Clin Cancer Res
· 2026 Apr · PMID 42048421
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PURPOSE: Familial adenomatous polyposis (FAP) confers a significant risk of colorectal/duodenal cancer. Encapsulated rapamycin (eRapa) has demonstrated promise as FAP chemoprevention in early clinical studies. METHODS: 3...PURPOSE: Familial adenomatous polyposis (FAP) confers a significant risk of colorectal/duodenal cancer. Encapsulated rapamycin (eRapa) has demonstrated promise as FAP chemoprevention in early clinical studies. METHODS: 30 FAP patients enrolled to three dosing regimens of eRapa (0.5 mg): cohort 1 - every other day, cohort 2 - daily every other week, or cohort 3 - daily. The primary endpoints were safety/tolerability, pharmacokinetics, and percentage change from baseline (PCFB) in colorectal polyp burden (CPB) at 6 mos. Secondary endpoints included PCFB total (TPB) and duodenal (DPB) polyp burden, and change in InSiGHT stage and Spigelman score at 6 and 12 mos. RESULTS: 29/ 30 patients (97%) completed the 12-mos study with predictable bioavailability. Low grade adverse events were frequent, but most pronounced in daily dosing. Two patients discontinued treatment related to toxicity. Cohort 1 had the largest decrease median PCFB CPB, DPB, and TPB at 6 mos: -39.4 % (IQR, 108.9; p = 0.28), -33.33 % (IQR, 90.0; p = 0.04), and -38.6 % (IQR, 88.5; p = 0.26), respectively. At 12 mos, Cohort 2 had the largest decrease median PCFB CPB and TPB: -29.3 % (IQR, 67.6; p = 0.37) and -26.3 % (IQR, 49.5; p = 0.29), respectively. Intermittent dosing cohorts (1 & 2) reduced DPB at 6 mos (p = 0.04), and improved TPB at 12 mos (p = 0.05) compared to daily dosing. CONCLUSION: eRapa was safe, tolerable and showed preliminary efficacy for FAP chemoprevention. The 0.5 mg daily every-other-week schedule will be evaluated in an upcoming phase III trial.
Akay M, Glendenning J, Tovey H
… +19 more, Tsai YT, Graham R, Carpenter E, Kakkassery H, Alaguthurai T, Finneran L, Roxanis I, Swampillai A, Harries M, Sandri I, Karthigan R, Barrington S, Gazinska P, Cook G, Chicklore S, Bliss J, Haider S, Tutt A, Irshad S
Clin Cancer Res
· 2026 Apr · PMID 42048392
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PURPOSE: Early identification of response to neoadjuvant chemotherapy (NACT) in triple negative breast cancer (TNBC) can facilitate timely treatment adjustments. This phase II analytical and clinical validity study (TNPE...PURPOSE: Early identification of response to neoadjuvant chemotherapy (NACT) in triple negative breast cancer (TNBC) can facilitate timely treatment adjustments. This phase II analytical and clinical validity study (TNPET01) evaluated whether [18F]-fluorodeoxyglucose (FDG) or [18F]-fluorothymidine (FLT) PET/CT can predict response after one NACT cycle Methods: In Part A (analytical validity phase), patients with stage II-III TNBC were randomised to FDG or FLT imaging. Baseline repeat scans assessed test-retest repeatability, followed by a post-cycle-1 scan in week 3. Dynamic imaging preceded static acquisitions at 90-, 120-, and 180-min (FDG) or 90-min (FLT), evaluating SUVmax, SUVmean, SUVpeak and SULpeak. Tracer selection for Part B was based on prespecified repeatability and response criteria. Part B (clinical validity phase) examined associations between changes in SUV (ΔSUV) after one cycle and post-cycle-3 MRI, end-of-treatment MRI, and residual cancer burden (RCB) at surgery. Exploratory analyses assessed relationships between PET response, Ki-67, and tumour-infiltrating lymphocytes (TILs). RESULTS: Twenty-two patients enrolled. Both tracers met repeatability thresholds; FDG was selected for Part B owing to superior image quality and availability. Fourteen patients underwent FDG-PET across both parts. ΔSUVmax/mean after one cycle significantly correlated with mid-treatment MRI and final RCB score (p < 0.005). Early post-cycle-1 TIL increases correlated with greater metabolic reduction and lower RCB, while Ki-67 changes were not predictive. CONCLUSIONS: FDG-PET after one NACT cycle was associated with histological response and stronger correlations with RCB than MRI. These findings support PET as an early biomarker for treatment response and warrant validation in larger, immunotherapy-era trials.
Jänne PA, Johnson ML, Li J
… +6 more, Pant S, Dünzinger U, Ilia L, Möldner K, Soh JE, Yamamoto N
Clin Cancer Res
· 2026 Apr · PMID 42048384
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BACKGROUND: BI 1701963 is a small molecule son of sevenless 1 (SOS1) inhibitor which selectively binds to SOS1, blocking the protein-protein interaction of SOS1 with guanosine diphosphate-bound RAS (rat sarcoma virus) pr...BACKGROUND: BI 1701963 is a small molecule son of sevenless 1 (SOS1) inhibitor which selectively binds to SOS1, blocking the protein-protein interaction of SOS1 with guanosine diphosphate-bound RAS (rat sarcoma virus) proteins (KRAS, HRAS and NRAS), thus inhibiting the growth of RAS-dependent cancer cells. STUDY DESIGN: Three Phase I dose-escalation studies evaluated BI 1701963 as monotherapy (starting dose: 50 mg) or in combination with trametinib (starting dose: 100 mg/1 mg), in patients with KRAS mutation-positive solid tumors (NCT04111458, USA and Europe; NCT04835714, Japan; NCT04627142, China). Primary endpoints were maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs; Part A NCT04111458), and number of patients with DLTs in the MTD evaluation period (Part A NCT04111458 and NCT04835714) or the on-treatment period (Part B NCT04835714). RESULTS: Ninety-four patients were treated; 75 with monotherapy (50-800 mg), 19 in combination (100 mg/1 mg; 100 mg/1.5 mg; 200 mg/1 mg). Six monotherapy patients (8.0%) and 6 combination patients (31.6%) experienced DLTs in the MTD evaluation period. All patients experienced adverse events; of note, three monotherapy patients had interstitial lung disease during the first treatment cycle leading to death, considered drug-related by the investigator. In the monotherapy group, one patient (1.8%) experienced partial response, and 12 patients (21.8%) had stable disease. In the combination group, four patients (33.3%) had stable disease, carrying different KRAS alleles. CONCLUSIONS: BI 1701963 treatment demonstrated limited efficacy as monotherapy. MTD was determined as 800 mg monotherapy (NCT04111458) and 100 mg/1 mg in combination with trametinib (NCT04111458).
Yousf S, Glunde K, Brown DR
… +7 more, Tressler C, Solaiyappan M, Krishnamachary B, Mironchik Y, Dbouk M, Goggins MG, Bhujwalla ZM
Clin Cancer Res
· 2026 Apr · PMID 42043783
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PURPOSE: Metabolic reprogramming plays an integral role in progression, immune evasion, and response to treatment in many cancers, including pancreatic ductal adenocarcinoma (PDAC). This study aimed to spatially characte...PURPOSE: Metabolic reprogramming plays an integral role in progression, immune evasion, and response to treatment in many cancers, including pancreatic ductal adenocarcinoma (PDAC). This study aimed to spatially characterize the metabolic and lipidomic alterations in PDAC and its precursor lesion, intraductal papillary mucinous neoplasm (IPMN), compared to normal/non-neoplastic pancreatic tissue. Experimental details: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was employed to perform spatial metabolic and lipidomic profiling of human PDAC, IPMN, and normal/non-neoplastic pancreatic tissues. MALDI-MSI provided multiplexed metabolic images of tissue samples at 200 um resolution, allowing spatial characterization of the tumor metabolic landscape. RESULTS: Our data identified metabolic signatures characteristic of PDAC, with several of these altered in IPMN compared to normal/non-neoplastic tissue. The metabolic fingerprint of PDAC was characterized by increased levels of taurine, ascorbic acid, and a variety of lipid species, including most of the phosphatidylcholines and sphingomyelins compared to normal/non-neoplastic pancreas tissue, alongside elevated acetylcarnitine, butyrylcarnitine, and phosphatidylcholine (PC 34:3) relative to IPMN; significant reductions were observed in creatine, malate, lysophosphatidylcholine (LPC 16:0). In contrast, IPMN tissues demonstrated a significant reduction of xanthine, arginine, and tryptophan compared to normal/non-neoplastic pancreas tissue. These metabolic signatures were spatially heterogeneous. CONCLUSION: Our findings provide novel insights into the metabolic and lipidomic underpinnings of PDAC. Metabolic alterations in PDAC were associated with proliferation, immune evasion, and treatment resistance.
Tiu C, Yau W, Silva D
… +38 more, Waldron N, Ameratunga M, Scaranti M, Biondo A, Welsh L, Creak A, Jones TL, Martin AJ, Bridges L, Zachariou A, Crespo M, Ferreira A, Riisnaes R, Gurel B, Figueiredo I, Bogdan D, Yuan W, Morilla R, Swales K, Decordova S, Prout T, Parmar M, Baikady B, Rata M, Blackledge M, Tunariu N, Benjamin P, Rich P, Daly R, Hu X, Yap C, Vivanco I, Paschalis A, Sharp A, Banerji U, Minchom A, de Bono J, Lopez J
Clin Cancer Res
· 2026 Apr · PMID 42043781
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PURPOSE: Activation of the phosphatodylinositol-3-kinase/AKT (PI3K/AKT) signalling pathway promotes tumor immune evasion by suppressing effector T-cell infiltration and enhancing regulatory T-cell activity contributing t...PURPOSE: Activation of the phosphatodylinositol-3-kinase/AKT (PI3K/AKT) signalling pathway promotes tumor immune evasion by suppressing effector T-cell infiltration and enhancing regulatory T-cell activity contributing to resistance to immune checkpoint inhibitors. Preclinical studies have demonstrated that inhibition of this pathway can restore anti-tumor immunity and synergize with PD-1/PD-L1 blockade. We explore the synergistic clinical potential of targeting the PI3K/AKT pathway in combination with atezolizumab to overcome immunotherapy resistance in recurrent glioblastoma and advanced solid tumors. EXPERIMENTAL DESIGN: Phase 1b, investigator-initiated, open-label study (NCT03673787) composed of a proof-of-concept dose escalation Part A of ipatasertib plus atezolizumab in a 3+3 design. Adult patients with treatment refractory advanced cancers were enrolled into Cohort A1 and recurrent glioblastoma onto Cohort A2. Part B enrolled patients into 6 exploratory cohorts. Study aims to evaluate the safety, immune-modulatory effects and preliminary efficacy of the combination of ipatasertib with atezolizumab. RESULTS: The combination was well tolerated, with no dose-limiting toxicities at the recommended phase 2 dose of ipatasertib 400 mg/daily plus atezolizumab 1200mg every 3 weeks. Pharmacodynamic analysis demonstrated depletion of FOXP3+ regulatory T cells and increased infiltration of CD8+ effector T cells within the tumor microenvironment. Durable exceptional responses were seen in some patients with treatment-refractory or recurrent glioblastoma. CONCLUSION: This is the first report in clinical samples showing that ipatasertib efficiently depletes FOXP3+ regulatory T cells and results in increased infiltration of effector CD8+ T cells in the tumor microenvironment. This was associated with preliminary efficacy in a subset of patients with treatment-refractory glioblastoma (GBM).
Lückerath K, Hadaschik B, Herrmann K
… +1 more, von Amsberg G
Clin Cancer Res
· 2026 Jul · PMID 42043778
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Radioligand therapy exemplifies precision oncology, yet its consequences remain incompletely understood. A recent article shows that [177Lu]Lu-PSMA promotes emergence and expansion of clonal hematopoiesis enriched for DN...Radioligand therapy exemplifies precision oncology, yet its consequences remain incompletely understood. A recent article shows that [177Lu]Lu-PSMA promotes emergence and expansion of clonal hematopoiesis enriched for DNA damage response gene mutations, reframing bone marrow effects as treatment-emergent clonal selection rather than collateral toxicity and informing biology-guided patient monitoring and theranostics. See related article by Munzur et al., p. 2644.
Nagrial A, Carlino MS, Gunjur A
… +23 more, Brown MP, Harris S, Underhill C, Zielinski R, Kee D, Lam WS, Chan H, Harrup R, So J, Collins IM, Michael M, Chionh F, Uy C, Mariadason J, Torres J, Ballinger ML, Grady JP, Tavancheh E, Palmer J, Thomas DM, Wilkie K, Cebon J, Klein O
Clin Cancer Res
· 2026 Apr · PMID 42029635
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PURPOSE: Anti-PD-1/PD-L1 blockade combined with chemotherapy has become first line treatment for advanced biliary tract cancers (BTC). Combined anti-PD-1/CTLA-4 blockade using nivolumab and ipilimumab has shown encouragi...PURPOSE: Anti-PD-1/PD-L1 blockade combined with chemotherapy has become first line treatment for advanced biliary tract cancers (BTC). Combined anti-PD-1/CTLA-4 blockade using nivolumab and ipilimumab has shown encouraging activity in patients with intrahepatic cholangiocarcinoma (iCCA) and gallbladder carcinoma (GBC) in two trials (CA209-538, SWOG1609). MoST-CIRCUIT further evaluated combined checkpoint blockade using nivo/ipi in patients with advanced iCCA and GBC. PATIENTS AND METHODS: Patients with a maximum of 1 line of prior systemic therapy were enrolled as cohort B into MoST-CIRCUIT, a single arm, non-randomised phase 2 trial. Patients received nivolumab 3mg/kg and ipilimumab 1mg/kg q3 weekly for four doses, followed by nivolumab 480mg q4 weekly for 96 weeks. Response (RECIST 1.1) was assessed every 12 weeks. Co-primary endpoints were objective response rate (ORR) and 6 month-progression free-survival (6-PFS) with the secondary endpoints being median overall survival (mOS), progression-free survival (PFS) and treatment related toxicity. RESULTS: 60 patients (37 iCCA and 23 GBC) were enrolled with 85% being pre-treated, including 13 patients with durvalumab. ORR was 12% (2% CR, 10% PR): 3% and 26% in iCCA and GBC subgroups respectively. The 6-month-PFS was 27% (iCCA 19%; GBC 39%) and mOS 7 months. In the immunotherapy-naïve population ORR was 19% (iCCA 10%; GBC 38%). Severe immune-related adverse events were observed in 20% of patients. CONCLUSIONS: Efficacy was limited in what is the largest BTC cohort treated to date with combined anti-CTLA-4/PD-1 blockade. Encouraging activity was observed in the GBC subgroup. Further evaluation of checkpoint inhibition in BTC should focus on GBC patients.
Funk AM, Brieske M, Schwarz FM
… +8 more, Link T, Jonas S, Wimberger P, Freitag L, Klimova A, Chavakis T, Mirtschink P, Kuhlmann JD
Clin Cancer Res
· 2026 Apr · PMID 42029478
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BACKGROUND: Reliable prognostic tools in ovarian cancer are urgently needed to guide risk-adapted treatment decisions, yet the clinical utility of urinary metabolites for non-invasive risk stratification remains largely...BACKGROUND: Reliable prognostic tools in ovarian cancer are urgently needed to guide risk-adapted treatment decisions, yet the clinical utility of urinary metabolites for non-invasive risk stratification remains largely undefined. Here, we define a clinically relevant urinary metabolite signature that enables non-invasive prognostic risk stratification in ovarian cancer. METHODS: Using targeted ¹H NMR spectroscopy, we profiled 149 metabolites involved in energy metabolism, oxidative stress, mitochondrial function, nitrogen metabolism, amino acid degradation, gut microbiome activity and inflammation in pre-operative urine from 199 consecutive patients with newly diagnosed ovarian cancer treated in routine clinical practice between 2013 and 2022. RESULTS: Unsupervised clustering revealed biologically heterogeneous subgroups but lacked prognostic resolution and alignment with overt clinical phenotypes. However, single-metabolite analysis identified a condensed three-metabolite prognostic signature comprising glycine, alanine and citrate. A final parsimonious model integrating this metabolite-signature with clinical covariates outperformed established risk factors alone (FIGO-stage, surgical outcome), accurately predicted 60-month overall survival (AUC = 0.839) and stratified risk. Patients in the highest-risk quartile (Q4) had markedly shorter progression-free survival (Δmedian ≈ 56 months; HR = 2.63, 95% CI: 1.54-4.52, p < 0.001) and overall survival (Δmedian ≈ 86 months; HR = 2.49, 95% CI: 1.39-4.46, p = 0.009) compared to the lowest-risk group (Q1). CONCLUSION: We define a urinary three-metabolite signature that enables non-invasive identification of high-risk ovarian cancer patients beyond established clinical factors and may support molecular stratification and risk-adapted clinical decisions, thereby supporting the clinical scalability of urine as a matrix for metabolic risk profiling in ovarian cancer.
Clin Cancer Res
· 2026 Jul · PMID 42024147
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The KGOG 3056/NIRVANA-R trial demonstrated that niraparib rechallenge combined with bevacizumab may potentially be a promising maintenance strategy in patients with platinum-sensitive recurrent ovarian cancer previously...The KGOG 3056/NIRVANA-R trial demonstrated that niraparib rechallenge combined with bevacizumab may potentially be a promising maintenance strategy in patients with platinum-sensitive recurrent ovarian cancer previously treated with poly(ADP-ribose) polymerase inhibitor (PARPi). With a 68% 6-month progression-free survival rate, this combination may synergistically be able to overcome acquired PARPi resistance, particularly in patients with favorable platinum sensitivity. See related article by Cho et al., p. 2537.
Garg A, Mannheimer JD, Gardner H
… +9 more, London CA, Hendricks WPD, Wang G, Day K, Sakthikumar S, Warrier M, Mazcko C, Beck JA, LeBlanc AK
Clin Cancer Res
· 2026 Apr · PMID 42018306
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PURPOSE: Osteosarcoma is a heterogeneous and aggressive primary bone malignancy that affects both canines and humans. Standardized treatment regimens prescribed to both species do not address the complexity of the diseas...PURPOSE: Osteosarcoma is a heterogeneous and aggressive primary bone malignancy that affects both canines and humans. Standardized treatment regimens prescribed to both species do not address the complexity of the disease and thus have resulted in stagnant patient outcomes for more than 30 years. EXPERIMENTAL DESIGN: Here we present the first multiomic dataset created from a large outcome-linked biobank of canine OS treatment-naïve primary tumors utilizing a computational framework designed to interrogate each dataset individually, and to compare and integrate findings. RESULTS: This exploratory work suggests the presence of MYC amplification is a poor prognostic indicator in canines and highlights alterations in DNA damage repair, metabolism, and cell cycle genes that are shared with humans. Further, we show relationships between the local tumor immune microenvironment, TP53 mutations, MYC and PTEN status, and global gene methylation patterns. CONCLUSIONS: This work highlight the complexity of the disease and provide new insight into the utility of prognostic biomarkers and potential druggable targets for future study.
Chang KY, Hsu YT, Chuang SS
… +9 more, Hsiao CF, Huang TC, Hsieh CY, Yeh SP, Ma WL, Wang MC, Chen TY, Hsueh PR, Wu SJ
Clin Cancer Res
· 2026 Apr · PMID 42018298
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PURPOSE: Primary central nervous system lymphoma (PCNSL) has a poor prognosis and limited treatment options. This phase 1b study evaluates the combination therapy of rituximab, acalabrutinib, and durvalumab (RAD) in rela...PURPOSE: Primary central nervous system lymphoma (PCNSL) has a poor prognosis and limited treatment options. This phase 1b study evaluates the combination therapy of rituximab, acalabrutinib, and durvalumab (RAD) in relapsed/refractory PCNSL. PATIENTS AND METHODS: The study was conducted with dose escalation (3+3 design) and expansion phases. Acalabrutinib (100 mg) was administered once or twice daily for dose determination; rituximab (375 mg/m²) and durvalumab (1500 mg) were treated every four weeks for up to 8 cycles. Primary endpoints assessed safety, tolerability, and the recommended phase 2 dose; secondary endpoints evaluated treatment responses and survival outcomes. RESULTS: Seventeen patients, including 15 with relapsed/refractory diseases, were enrolled between February 2021 and April 2024. One patient was unevaluable. No dose-limiting toxicities (DLTs) were observed in the 4-week observation period for 6 evaluable patients at dose levels 1 and 2. In the expansion cohort, 10 additional patients received dose level 2. Treatment-related adverse events (AEs) occurred in 14 patients (82%), with 59% experiencing grade 3/4 events, mainly including neutropenia, skin reactions, and transaminitis. Among 16 evaluable patients, the overall response rate was 62.5%, and complete response rate was 12.5%. All responders received dose level 2. Median overall survival (OS) and progression-free survival (PFS) were 11.9 and 4.3 months, respectively. Improved outcomes were observed for responders versus non-responders (OS, 20.6 vs. 10.2 months; PFS, 5.2 vs. 2.1 months). CONCLUSIONS: The RAD regimen is feasible for treating PCNSL patients and shows potential as a therapeutic option. Further large-scale trials are needed to confirm its clinical efficacy.
Thangavadivel S, Shaffer J, Misra S
… +15 more, Benrashid S, Gordon BK, He A, Li W, Oyman K, Chura A, Cabrera S, Turkoglu A, Lai TH, Rogers KA, Bhat SA, Byrd JC, Blachly JS, Woyach JA, Blaser BW
Clin Cancer Res
· 2026 May · PMID 42018044
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PURPOSE: The development of Bruton tyrosine kinase inhibitors (BTKi) and their introduction into clinical practice represents a major advance in the treatment of chronic lymphocytic leukemia (CLL). However, monotherapy w...PURPOSE: The development of Bruton tyrosine kinase inhibitors (BTKi) and their introduction into clinical practice represents a major advance in the treatment of chronic lymphocytic leukemia (CLL). However, monotherapy with ibrutinib or other BTKis does not induce complete remissions or undetectable minimal residual disease even with extended therapy. Therefore, there is a need to understand the differences between ibrutinib-sensitive and -resistant CLL cells along with immune microenvironment to identify therapeutic approaches for controlling residual disease during BTKi treatment. EXPERIMENTAL DESIGN: Here, we investigated the cellular heterogeneity of peripheral blood mononuclear cells from patients with CLL treated with ibrutinib using single-cell RNA sequencing. RESULTS: We identified unique transcriptional heterogeneity within the B-cell cluster in the ibrutinib-sensitive and -resistant patients. Ibrutinib-sensitive cells showed enrichment of B-cell populations with upregulation of MHC I molecules and TNF family members. Additionally, we observed that inflammatory response and metabolism-related pathways were decreased, whereas cellular response to stress and DNA repair programs were increased in the ibrutinib-resistant samples. T cells in ibrutinib-resistant patients showed expansion of regulatory T cells and an exhausted CD8 effector T-cell compartment. Furthermore, CD14+ and CD16+ monocytes from ibrutinib-resistant patients preferentially expressed a gene expression program of antiviral immunity. CONCLUSIONS: At single-cell level, our findings demonstrate a picture of transcriptional heterogeneity in the tumor compartment and immune milieu. Overall, these findings highlight transcriptional changes in circulating immune cells associated with ibrutinib resistance, suggesting that T-cell exhaustion and monocyte polarization accompany and may contribute to resistance during long-term BTKi therapy.
Foote MB, Harada G, Abdelfattah S
… +25 more, Urganci N, Manca P, Shia J, Walch H, Argilés G, Artz O, Yaeger R, Nusrat M, Patel S, Johannet P, Harrold EC, Rousseau B, Stadler Z, Wilde C, Jayaprakasam VS, Cremolini C, Lonardi S, Cercek A, Saltz L, Vakiani E, Pietrantonio F, Janjigian Y, Schultz N, Drilon A, Diaz LA
Clin Cancer Res
· 2026 Apr · PMID 42013404
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PURPOSE: Mismatch-repair deficient (MMRd) colorectal cancers (CRC) are classified based on MMR protein loss and BRAF-V600E mutations. BRAF-wild-type(wt) sporadic MMRd tumors exhibit a diverse landscape of alternative onc...PURPOSE: Mismatch-repair deficient (MMRd) colorectal cancers (CRC) are classified based on MMR protein loss and BRAF-V600E mutations. BRAF-wild-type(wt) sporadic MMRd tumors exhibit a diverse landscape of alternative oncogenes, including gene fusions, with unclear biologic and clinical significance. We evaluated mutually-exclusive subtypes of sporadic MMRd tumors defined by oncogenic MAPK variants and gene fusions to determine the relationship between predominant genomic driver, MMR deficiency mechanism, and clinical outcomes. PATIENTS AND METHODS: We assessed 6,789 patients with CRC sequenced by MSK-IMPACT to identify 518 patients with sporadic MMRd CRC. We defined mutually-exclusive oncogenic alteration subtypes, then assessed differences in allele-specific MMR-inactivating events, co-occurring oncogenic variants, and patient outcomes. We validated findings in an Italian cohort (n=69). RESULTS: We identify four sporadic MMRd CRC subtypes: (i) oncogenic fusion-positive, (ii) RAS-mutant(mut), (iii) BRAF-V600E-mut, and (iv) MAPK/fusion driver-negative. These mutually-exclusive subtypes were associated with conserved molecular lineages of MMR gene inactivation and WNT signaling variants. Oncogenic fusions were disproportionately prevalent in non-Caucasians, non-smokers and in the transverse colon, compared to subtypes that were enriched in smokers (BRAF-mut) and male, younger patients (RAS-mut and MAPK/fusion-driverless). Oncogene-defined molecular lineages were strong predictors of patient outcomes and response to immunotherapy and tyrosine kinase inhibition for metastatic disease. Fusion-positive patients demonstrated improved survival compared to BRAF mutant cancers and benefitted from immunotherapy and fusion inhibitors. MAPK/fusion driver negative tumors were aneuploid, responded poorly to immunotherapy, and were sensitive to EGFR blockade. CONCLUSIONS: Overall, MAPK and fusion oncogenic drivers distinguish MMRd CRC molecular lineages that inform molecular and clinical phenotypes.
Kong Z, Liu Y, Lin YS
… +15 more, Li Z, Cui XY, Liu S, Zhang X, Li R, Yang Y, Sun Y, Nie Y, Zhang Z, An C, Ni S, Zhu Y, Liu Z, Wang J, Liu S
Clin Cancer Res
· 2026 May · PMID 42013308
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PURPOSE: Medullary thyroid carcinoma (MTC) is curable only by complete resection of all malignant lesions; however, biochemical cure rates remain suboptimal because of imprecise lesion localization. We previously develop...PURPOSE: Medullary thyroid carcinoma (MTC) is curable only by complete resection of all malignant lesions; however, biochemical cure rates remain suboptimal because of imprecise lesion localization. We previously developed a covalent targeted radioligand fibroblast activation protein inhibitor (CTR-FAPI-30) with superior MTC detection rate and accuracy. This study evaluated whether [68Ga]Ga-CTR-FAPI-30 positron emission tomography-computed tomography (PET-CT)-guided surgery improves patient outcomes. PATIENTS AND METHODS: In this prospective, open-label phase II clinical trial, 50 patients with MTC were enrolled and underwent [68Ga]Ga-CTR-FAPI-30 PET-CT-guided surgery. Patients were stratified into three predefined arms: (i) newly diagnosed MTC, R0 resection; (ii) recurrent MTC, R0 resection; and (iii) unresectable disease or distant metastasis. The primary endpoint was the biochemical cure rate at 1 month postoperatively. Secondary endpoints included event-free survival, the diagnostic accuracy of [68Ga]Ga-CTR-FAPI-30, and surgical plan modification rate. RESULTS: The biochemical cure rates were favorable under [68Ga]Ga-CTR-FAPI-30-guided surgery, with 84.2% [95% confidence interval (CI), 60.4%-96.6%] in arm 1 (newly diagnosed, R0 resection) and 46.7% (95% CI, 21.3%-73.4%) in arm 2 (recurrent, R0 resection), both of which exceeded historical data (P = 0.007-0.049). For 231 lesions with gold-standard pathology, [68Ga]Ga-CTR-FAPI-30 demonstrated superior diagnostic accuracy (96.5% vs. 72.7%, P < 0.0001), sensitivity (98.5% vs. 81.7%, P < 0.0001), and specificity (85.3% vs. 20.6%, P < 0.0001) compared with conventional imaging. Surgical plans were modified in 46% of patients based on [68Ga]Ga-CTR-FAPI-30 PET-CT compared with investigator-determined approaches, with 91% of these modifications histopathologically justified. CONCLUSIONS: [68Ga]Ga-CTR-FAPI-30-guided surgery achieved favorable biochemical cure rates for both newly diagnosed MTC and recurrent MTC, enabling precision surgical resection through accurate lesion localization.
Yapindi L, Ghosh S, Shen L
… +3 more, Diao L, Wang J, Johnson FM
Clin Cancer Res
· 2026 Apr · PMID 42013305
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PURPOSE: Cancers driven by a loss of tumor suppressor function lack actionable druggable targets. We investigated the cell cycle-specific mechanisms underlying the efficacy of co-targeting TRIP13 and Aurora A by defining...PURPOSE: Cancers driven by a loss of tumor suppressor function lack actionable druggable targets. We investigated the cell cycle-specific mechanisms underlying the efficacy of co-targeting TRIP13 and Aurora A by defining their key functions in Rb-deficient cancers to develop effective treatment strategies. EXPERIMENTAL DESIGN: We used live-cell imaging to monitor individual cell fates and validated results using orthogonal measurements of apoptosis, pyroptosis, and cell cycle in vitro. In mouse xenografts, we used a clinically relevant Aurora A inhibitor and inducible TRIP13 protein degradation to elucidate this combination's effect in vivo. Human tumor mRNA expression was analyzed to establish clinical relevance. RESULTS: Co-targeting TRIP13 and Aurora A led to mitotic cell death by inducing prolonged mitotic arrest. We observed that TRIP13 contributes to this effect by further extending Aurora A inhibition-induced mitotic arrest, thereby enhancing its cytotoxicity. Orthogonal in vitro assays further revealed that dual targeting induces DNA damage and concurrent apoptotic and gasdermin E (GSDME)-mediated pyroptotic cell death in mitotically arrested Rb-deficient cancer cells. Additionally, this combination achieved marked antitumor efficacy in vivo accompanied by a measurable survival benefit in mice bearing Rb-deficient carcinoma. Rb-deficient human head and neck and lung squamous cell carcinoma tumors exhibited significantly higher CASP3 but lower GSDME expression, suggesting an adaptive mechanism to limit GSDME-mediated pyroptosis that is overcome by the combination. CONCLUSIONS: Combined inhibition of TRIP13 and Aurora A may have a high therapeutic index by inducing mitotic pyroptosis and apoptosis specifically in Rb-deficient cancer cells and potentially engaging anti-tumor immunity.
Schlaak M, Cimminiello C, Pigozzo J
… +18 more, Lee J, Grabbe S, Rutkowski P, Mackiewicz J, Tsai KK, Ascierto PA, Mandalà M, Carnevale-Schianca F, Haferkamp S, Atkinson V, Hassel JC, Sandhu S, Sharfman W, Dean E, Noor U, Iyer S, Rabbie R, Ribas A
Clin Cancer Res
· 2026 Apr · PMID 42012456
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INTRODUCTION: Data suggest that ceralasertib, a potent and selective oral inhibitor of the ATR DNA damage response kinase, may overcome resistance to prior immunotherapy. METHODS: In this phase II study, patients with un...INTRODUCTION: Data suggest that ceralasertib, a potent and selective oral inhibitor of the ATR DNA damage response kinase, may overcome resistance to prior immunotherapy. METHODS: In this phase II study, patients with unresectable or metastatic melanoma of cutaneous, acral or mucosal subtype and confirmed progression during anti-PD-(L)1 therapy with or without anti-CTLA-4 were randomized 2:1 to ceralasertib 240 mg BID on days 1-7 then durvalumab 1500 mg IV on day 8, every 28 days or ceralasertib 240 mg BID on days 1-7, every 28 days. The primary endpoint was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses of baseline (tumor and circulating) and on-treatment (circulating only) biomarkers were conducted. RESULTS: ORR was 9.3% (95% confidence interval [CI], 4.3-16.9) for ceralasertib plus durvalumab (below the prespecified minimum threshold) and 5.8% (95%CI, 1.2-15.9) for ceralasertib monotherapy; median PFS was 2.0 months (95%CI, 1.9-3.5) versus 1.9 months (95%CI, 1.9-3.1) (hazard ratio [HR], 0.80; 95%CI, 0.54-1.18); and median OS was 16.0 months (95%CI, 10.5-NC) versus 12.3 months (95%CI, 9.5-NC) (HR, 0.81; 95%CI, 0.49-1.37). Both regimens were well tolerated. Exploratory analyses indicated a possible link between higher baseline pre-treatment tumor CD8+ T cell counts and improved overall survival across both arms and suggested that ceralasertib treatment may induce transient, cyclical changes in circulating CD14+ monocytes and GDF-15 plasma levels. CONCLUSION: Both ceralasertib plus durvalumab and ceralasertib monotherapy demonstrated low response rates in anti-PD-(L)1-resistant advanced melanoma.
Makovec A, Gustafson AP, Gandhi N
… +15 more, Rampalli S, Arafa AT, Elliott A, Smith N, Felices M, Kennedy PR, Shenderov E, Patnaik A, Narayan V, Heath EI, Zorko NA, Shi X, Antonarakis ES, McKay RR, Hwang J
Clin Cancer Res
· 2026 Apr · PMID 42012455
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PURPOSE: B7-H3 (CD276) represents a promising therapeutic target tested in high-risk localized and treatment-refractory metastatic prostate cancer (PC). To guide therapeutic development and treatment strategies, we exami...PURPOSE: B7-H3 (CD276) represents a promising therapeutic target tested in high-risk localized and treatment-refractory metastatic prostate cancer (PC). To guide therapeutic development and treatment strategies, we examined prostate tumors and evaluated expression, molecular features, and overall survival (OS), accounting for tissue site, hormone-sensitivity status, and race. EXPERIMENTAL DESIGN: 8,157 PC samples with paired DNA/RNA were analyzed based on annotations by tissue site, self-reported race, and disease state: hormone-sensitive (HSPC), castration-resistant (CRPC), or neuroendocrine PC (NEPC). Expression quartiles were B7-H3-high (>75th percentile) or B7-H3-low (<25th percentile). OS was evaluated using Kaplan-Meier and Cox proportional hazards models. RESULTS: B7-H3 expression was broadly maintained but varied by tumor site, hormone-sensitivity status, and race. High expression aligned with AR-associated transcription factors (HOXB13, FOXA1), AR-associated pathogenic dysregulations (AR-V7, SPOP, FOXA1, TMPRSS2:ERG fusions), and actionable surface antigens (TROP2, NECTIN-4). Weak correlations were found for lineage-plastic program regulators (EZH2, SOX2, ASCL1) and NEPC-associated surface antigens (DLL3, CEACAM5). High B7-H3 expression in primary tumors and HSPCs portended adverse OS (HR: 1.342, 1.30, CI: 1.19-1.512, 1.15-1.46, q < 0.0001), although favorable in metastatic tumors (HR: 0.823, CI: 0.719-0.942, q = 0.0048). No significant differences in OS were observed among CRPCs and NEPCs, although OS varied by race, with poorest survival in Asian/Pacific Islander metastatic PC patients (HR = 3.72, CI: 1.49-9.29, q = 0.012). CONCLUSIONS: Maintained B7-H3 expression in various PC settings supports its viability as a target. Associations with AR-related molecular factors, surface antigens, and investigative targets for cell therapy or antibody-drug conjugates (ADC) suggest potential dual-targeting strategies.
Bianchi R, Kunz L, Hosse RJ
… +24 more, Brydon M, Amorim A, Schwalie PC, Speziale D, Varol A, Appelt B, Drozdowicz E, le Clech M, Valdeolivas A, Kumpesa N, Hahn K, Richardson M, Giroud N, Pesti B, Gassner C, Wimmer R, Henniger L, Villenave R, Boetsch C, Hopfer U, Bessa J, Trumpfheller C, Majety M, Umaña P
Clin Cancer Res
· 2026 Apr · PMID 42012453
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PURPOSE: Immune checkpoint inhibitors (CPIs) have revolutionized cancer therapy, yet many patients derive limited benefit due to poor immune infiltration within the tumor microenvironment (TME). The presence of tertiary...PURPOSE: Immune checkpoint inhibitors (CPIs) have revolutionized cancer therapy, yet many patients derive limited benefit due to poor immune infiltration within the tumor microenvironment (TME). The presence of tertiary lymphoid structures (TLS) and high endothelial venules (HEVs) correlates with improved immunotherapy responses. This study evaluated whether selective activation of lymphotoxin-beta receptor (LTβR) signalling, targeted to fibroblast activation protein (FAP)-expressing tumor stroma, could remodel the TME to enhance immune cell infiltration and potentiate immunotherapy. EXPERIMENTAL DESIGN: FAP-LTBR was engineered as a novel tumor-targeted LTβR agonist and was characterized for its binding, activation, and immunomodulatory properties in vitro and in vivo. Functional effects were assessed using primary human endothelial cells, 3D microfluidic vascular models, and multiple murine tumor models. Spatial transcriptomics and 3D immunophenotyping elucidated TME remodelling. Therapeutic efficacy was tested as monotherapy and in combination with CPIs or T cell engagers. RESULTS: FAP-LTBR selectively activated endothelial cells and induced chemokine secretion in a FAP-dependent manner, enhancing T cell adhesion and extravasation in vitro. In murine models, FAP-LTBR promoted HEV differentiation, TLS-like immune aggregates, and broad tumor inflammation marked by increased B and T cell infiltration, including stem-like TCF1+ CD8+ T cells. FAP-LTBR synergized with CPIs and T cell engagers to induce durable tumor regression, with superior CD8+ T cell recruitment and redistribution into tumor cores. CONCLUSION: FAP-LTBR represents a first-in-class tumor-targeted LTβR agonist that remodels the TME, promoting HEV differentiation, immune cell infiltration, and the formation of organized lymphoid aggregates, which collectively enhance immunotherapy efficacy in preclinical models.
Li S, Wu CC, Marczyk VR
… +25 more, Loberg MA, Thennavan A, Tarabichi M, Xu L, Henderson YC, Martin ME, Tran TM, Duose DY, Sanchez-Espitia A, Luthra R, Sheng Q, Xu GJ, Huang EC, Hofmann MC, Zhao X, Lai SY, Hosseini SM, Williams MD, Wang W, Hamidi S, Zafereo ME, Cabanillas ME, Navin NE, Weiss VL, Wang JR
Clin Cancer Res
· 2026 Jul · PMID 42008746
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PURPOSE: Papillary thyroid carcinoma (PTC) exhibits heterogeneous behavior, underscoring the need for effective biomarkers and improved risk stratification methods. We developed a thyrocyte-derived gene signature, Progno...PURPOSE: Papillary thyroid carcinoma (PTC) exhibits heterogeneous behavior, underscoring the need for effective biomarkers and improved risk stratification methods. We developed a thyrocyte-derived gene signature, Prognostic RNA Expression Cell-specific Integrated Signature (PRECISE), using single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) and evaluated its prognostic utility across cohorts. EXPERIMENTAL DESIGN: PRECISE was developed using a discovery cohort of patients with PTC [MD Anderson Cancer Center (MDACC), n = 109, median follow-up = 14 years]. Within the cohort, 11 PTC tumors and 4 normal thyroid samples were successfully sequenced using snRNA-seq. Differentially expressed genes were integrated with previously identified thyrocyte-associated genes from scRNA-seq. Prognostic significance was assessed using bulk RNA-seq in the discovery cohort and validated in two additional cohorts [Vanderbilt University Medical Center (VUMC), n = 65; The Cancer Genome Atlas (TCGA), n = 370]. A rank-based single-sample method was used for score calculation. Associations between PRECISE and progression-free survival (PFS) and disease-specific survival (DSS) were evaluated using multivariate Cox models, and predictive models were compared using Harrell's C-statistic and likelihood ratio tests. RESULTS: PRECISE is comprised of 41 epithelial genes downregulated in PTC tumor cells. Higher PRECISE was significantly associated with shorter PFS across all three cohorts [MDACC: hazard ratio (HR) = 1.64, P = 0.002; VUMC: HR = 2.54, P < 0.001; TCGA: HR = 1.63, P = 0.012] and remained significant after tumor-node-metastasis stage adjustment in two cohorts with ≥5 years of follow-up [MDACC adjusted HR (aHR) = 1.42, P = 0.038; VUMC aHR = 2.12, P = 0.024]. PRECISE was also associated with DSS in these cohorts (MDACC: HR = 4.16, P < 0.001; VUMC: HR = 2.23, P = 0.010). Incorporating PRECISE significantly improved predictive performance for PFS and DSS beyond stage-based models. CONCLUSIONS: PRECISE is a thyroid epithelial gene signature with independent prognostic value in PTC.
Lee JB, Kim DK, Lee SH
… +7 more, Kim KH, Choi SJ, Park SY, Kim JH, Hong MH, Cho BC, Lim SM
Clin Cancer Res
· 2026 Apr · PMID 42008740
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PURPOSE: SKYROCKET is a single-center, single-arm phase II study that evaluated the addition of SBRT to atezolizumab plus tiragolumab enhances anti-tumor efficacy in PD-L1-positive NSCLC. PATIENTS AND METHODS: Patients r...PURPOSE: SKYROCKET is a single-center, single-arm phase II study that evaluated the addition of SBRT to atezolizumab plus tiragolumab enhances anti-tumor efficacy in PD-L1-positive NSCLC. PATIENTS AND METHODS: Patients received SBRT to all metastatic sites, and subsequently received atezolizumab and tiragolumab every 3 weeks on day 1 of each 21-day cycle with 7 days of completion of SBRT. The primary endpoint was investigator-assessed progression-free survival (PFS) from the start of SBRT. Exploratory endpoints included single-cell RNA sequencing (scRNA-seq) obtained from tumor biopsies at baseline (BL) and on-treatment (OT), and were further characterized as clinical benefit (CB, PR or SD ≥6 months) and no clinical benefit (NCB, PD or SD <6 months). RESULTS: A total of 41 patients were enrolled. At a median duration of follow-up of 9.8 months, median PFS at the start of SBRT was 9.3 months (95% CI, 6.0-NR). No new safety signal was observed. ScRNA-seq of paired BL and OT (n=3) and single-time point (n=2) revealed that CD8 progenitor-exhausted (TPEX) cells markedly expanded after treatment, with high TIGIT and PD-1 expression in CD8 TPEX/TEX subsets. CD4 Tregs were reduced in the CB group but increased in the NCB group. The CB group showed reduced Treg suppression and NECTIN-TIGIT signaling, whereas NCB maintained proliferative CTLA4high/TIGIT high Tregs supported by ICAM/Galectin-CTLA4 pathways. CONCLUSIONS: SBRT followed by atezolizumab plus tiragolumab showed encouraging clinical activity with manageable safety in PD-L1-positive metastatic NSCLC.