Clinical Cancer Research最新文献

Purpose: Mismatch repair-deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment.

Patients and methods: We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-Molecular Analysis for Therapy Choice arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with noncolorectal dMMR tumors. Genomic analyses were performed using next-generation sequencing (NGS), whole-exome sequencing, and RNA sequencing and supplemented by multiplex immunofluorescence performed on tissue samples.

Results: In this dMMR population, more extensive alterations of microsatellites as assessed by measures of NGS were associated with clinical benefit and tumor mutational burden. RNA sequencing further revealed associations between clinical benefit and immune infiltration index. Gene sets enriched in patients with clinical benefit included IFN signaling, antigen processing, and PI3K-AKT-mTOR signaling, whereas hedgehog signaling was found to be enriched in subjects lacking clinical benefit.

Conclusions: These genomic data highlight the importance of immune infiltration and antigen presentation in dMMR tumors that respond to immune checkpoint blockade. In addition, they suggest that, even within a dMMR population, NGS-based measures of microsatellite instability could serve as biomarkers of immunotherapy response.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) patients with tumors enriched for the basal-like molecular subtype exhibit enhanced resistance to standard-of-care treatments and have significantly worse overall survival compared with patients with classic subtype-enriched tumors. It is important to develop genomic resources, enabling identification of novel putative targets in a statistically rigorous manner.

Experimental design: We compiled a single-cell RNA sequencing (scRNA-seq) atlas of the human pancreas with 229 patient samples aggregated from publicly available raw data. We mapped cell type-specific scRNA-seq gene signatures in bulk RNA-seq (n = 744) and spatial transcriptomics (ST; n = 22) and performed validation using multiplex immunostaining.

Results: Analysis of tumor cells from our scRNA-seq atlas revealed nine distinct populations, two of which aligned with the basal subtype, correlating with worse overall survival in bulk RNA-seq. Deconvolution identified one of the basal populations to be the predominant tumor subtype in nondissociated ST tissues and in vitro tumor cell and patient-derived organoid lines. We discovered a novel enrichment and spatial association of CXCL10+ cancer-associated fibroblasts with basal tumor cells. We identified that besides immune cells, ductal cells also express CXCR3, the receptor for CXCL10, suggesting a relationship between these cell types in the PDAC tumor microenvironment.

Conclusions: We show that our scRNA-seq atlas (700,000 cells), integrated with ST data, has increased statistical power and is a powerful resource, allowing for expansion of current subtyping paradigms in PDAC. We uncovered a novel signaling niche marked by CXCL10+ cancer-associated fibroblasts and basal tumor cells that could be explored for future targeted therapies.

Purpose: FHD-609, a potent, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), was evaluated for treating patients with advanced synovial sarcoma or SMARCB1-deficient tumors.

Patients and methods: In this multinational, open-label, phase I study (NCT04965753), patients received FHD-609 intravenously at escalating doses either twice weekly (5-80 mg; n = 40) or once weekly (40-120 mg; n = 15).

Results: Fifty-five patients received FHD-609 for a median of 43 days. The maximum tolerated doses were 40 mg twice weekly and the equivalent weekly dose, 80 mg once weekly. Dose-limiting toxicities of QTc (heart rate-corrected QT interval) prolongation and syncope were observed at 40 and 60 mg twice weekly. Treatment-related adverse events were predominantly grades 1 to 2 in severity, most commonly dysgeusia (40%), dry mouth (29.1%), fatigue (27.3%), and anemia (25.5%). Eleven (20%) patients had treatment-emergent QTc (Fridericia formula) prolongation preceded by T-wave inversions; 21 (38.2%) patients had T-wave inversions without further cardiac events or ECG abnormalities. FHD-609 showed dose-dependent increases in pharmacokinetic exposure, with no substantial accumulation. Extensive BRD9 degradation in tumor tissue corresponded to the downregulation of cancer cell proliferation gene sets. One (2%) patient achieved a partial response; eight (15%) patients achieved stable disease, which lasted longer than 6 months in two patients.

Conclusions: FHD-609 showed dose-dependent increases in systemic FHD-609 exposure and pharmacodynamic response profiles. The maximum tolerated doses were identified (40 mg twice weekly/80 mg once weekly) and preliminary clinical activity was observed. Future studies of BRD9 degraders will require strict cardiac monitoring given the QTc prolongation observed in this study.

Purpose: Even though smoking is associated with lung cancer, the exact molecular pathways that link carcinogens with inflammation and oncogenic transformation are not well elucidated. Two major carcinogens in cigarette smoke, nicotine-derived nitrosamine ketone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and benzo(α)pyrene (BaP), have not been tested in models that mimic inhaled exposure for prolonged periods of time.

Experimental design: Mouse models were used for intratracheal delivery of NNK and BaP (NB) for 18 months. Tissue microarrays from human lung cancers were evaluated for IL-1 receptor-associated kinase-4 (IRAK4) expression. Functional effects of IRAK4 inhibition were evaluated in cell lines and xenografts.

Results: Smoking-associated carcinogen-treated mice developed epithelial dysplasia followed by lung cancers at increased rates relative to controls. Histology revealed myeloid inflammation in murine lung tissues. Lung macrophages showed elevated levels of proinflammatory IL-1β when exposed to cigarette smoking condensate. A key downstream mediator of IL-1β signaling, IRAK4, was overexpressed in murine lung tissues exposed to carcinogens. The majority of human lung cancer samples also exhibited overactivated IRAK4 expression. IRAK4 localized in microtubules in lung cancer cell lines. Using mass spectrometry on isolated microtubules, we observed that IRAK4 inhibition was associated with decreased phosphorylation of tubular motility proteins, including myosin heavy-chain 9. Inhibition of IRAK4 resulted in decreased invasion in lung cancer cell lines and reduced growth of lung cancer xenografts.

Conclusions: These data demonstrate that smoking-associated carcinogens can be linked to oncogenic transformation via inflammatory IRAK4 activation.

Purpose: There is overwhelming interest to use actinium-225 ([225Ac]Ac) to develop targeted α therapies. Antibody-drug conjugates (ADC) are highly cytotoxic. Combining [225Ac]Ac with an ADC to develop an antibody-drug radioconjugate [225Ac]Ac-macropa-trastuzumab(T)-PEG6-emtansine (DM1), is expected to be more effective than its ADC (T-PEG6-DM1) against breast cancer.

Experimental design: [89Zr]Zr-p-isothiocyanatobenzyl desferrioxamine (DFO)-T-PEG6-DM1 (imaging) and [225Ac]Ac-macropa-T-PEG6-DM1 (radiotherapy) were developed. Biodistribution and safety evaluations of [225Ac]Ac-macropa-T-PEG6-DM1 were carried out in non-tumor-bearing BALB/c mice. MicroPET imaging and biodistribution were done using [89Zr]Zr-DFO-T-PEG6-DM1, and radiotherapy using [225Ac]Ac-macropa-T-PEG6-DM1 was carried out in athymic BALB/c nude mice bearing trastuzumab-resistant HCC1954 and trastuzumab-DM1 (T-DM1)/trastuzumab-resistant JIMT-1 tumor-bearing mice.

Results: After 7 days of incubation at 37°C, [225Ac]Ac-macropa-T-PEG6-DM1 was stable in both human serum (89.2% ± 0.9%) and PBS (82.8% ± 0.4%). T-PEG6-DM1 (8 mg/kg) and [225Ac]Ac-macropa-T-PEG6-DM1 (3 × 18 kBq) administered separately in non-tumor-bearing mice 10 days apart were well tolerated biochemically and hematologically. Imaging and biodistribution showed high tumor uptake of [89Zr]Zr-DFO-T-PEG6-DM1 in tumor-bearing mice at 120 hours after injection: 38.1% ± 2.8% IA/g (HCC1954) and 14.6% ± 1% IA/g (JIMT-1). In HCC1954 tumor-bearing mice, all treatment groups had complete remission (8/8), indicative of the responsiveness of the xenograft to T-DM1-based treatments, whereas for JIMT-1 xenografts (having 1/8 complete remission) at 23 days after treatment, tumor volumes were 332.1 ± 77.5 vs. 244.6 ± 63 vs. 417.9 ± 62.1 vs. 102.4 ± 18.5 for the saline (negative control), T-DM1 (positive control), T-PEG6-DM1, and [225Ac]Ac-macropa-T-PEG6-DM1, respectively.

Conclusions: [225Ac]Ac-macropa-T-PEG6-DM1 is more potent than ADC against trastuzumab-resistant breast cancer and necessitates clinical translation.

Purpose: The purpose of this study was to establish HMGA2 as a marker of basal-like disease in pancreatic ductal adenocarcinoma (PDAC) and explore its use as a biomarker for prognosis and treatment resistance.

Experimental design: We identified high-mobility group A2 (HMGA2) protein expression in basal PDAC cells in a single-cell RNA sequencing (RNA-seq) atlas of 172 patient samples. We then analyzed HMGA2 expression, along with expression of the classic marker GATA-binding factor 6 (GATA6), in a cohort of 580 PDAC samples with multiplex IHC. We further supplemented these data with an additional 30 diverse patient samples and multiple independent single-cell RNA-seq databases.

Results: We found that expression of HMGA2, but not previously described basal markers cytokeratins 5 or 17, predicted overall survival in our cohort. Combining HMGA2 and GATA6 statuses allowed for the identification of two key study groups: an HMGA2+/GATA6- cohort with worse survival, low tumor-infiltrating CD8+ T cells, increased FAP+ fibroblasts, and poorer response to gemcitabine-based chemotherapies (n = 94, median survival = 11.2 months after surgery) and an HMGA2-/GATA6+ cohort with improved survival, increased CD8+ T-cell infiltrate, decreased FAP+ fibroblasts, and improved survival with gemcitabine-based chemotherapy (n = 198, median survival = 21.7 months after surgery). HMGA2 was also prognostic for overall survival in RNA-seq from an independent cohort.

Conclusions: IHC stratification of primary tumors by HMGA2 and GATA6 statuses in pancreatic cancer is associated with differential outcomes, survival following chemotherapy, and tumor microenvironments. As a nuclear marker for basal disease, HMGA2 complements GATA6 to identify disease subtypes in PDAC.

Purpose: Human papillomavirus (HPV) is a significant cause of cervical cancer. We hypothesized that detecting viral cell-free HPV DNA (cfDNA) before, during, and after chemoradiation (chemoRT) could provide insights into disease extent, clinical staging, and treatment response.

Experimental design: A total of 66 patients with locally advanced cervical cancer were enrolled between 2017 and 2023, with 49 receiving standard-of-care treatment and 17 participating in a clinical trial combining a therapeutic HPV vaccine (PDS0101; IMMUNOCERV). Plasma was collected at baseline, weeks 1, 3, and 5 of chemoRT, and 3 to 4 months after chemoRT. HPV cfDNA was quantified using droplet digital PCR targeting the HPV E6/E7 oncogenes of 13 high-risk types. MRI was performed at baseline and before brachytherapy.

Results: The median follow-up was 23 months, with recurrence-free survival (RFS) of 78.4% at 2 years. Baseline nodal disease extent correlated with HPV cfDNA levels. HPV cfDNA levels peaked in week 1 of radiation and decreased through treatment. Patients receiving the PDS0101 vaccine had a higher rate of undetectable HPV type 16 cfDNA compared with those who received standard-of-care therapy. HPV cfDNA clearance correlated with better 2-year RFS (92.9% vs. 30%, log-rank; P = 0.0067). The strongest predictor of RFS was HPV cfDNA clearance in follow-up achieving a concordance index score of 0.83, which improved when combined with MRI response (concordance index, 0.88).

Conclusions: HPV cfDNA levels change dynamically during chemoRT. HPV cfDNA levels at follow-up predict RFS, and delivery of therapeutic HPV vaccine with chemoRT was linked to rapid HPV cfDNA decline. Monitoring HPV cfDNA during and after chemoRT may guide tailoring of personalized treatment.

Purpose: To characterize factors associated with response to immune checkpoint inhibitors (ICI) in advanced sarcoma.

Experimental design: This is a retrospective study with a cohort of 216 patients with advanced sarcoma treated with ICI between 2016 and 2023 at Stanford Health Care. Overall survival, progression-free survival (PFS), objective response rates (ORR) per RECIST criteria, and reason for ICI discontinuation were analyzed across histologic subtypes, ICI regimens, tumor mutational burden, and PD-L1 expression.

Results: The overall ORR in the cohort was 16.7%. The histologic subtypes with the highest ORR were Kaposi sarcoma (KS, 66.7%), alveolar soft part sarcoma (ASPS, 50%), angiosarcoma (33.3%), myxofibrosarcoma (MFS, 28.6%), and undifferentiated pleomorphic sarcoma (UPS, 27.8%). The subtypes with the lowest ORR were osteosarcoma (0%), synovial sarcoma (0%), and liposarcoma (3.7%). The subtypes with the highest median PFS were KS (median not reached), ASPS (median not reached), MFS (27.4 months), and UPS (11.3 months). The ORR for sarcomas with PD-L1 ≥ 1% was 27.8% (P = 0.02), whereas the ORR for sarcomas with tumor mutational burden ≥10 mutations per megabase of DNA was 28.6% (P = 0.20).

Conclusions: ORR and PFS were highly variable across sarcoma histologic subtypes. In this large analysis, KS, ASPS, angiosarcoma, MFS, and UPS demonstrated the highest ORR and longest PFS while osteosarcoma, synovial sarcoma, and liposarcoma had the lowest ORR and shortest PFS. PD-L1 expression was also associated with increased ORR. Our findings provide further insight into understanding the sarcoma histologic and immunologic factors that correspond with response to ICI.