Anaplastic ependymoma (AE) is a rare and aggressive central nervous system tumor that predominantly affects children and remains inadequately characterized at the genomic level. This study aimed to delineate the genomic and demographic landscape of histologically defined AE while identifying potential therapeutic targets. We conducted a retrospective analysis of AE cases from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) repository via cBioPortal, examining recurrent somatic mutations, copy number alterations, mutation co-occurrence, and exploratory sex- and race-based enrichment using descriptive and non-parametric statistics. The most frequent alterations included mutations in the telomerase reverse transcriptase (TERT) promoter, followed by recurrent changes in lysine methyltransferase 2D (KMT2D), lysine methyltransferase 2A (KMT2A), lysine methyltransferase 2C (KMT2C), E1A binding protein p300 (EP300), additional sex combs like 1 (ASXL1), and SET domain containing 2 (SETD2), indicating significant disruption of chromatin remodeling. Recurrent alterations in tumor protein p53 (TP53), ataxia telangiectasia mutated (ATM), and cyclin-dependent kinase inhibitor 2A (CDKN2A) suggested dysregulation of the p53 and DNA damage response pathways. Additionally, alterations in notch receptor 1 (NOTCH1) and notch receptor 2 (NOTCH2) indicated aberrant NOTCH signaling. Neurofibromin 2 (NF2) mutations were observed in male patients, and exploratory subgroup differences emerged across racial groups. Overall, AE appears to be driven by recurrent alterations in chromatin remodeling, p53, DNA damage response, and NOTCH signaling pathways, highlighting these areas as priorities for future biological validation and therapeutic investigation.

Natural killer (NK) cells are crucial innate immune effectors, mediating cytotoxicity against cancer and infected cells through receptors such as NKG2D. Reliable quantification of NK cell subsets is essential for evaluating NK cell-based immune responses in cancer research. Unlike other assays, including traditional flow cytometry used in assessing NK cells, imaging flow cytometry (IFC) is a simple and direct method for quantitative analysis of NK cells. This protocol describes the necessary procedures, including harvesting splenocytes, acquiring these cells labeled with NKG2D antibodies, and analyzing IFC data with IDEAS® software. We applied this protocol to quantitatively assess the number of splenic NKG2D+ NK cells in mice injected with SVTneg2 cancer cells (which carry the p53 G242A missense mutation) and compared them to mice injected with EMT6 cancer cells (which have wild-type p53) or normal fibroblasts. We found that the SVTneg2 cancer cells significantly decreased the number of NKG2D+ NK cells in mice by approximately 2-fold (933 cells vs. 2360 cells, p < 0.001) compared with mice injected with EMT6 cancer cells. This IFC protocol can be applied to directly quantify NK cells in vivo. This quantitative protocol allows novices to quickly handle the analysis of cytotoxic NK cells with a single NKG2D marker. Further multicolor flow cytometry and cytokine assay may be required to precisely define the subtypes and effects of NK cells in anticancer immunity. Key features • A simple and direct assay using imaging flow cytometry (IFC) to quantify cytotoxic NKG2D NK cells against breast cancer cells in mice. • Simultaneously collect the flow cytometry characters and each cell image of NK cells and other populations. • Step-by-step identification of interested NK cells mainly relying on image gating (focus, size, morphology). • Highly reliable and applicable to analyze other immune cell subsets or tumor-associated populations with corresponding conjugate antibodies.

Abstract Background Psoriasis is a non-communicable inflammatory skin disease that affects approximately 2%–3% of the world’s population. Given its high impact on quality of life and the fact that a subset of patients exhibits suboptimal or secondary loss of response to current treatments, identifying new therapeutic strategies is crucial. Proliferation-associated protein 2G4 (PA2G4) is a transcription factor that has been exclusively studied in cancer research, where it promotes cell growth and enhances tumourigenesis by inhibiting apoptosis. However, its role in inflammatory skin diseases remains largely unknown. Objectives This study focused on the pathophysiological and immunological functions of PA2G4 in psoriasis and evaluated its potential as a therapeutic target. Methods Bulk, single-cell, and spatial RNA sequencing combined with immunohistochemistry were used to assess PA2G4 expression in psoriatic skin compared with that in non-lesional controls. Functional studies were performed in primary human keratinocytes and reconstructed human epidermis (RHE) models using the CRISPR/Cas9-mediated knockout (KO) of PA2G4 and pharmacological inhibition of PA2G4 with the small-molecule WS6. The regulatory effects of PA2G4 on cellular processes, such as proliferation, differentiation, and survival, were investigated using RNA-seq, western blot analysis, scratch assays, and annexin V staining. Results PA2G4 was highly abundant in psoriasis, and its expression was predominantly restricted to basal proliferating keratinocytes. Its gene expression is positively correlated with psoriasis severity, the degree of acanthosis, neutrophil infiltration, and genes which are upregulated in psoriasis. PA2G4 KO in primary human keratinocytes activated differentiation pathways while suppressing proliferation pathways, resulting in the downregulation of proliferation- and inflammation-related genes (e.g. MKI67, IL20, VEGFA, and HIF1A) and the upregulation of differentiation and cell adhesion markers (e.g. KRT6C, LCE2C, and DSG4). Functionally, the PA2G4 KO reduced keratinocyte proliferation in scratch assays, attenuated interleukin-22-induced acanthosis in RHE models, and promoted keratinocyte death. Pharmacological inhibition of PA2G4 using the small-molecule inhibitor WS6 similarly downregulated genes associated with proliferation and cell survival. Conclusions PA2G4 could promote keratinocyte hyperproliferation and survival in psoriasis, thereby critically influencing epidermal homeostasis. Therefore, inhibition of PA2G4 may represent a new treatment option for psoriasis.

From bench to byte: A UK perspective on data-driven cancer research.

The mediating role of biological age acceleration in the associations between lifestyle factors and incident digestive system cancers: A Prospective Cohort Study from the UK Biobank.

Cancer is a global disease, yet a paradox persists: the most advanced research ecosystems are concentrated in countries with lower disease burden, whereas low- and middle-income countries (LMICs)-carrying 70% of the global cancer burden-face major constraints in research capacity. Closing this gap is essential for equitable progress in cancer prevention, diagnosis, and treatment. Researchers in LMIC are creatively adapting established technologies, research pipelines, and collaborative models from higher-resource settings to local solutions. Here, twenty-five American Association for Cancer Research (AACR) Global Scholar-in-Training Award's recipients from LMICs share how cancer research is advancing within resource-limited settings, focused on: (i) infrastructure and resources, (ii) training and talent retention, (iii) funding and sustainability, and (iv) cultural and social barriers. We identified shared challenges and cross-cutting solutions, discussed gaps and suggested steps to further advancing cancer research. We emphasized locally-led innovation, strategic partnerships, and community engagement. These perspectives offer a framework for inclusive, synergistic approaches to strengthening cancer research and accelerating impact where it is needed most.

Abstract Patients (pts) with metastatic (met) MSS CRC are treated with sequential lines of chemotherapy (chemo), but most experience progression and prolonged toxicities during their disease course. BOT is a 2nd-gen Fc modified anti-CTLA-4 agent, exhibiting enhanced antibody dependent cell mediated cytotoxicity of Tregs and Fc-receptor mediated myeloid activation. A phase I/II study with BOT/BAL (an anti-PD-1 antibody) in pretreated patients with MSS CRC achieved a 73% disease control rate (DCR) in pts without liver mets. We tested the hypothesis that anatomically selected pts with met MSS CRC would benefit from BOT/BAL in the 1L, delaying or negating the need for chemo.We enrolled 15 untreated Stage IV MSS CRC pts who did not have liver, bone, or brain mets (NCT06268015). Pts received BOT (75 mg q6 weeks (w) up to 4 doses)/BAL (240 mg q2w) 1L, followed by staging CT scans and iRECIST measurements q6w. If iCPD was observed, standard-of-care chemo (SOC: FOLFOX + bevacizumab or panitumumab) was added to BAL. Tissue biopsies were taken prior to treatment and at the time of progression. Primary objectives included safety, feasibility, and DCR to BOT/BAL. Secondary objectives included best overall response to BOT/BAL alone and at chemo crossover (ORR1, iRECIST; ORR2/DCR2, RECIST), overall and progression-free survival (OS, PFS1; PFS2). Exploratory objectives include spatial studies on tumor tissue biopsies taken prior to treatment and at the time of progression to predict response and resistance. As of 1/5/2026, one pt withdrew from treatment (BRAF mut); 13 pts were evaluable for response and 14 pts for irAEs (6 Gr 1-2; 7 Gr 3; no Gr 4), with a median follow up of 4.3 mo (95% CI, 1.6-Not Estimable, NE). Pts were a median age of 50 (Q1:40, Q3:62) at time of consent, with 10 (66.7%) males. Distribution of sites of mets included lymph nodes (3; 20%), other (3; 20%), peritoneum (4; 26.7%), and lungs (5; 33.3%). A median of 3 cycles of BOT were given. Gr 3 toxicity was primarily colitis (5), which we managed with short course prednisone that patients were given to take home before starting therapy, followed by infliximab within 48 hours. Categories of all grades of irAEs experienced by &amp;gt;1 pt included diarrhea/colitis (7), fatigue (7), rash (5), AST/ALT (3), fever (3), hypothyroidism (2), and arthritis (2), which was effectively managed with naproxen or ibuprofen. Median freedom from crossover to chemo was 8.7 mo (95% CI, 6.2-NE). There was 1 confirmed iPR to BOT/BAL alone in a pt with lung mets and TMB of 1 mut/mb, and 4 iSD at 24w of follow-up, resulting in a 71% DCR. Five BOT/BAL only pts are too early to assess at cutoff. Of 4 pts crossing over to SOC at a median of 6.3 mo (95% CI, 3.7-NE) from BOT/BAL start, 3 were evaluable for response to chemo by RECIST with a 67% DCR. No deaths occurred. Initial analysis of multiplex IHC demonstrated an increase in cDC1s in responders to BOT/BAL compared to non-responders, who exhibited an increase in Spp1/CXCL9 macrophage ratios.Our study is the first to demonstrate the safety and feasibility of 1L BOT/BAL in MSS CRC pts without liver, bone, or brain mets. 1L BOT/BAL has durable activity in some pts and can delay the need for chemo, which was added safely in pts who do progress. Further studies including the development of biomarkers are warranted in PhII studies to establish this approach in 1L MSS CRC. Citation Format: Nicholas C. Devito, Emily Bolch, Aman Opneja, Hope Uronis, Lisa Vlastelica, Gerard C. Blobe, John W. Hickey, Yuexi Kylee Li, Kevin S. Tanager, Cheryl H. Chang, Jingchen Chai, Kara Bonneau, Niharika B. Mettu, Michael A. Morse, Tucker W. Coston, Shiaowen David Hsu, Carol A. Wiggs, Donna Niedzwiecki, Dana A. Warren, John H. Strickler. Preliminary results of first-line botensilimab (BOT) and balstilimab (BAL) optimization in microsatellite stable colorectal cancer (MSS CRC) without liver, bone, or brain metastasis (BBOpCo) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT184.

Abstract Patient-derived tumor organoids have emerged as a promising translational model for oncology drug development. However, its utility has been limited by restricted access to patient-derived materials and insufficient donor-related data such as clinical records. Here, we report the establishment of the Samsung Organoids, a GxP-based, standardized patient-derived organoid designed to support data-driven cancer drug development. All organoids were generated and processed by GxP-qualified personnel under rigorously controlled and fully documented procedures, ensuring reproducibility, traceability, and regulatory readiness. Each organoid line is linked to clinical information of the corresponding donor and multi-omics data both original tumor tissues and derived organoids. Comparative analyses demonstrated high concordance of mutational profiles and gene expression patterns between tumor tissues and matched organoids, confirming preservation of the patient-specific characteristics. To examine the responsiveness of organoids to various drugs including small molecules and ADCs, we performed high-throughput drug screening combined with high-content imaging. Drug responsiveness data revealed substantial inter-patient heterogeneity, enabling classification of organoids into distinct groups. Further, we identified particular gene expression signatures by cross-group comparison, demonstrating explanation of different drug sensitivity between organoids. Conclusively, by integrating patient clinical information with genomic/genetic alterations, transcriptomic signatures, and functional drug response data, the Samsung Organoids provides translational insights into determinants of therapeutic sensitivity and resistance, helping successful cancer drug development such as drug candidate selection, biomarker discovery, and preclinical decision-making. Citation Format: Minhyung Lee, Sekyu Oh, Seongju Jeong, Sung Min Ha, Chihah Moon, Nayoun Choi, Yoonhyeok Kwon, Seahee Kim, Sangmyung Lee, Brian Hosung Min. Samsung Organoids: A GxP-based drug screening leveraging patient-derived tumor organoids platform accompanied with clinical records and multi-omics data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB397.

Abstract Background: Postoperative driver gene-specific circulating tumor DNA (ctDNA) monitoring stratifies recurrence risk in resectable stage III driver-mutant NSCLC (NCT06443684). Whether driver-specific ctDNA MRD can evaluate neoadjuvant response and predict recurrence in stage III driver-mutant NSCLC remains to be defined. Methods: From 2022 to 2025, 203 resectable stage III NSCLC patients with tissue-confirmed driver mutations were prospectively enrolled at 14 centers in China (NCT06443684). Peripheral blood was collected before neoadjuvant therapy, preoperatively, 3 days and 1 month after surgery, and every 3 months until investigator-confirmed recurrence. ctDNA was analyzed using a 10-gene driver panel (LC10). This analysis focused on peri-neoadjuvant ctDNA dynamics and clinical outcomes among 82 patients who received neoadjuvant therapy followed by surgery. Results: Among the 82 neoadjuvant-treated patients, regimens included chemo-immunotherapy (57.3%), TKI (3rd-EGFR TKI/2nd or 3rd-ALK TKI, 39.0%), and chemotherapy alone (3.7%). Post-neoadjuvant ctDNA positivity was associated with a significantly lower MPR rate versus ctDNA negativity (0% vs 42.3%, p=0.004), whereas baseline ctDNA status was not associated with MPR (16.7% vs 21.2%). Post-neoadjuvant ctDNA molecular residual level (hGE/mL) positively correlated with residual viable tumor cells (R=0.332, p=0.009). Post-neoadjuvant ctDNA-positive patients had significantly shorter event-free survival (median EFS 11.4 vs 23.8 months; HR=8.82; p=0.009). For non-MPR patients, post-neoadjuvant negative ctDNA status also indicated favorable prognosis (median EFS 23.8 vs 4.7 months; HR=5.80; p=0.054). Compared with other regimens, neoadjuvant TKI was associated with a lower post-treatment ctDNA residual rate (0% vs 15.3%; p=0.05). Patients with persistent ctDNA positivity (baseline→post-neoadjuvant) had the shortest EFS (median 4.7 months), followed by negative→positive (23.8 months), while positive to negative and persistent negative ctDNA indicated disease free status(log-rank p&amp;lt;0.001). Conclusions: A driver-specific ctDNA MRD strategy provides a practical tool for neoadjuvant efficacy assessment and postoperative recurrence risk stratification for stage III driver-mutant NSCLC patients. Citation Format: Jian Hu, Xiao Teng, Ziming Li, Yu Qi, Feng Li, Qixun Chen, Changbin Zhu, Xing Li, Shun Lu. Driver-specific MRD strategy associated with pathological response and predicted recurrence in stage III driver-mutant NSCLC receiving neoadjuvant treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB120.

Abstract Background: PARP inhibitors (PARPi) selectively kill tumor cells harboring genetic mutations in critical DNA repair genes (e.g., BRCA1/2). Approved nonselective PARPi have demonstrated robust antitumor activity, but are associated with significant hematologic toxicities that limit dose intensity and clinical benefit. Drugs that selectively inhibit PARP1, but spare PARP2, may improve the risk-benefit profile by retaining antitumor activity while avoiding PARP2-related toxicities. Furthermore, current PARPi have variable brain penetrance, limiting their utility for targeting CNS tumors or brain metastases. EIK1004 (IMP1707) is a potent, CNS-penetrant, PARP1-selective inhibitor that demonstrates tumor growth inhibition in preclinical brain metastasis models. Methods: Study EIK1004-001 (IMP1707-101) is a FIH, global, multi-center, Phase 1/2 study evaluating the safety and potential antitumor activity of EIK1004 monotherapy in patients with advanced ovarian, breast, prostate, or pancreatic cancer, with or without brain metastases (NCT06907043). The study consists of Part 1 (Dose Escalation; using the Bayesian optimal interval [BOIN] design) and Part 2 (Dose Optimization). All participants must have a deleterious or suspected deleterious mutation in select homologous recombination repair genes and received no more than one prior line of PARPi treatment. Eligible participants must be ≥ 18 years, have histologically or cytologically confirmed tumors and received appropriate prior antitumor therapies, and have evaluable disease (eg, at least 1 measurable lesion by RECIST 1.1 [or RANO-BM for brain metastases] and/or serum tumor markers). Primary endpoints include safety and tolerability including identifying the maximum tolerated dose or maximum achievable dose, and recommended dose(s) for expansion (RDE). Secondary endpoints include evaluation of EIK1004 pharmacokinetics and preliminary antitumor activity including overall response, duration of response, and progression-free survival. Part 2 will open once the RDE is determined from Part 1. This study opened on 23-Jan-2025 and is actively enrolling participants. Citation Format: Timothy A. Yap, Jian Zhang, Yanhua Xu, Sanum Chaudry, Kevin H. Eng, Yawei Zhang, Viola J. Chen, Gerald Falchook. A first-in-human (FIH), Phase 1/2, dose-escalation and dose-optimization study of central nervous system (CNS)-penetrant, PARP1-selective inhibitor EIK1004 in patients with advanced solid tumors with or without brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT287.

Abstract Background: Platinum-resistant ovarian cancer (PROC) and clear cell gynecologic cancer (CCGC) are associated with poor prognoses and have limited effective treatment options. PROC has a recurrence rate of approximately 70%, while CCGC, a rare histologic subtype, demonstrates resistance to most standard therapies. These unmet clinical needs underscore the importance of developing novel therapeutics to improve patient outcomes. Immune checkpoint inhibitors have shown promising preliminary antitumor activity in PROC and CCGC, although they are not currently approved for either indication. Lorigerlimab is an investigational bispecific (PD-1 x CTLA-4), tetravalent DART® molecule. It is engineered to enhance CTLA-4 blockade in a PD-1-binding-dependent manner, intended to improve activity in the tumor microenvironment while minimizing off-tumor toxicity. Preclinical and early-phase clinical data support lorigerlimab immunomodulatory activity and tolerability. This study investigates the efficacy and safety of lorigerlimab monotherapy in patients with PROC and CCGC. Methods: This open-label, multicohort, multi-institutional, phase 2 study (NCT06730347) evaluates lorigerlimab monotherapy in participants with PROC (cohort A) or CCGC (cohort B). Cohort A utilizes a Simon’s two-stage design to enroll up to 40 participants and cohort B will enroll up to 20 participants. Participants receive lorigerlimab intravenously every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxicity, or withdrawal. The primary objective is to evaluate the antitumor activity as measured by objective tumor response. Secondary objectives include characterization of safety, tolerability, and evaluation of efficacy by duration of response, disease control rate, progression-free survival, and change in tumor size from baseline. Eligible participants must have persistent or recurrent high-grade serous ovarian carcinoma or clear cell gynecologic cancers with at least 50% clear cell histomorphology. Participants with PROC must have received at least one and up to three prior lines of systemic therapy, which may include prior bevacizumab. Individuals with a germline or somatic BRCA mutation must have received PARP inhibitor therapy. Participants with CCGC must have received at least one prior line. All participants must have good functional status, measurable disease, adequate organ function, and no contraindications to immunotherapy. Individuals with primary platinum-refractory disease are excluded. Prior use of checkpoint inhibitor therapy is permitted for participants with clear cell endometrial or clear cell cervical cancer. Tumor assessments occur every 9 weeks for the first 54 weeks, then every 12 weeks until treatment discontinuation. Enrollment commenced in May 2025 and is ongoing. Citation Format: Helen D. Clark, Kelly M. Rangel, Shawana N. Richard, Jichao Sun, Pepi Pencheva, Chad Hamilton, Amir A. Jazaeri. A phase 2 multicohort study to evaluate lorigerlimab (PD-1 x CTLA-4) in participants with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT279.

Abstract The ability of tumor cells to tolerate DNA damage through a robust DNA damage response (DDR) limits the efficacy of many anticancer therapies, including genotoxic agents; however, the epigenetic mechanisms that sustain DDR gene expression remain poorly understood. Here, we identify Class I histone deacetylases (HDACs) as critical regulators of the DDR in pancreatic ductal adenocarcinoma (PDAC). HDAC1/2 maintain a proper genome-wide distribution of H3K27 acetylation, ensuring efficient recruitment of BRD4 and RNA polymerase II to DDR gene promoters. Pharmacological HDAC inhibition with entinostat preferentially enriches H3K27 acetylation at intergenic regions, diverting transcriptional machinery away from promoters and suppressing DDR gene expression. Consequently, HDAC inhibition increases DNA damage and sensitizes PDAC to diverse DNA-damaging (e.g., platinum agents, topoisomerase inhibitors) and DDR-targeting therapies (e.g., PARP inhibitors). To overcome the systemic toxicity that has limited the clinical translation of HDAC inhibitors, we developed a bottlebrush prodrug (BPD) nanoparticle platform for tumor-selective entinostat delivery. Entinostat-BPD enables tumor-specific HDAC inhibition, reduces system toxicity, and achieves tumor suppression comparable to free entinostat with only one-seventh of the cumulative drug exposure, demonstrating enhanced translational potential of this platform. Together, these findings uncover an HDAC-directed epigenetic mechanism that drives resistance to DNA damage-inducing agents and further establish combinatorial and precision-targeting strategies to improve PDAC outcomes. Given the central role of the DDR across cancer types and the widespread use of DNA-damaging therapies, this work may have broad therapeutic relevance beyond pancreatic cancer. Citation Format: Gaoyang Liang, Hung V. Nguyen, Jonathan Zhu, Hervé Tiriac, Hadiqa Zafar, Daniel Y. Cao, Gabriela Estepa, Dylan C. Nelson, Yang Dai, Tae Gyu Oh, Christopher Liddle, Ruth T. Yu, Andrew M. Lowy, Weiwei Fan, Morgan L. Truitt, Annette R. Atkins, Jeremiah A. Johnson, Michael Downes, Ronald M. Evans. HDAC inhibition sensitizes pancreatic cancer to DNA-damaging therapies via genome-wide redistribution of transcriptional machinery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB097.

Abstract Introduction: V-domain Ig Suppressor of T-cell Activation (VISTA) is an immune checkpoint regulator found on tumor, myeloid, and other immune cells. Its presence has been shown to enhance tumor growth, create an immunosuppressive microenvironment and may potentially contribute to resistance to anti-CTLA-4 and anti-PD-1/PD-L1 therapies. Therefore, VISTA represents a promising therapeutic target. HMBD-002, a non-depleting, high-affinity IgG4 monoclonal antibody against VISTA, has demonstrated significant inhibition of tumor growth in preclinical studies, both as a monotherapy and in combination with pembrolizumab. HMBD-002 is intended to increase T-cell activity and reprogram the suppressive tumor microenvironment to a proinflammatory antitumor phenotype. Cancer types including triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) exhibit high expression levels of VISTA in the TME providing a rational basis for exploring these solid tumor indications. Methods: Phase 1, first-in-human, open-label, study evaluating multiple repeat doses of intravenously (IV) administered HMBD-002, with or without pembrolizumab, in participants with advanced solid tumors (i.e., locally advanced and unresectable, or metastatic). A standard 3+3 design was utilized. Dose escalation was initiated with single-agent HMBD-002. After completion of the first 4 cohorts as monotherapy HMBD-002 dose escalation, HMBD-002 was dose escalated in combination with fixed dose pembrolizumab (200 mg IV Q3W). HMBD-002 was administered as a single weekly dose, with or without pembrolizumab, in 21-day treatment cycles. Primary endpoints were safety and tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary antitumor activity. Results: A total of 48 subjects were enrolled, 28 receiving HMBD-002 as monotherapy at doses ranging from 20mg to 1400mg. Dose escalation in combination with pembrolizumab (20 subjects) ranged from 180mg to 1400mg. 18 subjects (37.5%) experienced a treatment related AE with 3 subjects having a grade 3 or greater TRAE. The most common TRAEs were fatigue, rash and nausea. 1 dose limiting toxicity, immune related hepatitis, was seen at 360mg monotherapy and resolved with corticosteroids after drug was held. No cytokine release syndrome (CRS) was observed. No MTD was declared. PK data indicates a RP2D of 720mg QW. Best observed response was stable disease (SD) in 5/28 (18%) monotherapy subjects and 5/20 (25%) combination therapy subjects. A subset of subjects experienced SD for 6 cycles or greater, including subjects with NSCLC and TNBC. Conclusions: HMBD-002 demonstrated preliminary safety and tolerability in this phase 1 study. A RP2D of 720mg QW was determined. Further investigation in tumor specific phase 2 cohorts is warranted and planned for 2026. Citation Format: Jordi Ahnert Rodon, Joshua J. Gruber, Melinda L. Telli, Andrew Hendifar, Joseph W. Kim, Sharonlin Bhardwaj, Padmanee Sharma, Dipti Thakkar, Jerome Boyd-Kirkup, Eugene Kennedy. Results of phase 1 first-in-human clinical trial of HMBD-002, an IgG4 monoclonal antibody targeting VISTA, in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT126.

Abstract Cancer arises within a complex cellular milieu, where the extent and composition of tumor-infiltrating immune cells strongly influence tumor progression and patient prognosis. Emerging research highlights the therapeutic potential of fasting mimicking diets (FMDs) in delaying cancer onset, providing cellular protection and regulating immunity. My project investigates immune profiles, before and after the transfer of donor-derived immune cells previously exposed to fasting, either independently or combined with therapeutic drugs. We aim to identify immune populations, enhanced by this combined treatment, and to recognize their impact on tumor advancement and immune activation. Using the syngeneic 4T1, triple negative breast cancer mouse model, we evaluated how fasting and chemotherapy affect tumor growth and immune competence. Flow cytometry and immunohistochemistry were used to characterize immune cells, recruited at tumors, spleens and bone marrows of treated hosts. A subpopulation of preconditioned splenocytes and tumor-infiltrating lymphocytes, recognized through immunophenotyping, were transplanted into tumor-bearing recipients to assess tumor control, immune priming and cytotoxicity. We observed reduced tumor volume, delayed progression and increased survival rate in the transplants exposed to FMD and doxorubicin. The treatment preserved the size, morphology, and cellularity of healthy, primary and secondary lymphoid organs, while expanded beneficial, antitumor immune signatures. Integrating FMD with standard therapeutic strategies could enhance antitumor immunity and broaden the spectrum of malignancies that respond effectively. Exploring the underlying mechanisms may reveal immune pathways that can be therapeutically leveraged to eradicate tumors, in a field that currently remains unexplored. Citation Format: Evangelia Pavlou, Olga Blazevits, Giulia Salvadori, Sara Martone, Valter Longo. Integrating a fasting mimicking diet to augment antitumor immunity following adoptive cell transfer in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB146.

Papillary thyroid cancer (PTC) is the most common form of thyroid malignancy, with an incidence that has been steadily rising globally. Early and accurate diagnosis remains crucial for effective treatment and improved outcomes. MicroRNAs (miRNAs), small non-coding RNA molecules that regulate gene expression, have emerged as promising biomarkers in cancer research due to their stability and accessibility in serum. In this pilot study we compared the expression of 84 consistently reported, malignancy-associated serum miRNAs in patients with PTC (PTC group) and benign thyroid disease (Control group) as potential PTC markers. A focused panel containing primer assays for 84 human miRNAs that are consistently reported in the literature as being detectable and differentially expressed in serum in various organ-specific cancers was used to measure miRNA levels in serum samples from PTC (n = 8) and benign thyroid disease (n = 6) patients prior to thyroidectomy. Among the 84 miRNAs analyzed, a panel of ten miRNAs showed numerical trends of differential expression between the two groups, including three upregulated (hsa-miR-150-5p, hsa-miR-21-5p, hsa-miR-23a-3p) and seven downregulated miRNAs (hsa-miR-17-5p, hsa-miR-17-3p, hsa-miR-200c-3p, hsa-miR-296-5p, hsa-miR-574-3p, hsa-miR-885-5p, hsa-miR-130-3p). The serum expression levels of hsa-miR-23a-3p were markedly elevated in patients with malignant nodules compared with those with benign lesions, while hsa-miR-574-3p was significantly downregulated in the PTC group. These findings warrant further investigation of hsa-miR-23a-3p and hsa-miR-574-3p in larger cohorts of patients with PTC to validate their potential clinical relevance.

Prostate cancer, particularly metastatic castration-resistant prostate cancer (mCRPC), presents therapeutic challenges rooted in adaptive lineage plasticity and neuroendocrine transdifferentiation. Conventional genome-based models fail to account for the divergent clinical trajectories observed among tumors that share identical driver mutations. This limitation requires reconceptualizing cancer as a dynamic system in which tumor cells can execute context-dependent molecular programs governed by epigenetic and transcriptional network remodeling. This review critically evaluates three convergent technological pillars reshaping prostate cancer research and clinical care. First, conditional reprogramming (CR) enables the rapid generation of patient-derived models that preserve genomic fidelity, intratumoral heterogeneity, and reversible phenotypic plasticity without genetic manipulation. Second, single-cell and spatial multi-omics approaches have clarified the cellular trajectories underlying luminal-to-neuroendocrine transdifferentiation, identifying a therapeutically actionable intermediate state. They have revealed the hierarchical transcription factor network (FOXA2-NKX2-1-p300/CBP) which orchestrates chromatin remodeling during this lethal transition. Third, physics-informed machine learning and digital twin architectures aim to move beyond correlative risk prediction toward mechanistically sound forecasting of tumor evolution, treatment response, and resistance emergence. We address unresolved challenges in prospective clinical validation, spatial heterogeneity capture, regulatory pathways for functional diagnostics, and the imperative for causal, as opposed to associative, inference from perturbational datasets. The integration of these three domains through closed-loop experimental-computational feedback cycles represents a paradigm shift from reactive to anticipatory precision oncology.

The FUCCI sensor fluorescently labels cell cycle phases, which is essential to assess normal and abnormal cell-cycle progression in physiological and pathological conditions of developing organisms. However, accurate cell-cycle decoding is challenging in the low signal-to-noise conditions typical of multiplexed live cell imaging. To address this challenge, we developed deep learning networks that integrate FUCCI signals with a cytoplasmic alpha-tubulin fluorescent reporter. Our approach outperforms existing methods for both segmenting and classifying FUCCI nuclei, even in low signal-to-noise conditions. The resulting high-accuracy segmentation enables robust automated tracking. We leverage this to introduce a dynamic time warping analysis that determines cell cycle pseudotime from incomplete tracks and can detect cell cycle arrest. We provide pre-trained networks for multichannel FUCCI analysis, offering a powerful tool for studies in cancer research, development, and mechanobiology.

Patient-derived in vitro systems are powerful preclinical models that replicate key features of human tumors and enable investigation of cancer biology and drug response. They are particularly promising for pancreatic cancer research. We examined whether culture dimensionality and basement membrane extract (BME) composition affect establishment rates, morphology, proliferation, marker expression, and drug response in patient-derived models of pancreatic ductal adenocarcinoma (PDAC). From 12 PDAC samples, matched two-dimensional primary cell lines (PDCLs) and three-dimensional organoids were established in Cultrex (PDOCs) and Matrigel (PDOMs). PDCLs formed monolayers, while PDOCs and PDOMs developed cystic or dense organoids, independent of BME type. Immunohistochemistry showed no differences in key diagnostic markers between culture systems, and Ki-67 levels were consistently higher in vitro compared to original tumors. Pharmacological testing with five standard chemotherapeutics revealed no significant differences in drug response between dimensionalities or BMEs, although 3D models were detected to be slightly more chemoresistant. In two patients treated with gemcitabine monotherapy, in vitro therapy response correlated with clinical relapse. Our findings indicate that while drug responses are largely patient-specific and independent of dimensionality and matrix composition, 3D models more realistically recapitulate tumor architecture and phenotypes, supporting their value for translational PDAC research.Trial registration: The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical approval was requested and granted by the ethics committee of the CharitéUniversitätsmedizin Berlin (EA1/157/21) on 26th May 2021.

Cancer is an evolutionary inevitability of multicellularity that emerges when cooperative cellular networks collapse into competition for survival and replication. Despite decades of extensive research, progress in cancer treatment remains limited, partly because of the lack of an interdisciplinary perspective and an overreliance on murine models that fail to capture the full evolutionary spectrum and dynamics of oncogenesis. Comparative oncology is an interdisciplinary field that offers an eco-evolutionary framework to address these challenges by examining variation in cancer prevalence and defense mechanisms across the tree of life. In this review, we first explain why adopting an evolutionary lens is essential for understanding the challenge of cancer. Then, we review recent discoveries on genomic and life history determinants of cancer prevalence, remarkable species-specific cancer defense mechanisms, and methodological advances in analyzing cross-species cancer data. Insights from these findings can ultimately inform human cancer research and guide future directions in biodiversity conservation.

This review describes recent developments in DNA-encoded library (DEL) technology, which has enabled transformative discoveries in cancer research. Successful DEL screening campaigns for cancer-relevant targets are described in detail to highlight the unique advantages of this technology compared to other hit-generation strategies. Moreover, recent developments in screening methods that have helped expand the DEL-addressable target space are described, and their implications for cancer research are emphasized. DEL screening campaigns targeting RNA and transcription factors are discussed, and various cell-based DEL evaluation methods for membrane proteins are compared and put into context. Finally, the use of DEL technology for the discovery of novel bifunctional degraders is presented. Overall, this article provides a comprehensive overview of key DEL discoveries that are expected to be of significant interest to cancer researchers and medicinal chemists working in the field of oncology.