonstrated improved accuracy and reduced variability, confirming the prognostic significance of CTC counts for OS. However, CHC enumeration showed no significant association with clinical outcomes, suggesting sporadic detection rather than consistent prognostic value. These findings underscore the reliability of automated CTC enumeration in mCRC prognosis while highlighting the need for further research into the biological and clinical roles of CHC.
Medulloblastoma (MB) is the most common malignant tumor in the central nervous system in childhood and regularly metastasizes to the leptomeninges following radiation therapy. Using patient-derived medulloblastoma models...Medulloblastoma (MB) is the most common malignant tumor in the central nervous system in childhood and regularly metastasizes to the leptomeninges following radiation therapy. Using patient-derived medulloblastoma models and genetically engineered mouse models, Nör et al. observed enhanced inflammation and infiltration of myeloid cells within the brain following irradiation. The authors identified inflammatory cytokines and the resulting breakdown of blood-brain barriers as the main culprits of MB leptomeningeal metastasis. This study demonstrated that targeting inflammation through the use of dexamethasone effectively reduced systemic inflammatory cytokines and the resulting radiation-induced leptomeningeal metastasis.
Wu S, Zhao J, Azmi AA
… +16 more, Gupte A, Thibodeau J, Liu S, Yang J, Wang G, Edwards H, Polin LA, Kushner J, Dzinic SH, White K, Boerner J, Hüttemann M, Yang J, Wang Y, Taub JW, Ge Y
Relapsed/refractory (R/R) disease is a major hurdle to long-term survival of acute myeloid leukemia (AML) patients treated with intensive cytarabine (AraC)-based chemotherapy. R/R AML salvage treatment with venetoclax (V...Relapsed/refractory (R/R) disease is a major hurdle to long-term survival of acute myeloid leukemia (AML) patients treated with intensive cytarabine (AraC)-based chemotherapy. R/R AML salvage treatment with venetoclax (VEN) + azacitidine (AZA) results in overall response rates between 20% and 60%, and responses are not durable, highlighting the need for new therapies. Here, we report elevated mTORC1 signaling in AraC-resistant AML cell lines, primary AML patient samples, and patient-derived xenograft (PDX) AML cells derived from patients at relapse postchemotherapy. The CDK9 inhibitor AZD4573 suppresses mTORC1 signaling and downregulates c-MYC and MCL-1, inducing AraC-resistant AML cell death. AZD4573 in combination with VEN + AZA significantly increases AML cell death compared to any of the two-drug combinations and suppresses AML progenitor cells but spares normal hematopoietic progenitor cells. The efficacy of this triple combination remains even with a 10-fold reduction of VEN concentration. The roles of MCL-1 and c-MYC in the three-drug combination were confirmed by knockdown. This study demonstrates that AZD4573 enhances the activity of VEN + AZA against AraC-resistant AML by downregulating c-MYC and MCL-1 and to a lesser extent cellular respiration.