The small GTPase KRAS is frequently mutated in cancer and KRASG12D is its most common mutation, with ∼34% incidence in pancreatic ductal adenocarcinoma (PDAC), ∼12% in colorectal cancer (CRC) and ∼4% in non-small cell lung cancer (NSCLC). KRASG12D mutations disrupt the GTPase activity of the protein, resulting in elevated cellular levels of active, GTP-bound KRASG12D. KRASG12D mutations are therefore associated with increased and deregulated RAS signalling, driving uncontrolled cell proliferation and survival. Despite major advances in RAS-targeting in recent years, KRASG12D-cancers continue to represent an unmet medical need. AZD0022 is a potent, orally bioavailable, KRASG12D-selective reversible inhibitor with the potential to provide therapeutic benefit to patients with KRASG12D-mutated cancers. AZD0022 shows high affinity to both the active (KRASG12D-GTP) and inactive forms of KRASG12D (KRASG12D-GDP) protein by Surface Plasmon Resonance, and selectivity over wild-type KRAS. AZD0022 treatment drives robust and concentration-dependent biomarker inhibition in KRASG12D CRC, PDAC and NSCLC models in vitro and in vivo and inhibits proliferation and viability of KRASG12D-tumour cells across these indications. Following oral administration in mouse, rat and dog, AZD0022 exhibited significant oral exposure and long terminal elimination phase half-life values. Oral, chronic daily treatment of a panel of CRC, PDAC and NSCLC CDX (cell line-derived xenograft) and PDX (patient-derived xenograft) models with AZD0022 demonstrated broad anti-tumour activity of AZD0022 across KRASG12D-mutant tumour types. The therapeutic responses of KRASG12D CRC and PDAC models to AZD0022 were further improved by cetuximab combination treatment, with sustained regressions observed in both tumour types. Together, the pre-clinical pharmacology of AZD0022 supports its oral anti-tumor activity and KRASG12D-selectivity and shows that it has the potential to improve outcomes for patients with KRASG12D mutated cancers, either as monotherapy or in combination with other agents. AZD0022 is currently being investigated in the ALAFOSS-01 (NCT06599502) study, a first-in-human, open-label, multicenter, phase 1/2a study of AZD0022 in patients with KRASG12D-mutated solid tumors. Carla P. Martins, Alex Koers, Sreyoshi Mitra, Alison Peter, Katie Young, Christopher Chambers, Zoe Underwood, Kevin Beaumont, Sofia Guzzetti, Christopher Stubbs, Derek Barratt, Benjamin Phillips, Eleanor Wigmore, Melissa Chapman, Michele Moschetta, Simon Barry, Susan Critchlow, Michael Niedbala. AZD0022: a potent, oral KRASG12D-selective inhibitor that drives robust pathway inhibition and anti-tumour activity in KRASG12D models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr ND11.

Supplementary Fig. S1. Preclinical evaluation and characterization of YTB323 and CTL*019 for Donor 2 and 3; Supplementary Fig. S2. Differential gene expression of CTL*019 cells versus YTB323 cells (preclinical); Supplementary Fig. S3. Preclinical validation of YTB323; Supplementary Fig. S4. Dose-dependent expansion (Cmax and AUC0-21d) of YTB323 and CTL*019 in NSG mice with NALM6; Supplementary Fig. S5. CD4:CD8 ratio comparison of leukapheresis and cell products of YTB323 and tisagenlecleucel; Supplementary Fig. S6. Stemness and memory differentiation gene signatures are retained or enriched for in YTB323 final product; Supplementary Fig. S7. Differential gene expression of tisagenlecleucel versus YTB323 final product; Supplementary Fig. S8. Naive/TSCM cells and a naive stem-like gene signature correlate with higher expansion and a better response; Supplementary Fig. S9. T-cell subset and checkpoint inhibitor analysis by flow cytometry on PBMCs collected post-YTB323 infusion; Supplementary Fig. S10. Pre-clinical T-cell gating strategies.

Tables that provide additional information to support the main article

Supplementary Table S1. Bridging chemotherapies by ATC class and preferred term (safety set); Supplementary Table S2. Lymphodepleting chemotherapies (safety set); Supplementary Table S3. Cytokine release syndrome following YTB323 infusion; Supplementary Table S4. Neurological adverse reactions following YTB323 infusion; Supplementary Table S5. Summary of cellular kinetic parameters in peripheral blood by flow cytometry for YTB323 at DL1 and DL2; Supplementary Table S6. Summary of cellular kinetic parameters in peripheral blood by flow cytometry and qPCR for YTB323 at DL1 and DL2.

AZD0022 is a small molecule selective inhibitor of KRASG12D. These studies investigate the preclinical PKPD relationships of AZD0022 to inform clinical development. Measurement of plasma and tumor concentrations were completed using standard extraction techniques with quantitation by LC-MS/MS methods. Target modulation (pRSK inhibition) was assessed in Nude mice implanted with GP2D human tumors by Western blot. The preclinical PK properties of AZD0022 are defined by its physicochemistry (MW 614, extensive lipophilicity with log D(7.4) 2.5, dibasic with pKa values of 8.4 and 7.4). Oral administration studies suggest that AZD0022 is 30 to 70% absorbed from the gastrointestinal tract. AZD0022 exhibits extensive distribution into tissues. It also undergoes time-dependent partitioning into the red blood cell fraction of whole blood, suggesting that whole blood is the matrix that best represents the PK of the molecule. Blood clearance of AZD0022 was 8.2 and 8.6 mL/min/kg in mice and dogs, respectively. The measured Vss values based on blood were 10.8 and 20.4 L/kg, respectively. These characteristics suggest that in human, AZD0022 should be orally absorbed and exhibit a half-life consistent with once daily administration. In the GP2D model, single oral 150 mg/kg doses displayed prolonged plasma and tumour exposure. AZD0022 was estimated to be 18x more bound in tumour tissue than in plasma. Seven days of continuous 150mg/kg BID dosing resulted in up to approx. 75% pRSK inhibition. A dose range of 10, 50 and 150 mg/kg BID over 7 days displayed exposure-dependent pRSK modulation, with maximal of 75% pRSK inhibition. PKPD modelling suggested an unbound IC50 of 1.4 nM for pRSK inhibition. The results presented here support the clinical development of AZD0022 which is currently being tested in a first in human Phase I/IIa study (ALAFOSS-01, NCT06599502) Kevin Beaumont, Sofia Guzzetti, Pablo Morentin-Gutierrez, Rhys D. Jones, Ken Grime, Carla Martins, Alex Koers, Alison Peter, Simon T. Barry, Susan Critchlow, Michele Moschetta, Michael Niedbala. The preclinical pharmacokinetics and pharmacodynamics of AZD0A potent, oral KRASG12D-selective agent exhibiting oral bioavailability and KRAS pathway suppression in the GP2D xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 841.

Head and neck squamous cell carcinoma (HNSCC) is a deadly disease with a poor prognosis due to late diagnosis and limited treatment options. Immunotherapy (IT) is emerging as a promising approach, especially after the failure of standard of care therapies (STs). The objective of this systematic review and meta -analysis was to evaluate whether the addition of IT to STs improves outcomes for patients with HNSCC, including overall survival (OS), progression -free survival (PFS), and quality of life (QoL). This review employed the Population Intervention Comparison and Outcome (PICO) framework to identify relevant search terms in electronic databases, and also included supplementary hand searches. Six primary research articles were selected using the Preferred Reporting Items for Systematic Review and Meta -analysis (PRISMA) flow chart, and were critically appraised. Data extraction from these studies was conducted, and a meta -analysis was performed to aid in the generation of forest plots. The addition of IT to standard anticancer therapies was found to enhance patient outcomes, such as OS, PFS, and QoL. The toxicity profile of IT was acceptable, with minimal treatmentrelated deaths. The most frequently observed adverse events (AE) were related to the skin, followed by hematological toxicities. Based on our analysis, the addition of IT to STs is a suitable treatment option and is supported by current research. However, further studies are needed to investigate factors that influence treatment effectiveness and to develop optimal therapies. To achieve this, we recommend a comprehensive treatment approach that involves the multidisciplinary team (MDT) and patient assessment tools.

Ovarian cancer (OC) is the most lethal gynaecologic malignancy, attributed to its insidious growth, non-specific symptoms and late presentation. Unfortunately, current screening modalities are inadequate at detecting OC and many lack the appropriate specificity and sensitivity that is desired from a screening test. Nearly 70% of cases are diagnosed at stage III or IV with poor 5-year overall survival. Therefore, the development of a sensitive and specific biomarker for early diagnosis and screening for OC is of utmost importance. Currently, diagnosis is guided by CA125, the patient's menopausal status and imaging features on ultrasound scan. However, emerging evidence suggests that a combination of CA125 and HE4 (another serum biomarker) and patient characteristics in a multivariate index assay may provide a higher specificity and sensitivity than either CA125 and HE4 alone in the early detection of OC. Other attempts at combining various serum biomarkers into one multivariate index assay such as OVA1, ROMA and Overa have all shown promise. However, significant barriers exist before these biomarkers can be implemented in clinical practice. This article aims to provide an up-to-date review of potential biomarkers for screening and early diagnosis of OC which may have the potential to transform its diagnostic landscape.

BACKGROUND:Genetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib. METHODS:This first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50-350 mg once daily [QD] or 300-600 mg twice daily [BID]) with rineterkib (100-300 mg QD) in patients with KRAS-/BRAF-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with KRAS-/BRAF-mutant NSCLC and NRAS-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics. RESULTS:Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAFnon-V600-mutant NSCLC) treated with naporafenib plus rineterkib and two patients (both with KRAS-mutant NSCLC) treated with naporafenib plus trametinib. On-treatment median reductions in DUSP6 mRNA levels from baseline were 45.5% and 76.1% with naporafenib plus rineterkib or trametinib, respectively. CONCLUSIONS:Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect. CLINICALTRIALS:gov identifier: NCT02974725.

Quality control of RNA after human exon enrichement.

PDF file - 23K, Proteins identified in MMECs upon HIF-1siRNA and panobinostat treatment (MALDITOFF mass spectrometry).

Supplementary Figure S1. No effects on MMECs apoptosis and proliferation by the cMET inhibition.

Combination platinum-based chemotherapy has been the standard of care for several decades in first-line treatment of advanced urothelial carcinoma (UC) patients. UC is often chemosensitive, though durable responses are quite rare and the development of chemoresistance still leads to poor clinical outcomes. Up until a few years ago, UC patients could not benefit from any valuable alternatives to cytotoxic chemotherapy, but the scenario has been recently transformed by the advent of immunotherapy. Molecular biology of UC is characterised by a relatively high prevalence of alterations in DNA damage response pathway, genomic instability, high tumour burden, and elevated programmed cell death ligand 1 (PD-L1) protein expression, which are established factors predicting favourable response to immune checkpoint inhibitors (ICIs) in several tumour types. To date, various ICIs have been approved as systemic anti-cancer therapy for advanced UC in multiple settings, including first-line, maintenance, and second-line therapy. ICIs are also in development either as monotherapy or in combination with chemotherapy or other targeted agents. Moreover, a number of alternative ICIs, interleukins, and novel immune molecules have been identified as promising agents in advanced UC. Herein, we review rational and current literature evidence supporting the clinical development and current indications of immunotherapy, particularly focusing on ICIs.

PURPOSE No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog ( NRAS)–mutant melanoma is currently available. PATIENTS AND METHODS In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725 ), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non–small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms). RESULTS Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. CONCLUSION Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.

Tumor-interacting platelets could be removed by wash process completely.

Supplementary Figure S2. SU11274 dose finding.

Ovarian cancer has become the largest cause of gynaecological cancer-related mortality. It is typically diagnosed at a late stage and has no effective screening strategy. Ovarian cancer is a highly heterogeneous disease that can be subdivided into several molecular subsets. As a result of a greater understanding of molecular pathways involved in carcinogenesis and tumor growth, targeted agents have been approved or are in several stages of development. Poly(ADP-ribose) polymerase (PARP) inhibitors and the anti-vascular endothelial growth factor (VEGF)-A antibodies are two types of approved and most effective targeted drugs for ovarian cancer at present. With the success of bevacizumab, tyrosine kinase inhibitors which could target alternate angiogenic pathways are being studied. Furthermore, many treatments targeting the PI3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways, are being developed or are already in clinical studies. MicroRNAs have also become novel biomarkers for the therapy and clinical diagnosis of ovarian cancer. This manuscript reviews the molecular, preclinical and clinical evidence supporting the targeting of growth-dependent pathways in ovarian cancer and assesses current data related to targeted treatments beyond PARP inhibitors.

Supplementary Figure 1. Participant Flow Diagram

Fifteen cytokines were secreted by the MM cell-mediated platelet activation.

PDF file, 104K, Effect of SU11274 treatment on cMET/phospho(p)-cMET expression in R5 vs. RPMI8226 cells; and plasma cells (PCs) from relapsed/resistant vs. newly diagnosed MM patients.