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Palbociclib and dsRNA sensor co-operate to enhance anti-cancer effects through ER stress and modulation of immune evasion.
No full textCytoplasmic pattern recognition receptors (PRR) for double-stranded RNA, such as RIG-I/MDA5, are key mediators of anti-viral responses. Here we screen for synergistic drug-virotherapy combinations and find that the reovirus type III Dearing strain (Rt3D)-palbociclib combination augments oncolytic virus-induced stress responses and increases interferon production and signaling. Data from RIG-I agonist and ER stress-inducing agents further confirms the crosstalk between RNA-sensing and ER stress in inducing cancer cell death and interferon production. Combined Rt3D-palbociclib also increases innate immune activation and IFN-induced HLA expression within tumor cells, with accompanying alterations in the epigenetic landscape and endogenous retroviral (ERV) elements. Analysis of the immunopeptidome in treated cells further reveals changes to HLA-captured peptides, including altered expression of peptides from cancer or testis antigens and ERVs. Our findings thus highlight the crosstalk between stress signaling and PRR activation for mediating enhanced anti-cancer efficacy
Dysregulated SASS6 expression promotes increased ciliogenesis and cell invasion phenotypes.
No full textCentriole and/or cilium defects are characteristic of cancer cells and have been linked to cancer cell invasion. However, the mechanistic bases of this regulation remain incompletely understood. Spindle assembly abnormal protein 6 homolog (SAS-6) is essential for centriole biogenesis and cilium formation. SAS-6 levels decrease at the end of mitosis and G1, resulting from APCCdh1-targeted degradation. To examine the biological consequences of unrestrained SAS-6 expression, we used a nondegradable SAS-6 mutant (SAS-6ND). This led to an increase in ciliation and cell invasion and caused an up-regulation of the YAP/TAZ pathway. SAS-6ND expression resulted in cell morphology changes, nuclear deformation, and YAP translocation to the nucleus, resulting in increased TEAD-dependent transcription. SAS-6-mediated invasion was prevented by YAP down-regulation or by blocking ciliogenesis. Similarly, down-regulation of SAS-6 in DMS273, a highly invasive and highly ciliated lung cancer cell line that overexpresses SAS-6, completely blocked cell invasion and depleted YAP protein levels. Thus, our data provide evidence for a defined role of SAS-6 in cell invasion through the activation of the YAP/TAZ pathway
Fatal intracranial haemorrhage shortly after belzutifan initiation in von Hippel-Lindau (VHL) disease-associated haemangioblastoma.
No full textBACKGROUND: Belzutifan, a selective hypoxia-inducible factor-2α inhibitor, is approved for von Hippel-Lindau (VHL) disease-associated tumours and is Food and Drug Administration-approved for the management of advanced sporadic clear-cell renal-cell carcinoma. While belzutifan has demonstrated efficacy across VHL-related lesions, real-world safety data remain limited. PATIENTS AND METHODS: We report a fatal intracranial haemorrhage occurring within 72 h of belzutifan initiation in a patient with VHL-associated central nervous system haemangioblastomas (CNS-HBs). RESULTS: This represents the third post-marketing case of early haemorrhage involving CNS or spinal haemangioblastomas, following previously reported spinal and cerebellar bleeds. Although CNS-HBs are highly vascular, spontaneous haemorrhage is exceedingly rare. The clustering of haemorrhagic events in these cases, within days of treatment initiation, suggests a rare but potentially serious adverse event not currently listed on regulatory labels. CONCLUSIONS: This case highlights the importance of pharmacovigilance as belzutifan use expands into broader real-world populations, particularly in rare disease settings where trial cohorts are small and long-term safety data are limited
Xevinapant plus Chemoradiotherapy Negatively Sculpts the Tumor-Immune Microenvironment in Head and Neck Cancer.
No full textUNLABELLED: Xevinapant is an orally bioavailable antagonist of select members of the inhibitor of apoptosis protein family. Despite promising phase II data, combining xevinapant with chemoradiotherapy (CRT) failed to improve outcomes in the phase III TrilynX trial when combined with CRT for locally advanced head and neck squamous cell cancer (SCCHN). In immunocompetent mouse models of SCCHN, xevinapant plus CRT maintained or improved locoregional control but in a CD8+ T cell-independent manner. On addition of xevinapant to CRT, the numbers of tumor-infiltrating cytotoxic CD8+ T cells and NK cells were reduced, with remaining CD8+ T cells characterized by PD-1hi CD38hi expression and Nr4a3 dynamics consistent with nonresponsiveness to antigenic restimulation. Furthermore, combination treatment significantly downregulated gene expression associated with immune-related pathways, increased levels of immunodysregulatory acute-phase proteins, and decreased levels of necroptosis mediator receptor-interacting protein kinase 3. Overall, xevinapant plus CRT has an immunosuppressive effect on the tumor-immune microenvironment, which may explain its lack of clinical benefit. SIGNIFICANCE: Despite hugely promising randomized phase II study data, combined CRT plus xevinapant failed in the TrilynX phase III clinical trial in locally advanced SCCHN. We show that adding xevinapant to chemoradiotherapy in vivo dysregulates antitumor lymphocyte function, acute-phase proteins, and cell death pathways, with net immunosuppressive effects on the tumor-immune microenvironment
Characterising the effect of metabolic perturbation on oncogenic signalling transduction
No full textMetabolic rewiring, including increased glucose dependence known as the Warburg
effect, is a hallmark of cancer. This PhD thesis investigates how metabolic
perturbations, specifically glucose deprivation, influence oncogenic signalling and the
initial response to inhibitors of oncogenic drivers, which remain underexplored. In EGFR
and BRAF-driven glioblastoma models, glucose deprivation causes super-activation of
driver oncogenes, leading to cell death—a process mitigated by selective tyrosine
kinase inhibitors. This suggests that glucose deprivation induces cell death through
oncogene overdose, irrespective of the oncogene type. Similar effects are observed in
other oncogene-driven models, hinting at broader applicability in oncogene-dependent
cancers. Molecular profiling reveals that glucose deprivation induces notable
transcriptional and phosphorylation changes, many reversible by oncogene inhibition.
Our findings indicate that glucose depletion triggers a non-apoptotic, possibly necrotic,
form of cell death linked to disrupted cell cycle checkpoint control. These insights
advance our understanding of the Warburg effect and inform strategies for combining
targeted therapies in cancer treatment
Evaluating the impact of CRBN mutations on response to immunomodulatory drugs and novel cereblon E3 ligase modulators in myeloma.
No full textImmunomodulatory drug (IMiD) resistance is a key clinical challenge in myeloma treatment. Previous data suggest almost one-third of myeloma patients acquire genetic alteration of the key IMiD effector cereblon (CRBN) by the time they are pomalidomide refractory. Some events, including stop codons/frameshift mutations and copy loss, have clearly explicable effects on CRBN protein function. Missense mutations have also been reported throughout the length of CRBN but their functional impact has not been systematically studied. This study modeled selected missense mutations and examined their effect on CRBN function also analyzing whether any mutations deleterious to IMiD action could be overcome using the novel cereblon E3 ligase modulators (CELMoDs). Three patterns of response to missense mutations were apparent: mutations that led to complete loss of CRBN function for all agents, those that had no effect on CRBN function, and those with agent-dependent effect on CRBN function. The latter group of 4 mutations were profiled in more detail with confirmatory experiments demonstrating an ability of the more potent CELMoDs to lead to neosubstrate degradation and cell death even though IMiDs were not active. Dynamic modeling based on a newly generated crystal structure of the DDB1/CRBN/lenalidomide complex, with greater resolution than those published to date, helped to understand the impact of these mutations. These results have important implications for the interpretation of CRBN sequencing results from patients for future therapy decisions, particularly differentiating those who may, despite relapsing on IMiDs with CRBN mutations, have the potential to still benefit from the use of CELMoD agents
Creation, curation, and utility of public health genomics datasets for Lynch syndrome
No full textThis thesis will describe methods of dataset planning, creation, and curation for genomic, clinical, and epidemiological data in Lynch syndrome, and demonstrate the utility of such data for healthcare provision, system audit, and medical research.
In the first chapter, I will outline the inception of two new Lynch syndrome datasets – a germline genomics dataset containing details of all germline genetic testing taking place in England, and a National Lynch Syndrome Registry containing demographic and genetic data on all known Lynch syndrome carriers in England. I will also provide a description of their contents and what this tells us about the epidemiology of Lynch syndrome in England.
In the second chapter, I will demonstrate the utility of the germline genomic dataset by using it (along with additional existing datasets) to describe the patterns of Lynch syndrome testing in endometrial cancer in England in 2019, and investigate factors that are associated with an increased likelihood of testing.
In the third chapter, I will demonstrate the utility of the Lynch Syndrome registry by using it as a study cohort to explore the distribution of surveillance colonoscopies in the Lynch syndrome population, and assess the impact of surveillance colonoscopies on colorectal cancer incidence and mortality
Randomized clinical efficacy and safety study of peltopepimut-S plus cemiplimab compared to cemiplimab alone in patients with recurrent/metastatic HPV16-positive head and neck cancer.
No full textBACKGROUND: Peltopepimut-S is a therapeutic vaccine, which induces specific expansion of both CD4+helper and CD8+cytotoxic T-cells against human papillomavirus type 16 (HPV16) E6/E7 oncoproteins. PATIENTS AND METHODS: In a randomized phase 2 trial, we evaluated the efficacy and safety of peltopepimut-S plus cemiplimab compared with cemiplimab alone as first-line or second-line therapy in recurrent/metastatic HPV16-positive head and neck cancer. The primary efficacy endpoint was the objective response rate (ORR) by an independent review (Response Evaluation Criteria in Solid Tumors version 1.1, RECIST v1.1), while the primary safety endpoint was frequency and severity of adverse events. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: Overall, 198 anti-programmed cell death protein-1 therapy-naïve patients with confirmed HPV16-positive recurrent/metastatic oropharyngeal cancer were randomized to receive cemiplimab plus peltopepimut-S (n=100) or placebo (n=99). The trial did not meet its primary objective (ORR, 25.3% in peltopepimut-S arm vs 22.9% in placebo arm; p=0.735). The median OS (mOS) and PFS in the placebo arm were unexpectedly longer than in the peltopepimut-S arm (26.9 vs 15.8 months) and (20.3 vs 5.5 months), respectively. In predefined exploratory analyses this was associated with an excess death rate from progressive disease in patients with pre-treatment programmed death-ligand 1 (PD-L1) combined positive score (CPS) <20. In contrast, patients with CPS ≥20 had a higher ORR of 51.7% (95% CI, 32.5% to 70.6%) vs 25.8% (95% CI, 11.9% to 44.6%) and a longer mOS in the peltopepimut-S arm (34.8 vs 28.8 months) compared with the placebo arm, respectively. If patients had received all three vaccine or placebo doses, the ORR in patients with CPS ≥20 was 70.0% (95% CI, 45.7% to 88.1%) vs 29.2% (95% CI, 12.6% to 51.1%) in the peltopepimut-S arm and placebo arms, respectively, associated with mOS not reached (after 42 months) versus 23.3 months. The addition of peltopepimut-S to cemiplimab did not increase cemiplimab's toxicity. CONCLUSION: Adding peltopepimut-S to cemiplimab did not improve ORR and worsened mOS in the primary analysis. Divergent outcomes were seen in patients with pretreatment PD-L1 CPS <20 (worse ORR and mOS compared with placebo) and CPS ≥20 (higher ORR and longer mOS compared with placebo) values. Future drug development is justifiable in the CPS ≥20 patient population. TRIAL REGISTRATION NUMBER: NCT03669718
Resistance to CDK7 inhibitors directed by acquired mutation of a conserved residue in cancer cells.
No full textCDK7 has emerged as a cancer target because of its pivotal roles in cell cycle progression and transcription. Several CDK7 inhibitors (CDK7i) are now in clinical evaluation. Identifying patients most likely to respond to treatment and early detection of tumour evolution towards resistance are necessary for optimal implementation of cancer therapies. Continuous culturing of prostate cancer cells with Samuraciclib, a non-covalent ATP-competitive CDK7i, led to outgrowth of resistant cells. These were characterised by the acquisition of a single base change in the CDK7 gene, Asp97 to Asn (D97N). Mutant cells were resistant to other non-covalent CDK7i but remained sensitive to covalent CDK7i. Cryo-EM structure and kinase ligand affinity determinations revealed reduced affinity of the CDK7-D97N mutant for non-covalent CDK7i. Remarkably, Asp97 is absolutely conserved in human CDKs, inferring its importance for the activities of all CDKs. Consistent with this, mutation of the homologous residue in CDK12 (D819N) or CDK4 (D99N) promoted resistance to drugs that inhibit these CDKs. Our findings reveal a general mechanism for acquired resistance with obvious implications for patients treated with CDK inhibitors
The Roles of SWI/SNF Chromatin Remodelling Complexes and Centromere Proteins Across the Genome
No full textThe thesis will first explore the roles of the human SWI/SNF chromatin remodelling complexes at centromeres. We find that loss of function of the SWI/SNF subunit PBRM1 results in the dysregulation of centromere structure and function. Genome-wide mapping of the SWI/SNF subunit SMARCA4 and PBAF-specific subunit PBRM1 in wildtype cells demonstrate that the two subunits are associated with pericentromeres. Mapping of SMARCA4 in PBRM1 knockout cells shows that PBRM1 loss results in changes in SMARCA4 association at centromeres, indicating that PBRM1 is required for PBAF’s recruitment to centromeres. Genome-wide mapping of the histone modification H3K9me2 and H3K9me3 in wildtype and PBRM1 knockout cells show changes in heterochromatin upon PBRM1 loss.
The next part of the thesis will describe the roles of centromere protein CENPB along chromosome arms. We find that CENPB is localised to open chromatin regions outside centromeres in an epithelial cell line, including gene promoters. Ectopic CENPB binding sites do not contain the CENPB-box motif, suggesting an alternative mode of recruitment from the centromeres. Motif-based sequence analysis shows a significant enrichment of the CCAAT box motif within these promoters which could represent a potential mode of CENPB recruitment. CENPB also exhibits binding at gene promoters in a leukaemia cell line. There are some overlaps in binding sites between the epithelial and the cancer-derived cells, suggesting cell type specificity in CENPB’s activity at gene promoters. We found that CENPB can potentially act as a transcriptional regulator of these target genes through transcriptomic analysis of CENPB-depleted cells. These findings demonstrate a non-canonical role of CENPB as a possible transcriptional regulator and raises questions about the molecular mechanisms of CENPB recruitment to promoters and regulation of gene transcription