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Background: Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to efficiently treat desmoid tumor. However, molecular mechanism of why imatinib works remains poorly understood. Here, we describe the potential roles of NOTCH2 and HES1 in association with clinical response to imatinib as in genome and transcriptome levels. Methods: We identified all somatic mutations in coding and non-coding regions via whole genome sequencing using desmoid tumor samples. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale Whole-genome sequencing (WGS) and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response. Results: Among 20 patients, 4 (20%) had a partial response and 14 (66.7%) had stable disease, 11 of which continued for ≥1 year. With gene-wise functional analyses, we detected significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on PCAWG data analyses, NOTCH2 mutations affect its expression levels particularly in the presence of CTNNB1 missense mutations. By analyzing RNA-sequencing with additional desmoid tumor samples, we found that NOTCH2 expression was significantly correlated with HES1 expression. Interestingly, NOTCH2 had no statistical power to discriminate responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders Conclusions: Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, which provides an important therapeutic consideration for desmoid tumor. Trial Registration: ClinicalTrials.gov, NCT02495519, Registered July 13, 2015- Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT02495519

Supplementary Figure from Phase II Clinical Trial of Eribulin–Gemcitabine Combination Therapy in Previously Treated Patients With Advanced Liposarcoma or Leiomyosarcoma

Purpose:Monotherapy with eribulin or gemcitabine has been found to be moderately effective in treating soft-tissue sarcomas (STS). In this study, we evaluated the efficacy and safety of eribulin–gemcitabine combination therapy for the two most common histologic types of STS, liposarcoma and leiomyosarcoma.Patients and Methods:In this nonrandomized, multicenter, phase II study, we included patients with progressive disease who had received one or two courses of chemotherapy that included doxorubicin. Patients were administered 1.4 mg/m2 eribulin and 1,000 mg/m2 gemcitabine on days 1 and 8 every 3 weeks. The primary endpoint was progression-free survival rate at 12 weeks (PFSR12wks), with null and alternative hypotheses of PFSR12wks ≤20.0% and ≥40.0%, respectively. Exploratory biomarker analyses with next-generation sequencing (NGS) were performed on pretreatment tumor samples.Results:Among the 37 patients included, the overall PFSR12wks was 73.0%, achieving the primary endpoint. The objective response rate, disease control rate, median progression-free survival, and median overall survival were 16.2%, 78.4%, 5.6 months, and 31.9 months, respectively, without differences according to histologic type. New safety signals and treatment-related deaths were not documented. NGS-based transcriptome analysis revealed that functional enrichment in the TGFβ pathway was mostly associated with a poor outcome, whereas single genetic alterations largely failed to predict treatment outcome.Conclusions:Eribulin–gemcitabine combination therapy showed promising activity and an acceptable safety profile in patients with liposarcoma or leiomyosarcoma. Gene expression profiling with pathway enrichment analysis would have possibilities to have predictive value for survival outcome, necessitating further investigation to confirm.

Supplementary Data from Phase II Clinical Trial of Eribulin–Gemcitabine Combination Therapy in Previously Treated Patients With Advanced Liposarcoma or Leiomyosarcoma

(1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of life and prolong survival. (2) Method: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. Then, we performed targeted sequencing and whole RNA sequencing. To compare the data with other cancer types, we used NGS data from sarcoma patients at Yonsei Cancer Center (YCC-sarcoma cohort, n = 48) and The Cancer Genome Atlas (TCGA, n = 9235). Secondly, we established the novel patient-derived preclinical models (n = 2) for the validation of treatment strategy. The same gene alteration of primary tissue was demonstrated. (3) Results: We discovered specific gene sets related to the TGF-β signaling pathway. Moreover, we selected the combination treatment comprising TGF-β inhibitor, vactosertib, and imatinib. In screening for the anti-proliferation effect, the combination treatment of TGF-β inhibitor was more effective for tumor suppression than monotherapy. (4) Conclusion: We found preclinical indications that TGF-β inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials.

Purpose Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy.Materials and Methods We obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, programmed death-ligand 1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA.Results Of the 35 patients receiving pazopanib-based treatment, nine achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs. 7.9 months, p=2.09×10–4) and a poorer response (ORR; 0% vs. 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, seven of the 17 patients (41.2%) achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising natural killer cells, compared to non-responders as well as increased expression of CD19, a B-cell marker.Conclusion Despite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies.

We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in soft tissue sarcoma (STS). Further, we performed molecular characterisation with whole exome and transcriptomic sequencing to identify the determinants of response. In this single-arm, phase 2 trial (NCT#03798106), we enrolled patients with metastatic and/or recurrent STS who had received up to two previous lines of systemic anticancer therapy and had at least one measurable lesion. Treatment consisted of pazopanib 800 mg orally, administered once a day, continuously, and durvalumab 1500 mg administered via intravenous infusion once every 3 weeks. The primary endpoint was the overall response rate. Between September 2019 and October 2020, fourteen (30.5%) of the 46 evaluable patients showed an objective response, including in alveolar soft-part sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, and desmoplastic small round cell tumour. During a median follow-up period of 18.4 months, the median progression-free survival (PFS) was 7.7 months (95% confidence interval: 5.7-10.4). The common treatment-related adverse events of grades 3-4 included neutropenia (n = 9), elevated aspartate aminotransferase (n = 7) and alanine aminotransferase (n = 5) levels, and thrombocytopenia (n = 4). In the exploratory analysis, the B lineage signature was a significant key determinant of overall response (P=0.014). In situ analysis also showed that tumours with high CD20+ B cell infiltration and vessel density had a longer PFS than those with low B cell infiltration and vessel density (P=6.5 × 10−4) as well as better response (50% vs 12%, P=0.019). In conclusion, durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile. Our findings provide insights into combined high B cell infiltration and vessel density as potentially relevant biomarkers for the selection of patients who may benefit to a greater extent from PD-L1 blockade and VEGF inhibitor combination. Citation Format: Hee Jin Cho, Kum-Hee Yun, Su-Jin Shin, Young Han Lee, Seung Hyun Kim, Wooyeol Baek, Yoon Dae Han, Sang Kyum Kim, JooHee Lee, Iksung Cho, Heounjeong Go, Jiwon Ko, Inkyung Jung, Min Kyung Jeon, Hyang Joo Ryu, Sun Young Rha, Hyo Song Kim, Hyun Jung Jun. Comprehensive molecular characterization of clinical response to durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: A phase 2 clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT038.

Purpose: Monotherapy with eribulin or gemcitabine has been found to be moderately effective in treating soft-tissue sarcomas (STS). In this study, we evaluated the efficacy and safety of eribulin–gemcitabine combination therapy for the two most common histologic types of STS, liposarcoma and leiomyosarcoma. Patients and Methods: In this nonrandomized, multicenter, phase II study, we included patients with progressive disease who had received one or two courses of chemotherapy that included doxorubicin. Patients were administered 1.4 mg/m2 eribulin and 1,000 mg/m2 gemcitabine on days 1 and 8 every 3 weeks. The primary endpoint was progression-free survival rate at 12 weeks (PFSR12wks), with null and alternative hypotheses of PFSR12wks ≤20.0% and ≥40.0%, respectively. Exploratory biomarker analyses with next-generation sequencing (NGS) were performed on pretreatment tumor samples. Results: Among the 37 patients included, the overall PFSR12wks was 73.0%, achieving the primary endpoint. The objective response rate, disease control rate, median progression-free survival, and median overall survival were 16.2%, 78.4%, 5.6 months, and 31.9 months, respectively, without differences according to histologic type. New safety signals and treatment-related deaths were not documented. NGS-based transcriptome analysis revealed that functional enrichment in the TGFβ pathway was mostly associated with a poor outcome, whereas single genetic alterations largely failed to predict treatment outcome. Conclusions: Eribulin–gemcitabine combination therapy showed promising activity and an acceptable safety profile in patients with liposarcoma or leiomyosarcoma. Gene expression profiling with pathway enrichment analysis would have possibilities to have predictive value for survival outcome, necessitating further investigation to confirm.

Background: Inhibitors of programmed death-ligand 1 (PD-L1) have potential therapeutic value in gastric cancer. We investigated PD-L1 expression patterns in paired biopsy and resection specimens. Patients and Methods: Thirty-nine formalin-fixed, paraffin-embedded paired samples were assessed using PD-L1 22C3 pharmDx immunohistochemistry technique. Combined positive score (CPS) was calculated as the ratio of PD-L1 stained cells (tumor cells, lymphocytes, and macrophages) to the total number of viable tumor cells, multiplied by 100. The CPS ≥1 indicated PD-L1 positivity. Results: PD-L1 positivity was evident for 33 (84.6%) of 39 resection cases; all displayed low positivity (1≤CPS

Background: Developing personalized strategies for cancer has shown good efficacies. Methods: We assessed the molecular targets programmed death ligand 1 (PD-L1), microsatellite instability (MSI), and PIK3CA. Seventy-four patients with liposarcomas who underwent curative resection were assessed for PD-L1 expression in the tumor and tumor-infiltrating lymphocytes (TILs), mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry, MSI using polymerase chain reaction, and PIK3CA mutation/amplification using pyrosequencing and fluorescence in situ hybridization. Results: Seventeen (23%) cases were TIL+ (≥1 + expression) and associated with longer 5-year overall survival than those with TIL– tumors (84.4 vs. 60.8%, p = 0.007). Six (35.3%) PD-L1+ tumors were detected only in TIL+ cases, with none detected in tumor cells. Two well-differentiated liposarcomas showed MSI, one low and one high with concurrent loss of MLH1, MSH6, and PMS2. PIK3CA mutation was detected in 7 (9.5%) [exon 9 (n = 4) and exon 20 (n = 3)] and only 1 Q546K mutation was a PD-L1+ tumor. PIK3CA copy number gain was detected in 18 (24.4%) and was associated with TIL+ tumors (p = 0.045). Conclusions: Our comprehensive immuno-molecular panel suggests that liposarcoma should be categorized based on the molecular genomic subtype for precision medicine.

Introduction: Desmoid tumor is a rare aggressive tumor where there is no satisfying systemic treatment. Previous studies showed increased expression of transforming growth factor-β (TGF-β) in the desmoid tumor. Here, we analyzed genomic and transcriptomic data of tumor samples from patients with desmoid tumor to evaluate therapeutic applicability of inhibition of TGF-β response. Methods: We collected pre-treatment desmoid tumor samples from 31 patients in Yonsei cancer center, (YCC)-desmoid cohort and performed targeted next-generation sequencing and whole RNA sequencing. To compare the data with other cancer types, we used whole exome sequencing and whole RNA sequencing data from sarcoma patients from Yonsei Cancer Center (YCC-sarcoma cohort, n = 17 and n =53, respectively) and The Cancer Genome Atlas (TCGA, n = 9,235). Transcriptomic data was normalized throughout the three cohorts to reduce batch effect. To evaluate the enrichment of TGF-β responsive signature (TBRS) in tumor and microenvironment, we calculated the mean expression values of fibroblast-TBRS (F-TBRS) from previous study. Results: In the two sarcoma cohorts (YCC-desmoid and YCC-sarcoma cohorts), desmoid tumor samples had the highest F-TBRS score among the various types of sarcoma. When compared with other cancer types in TCGA, desmoid tumor samples showed the higher F-TBRS than all other cancer types except for pancreatic adenocarcinoma. In the desmoid tumor samples, CTNNB1, GNAQ, and APC mutations were the top 3 frequent mutations (23, 19, and 2 samples, respectively). In the merged two sarcoma cohorts, CTNNB1/APC mutation and GNAQ mutation were both associated with higher enrichment in F-TBRS (p < 0.001, respectively). Conclusion: Desmoid tumors are enriched with expression of genes associated with TGF-β response of fibroblast compared with other cancer types including other sarcomas. In addition, CTNNB1, APC and GNAQ mutations were associated with higher enrichment in TBRS. Therapeutic intervention to decrease the TGF-β response of fibroblast by using TGF-β receptor inhibitor may show clinical benefit in patients with desmoid tumors. Citation Format: Changhee Park, Kum-Hee Yun, Sanghoon Song, Jin Kyung Lee, Jiyeon Ryu, Bitna Oh, Sunjin Hwang, Ki Baik Hahm, Seung-Jin Kim, Seung Hyun Kim, Chan-Young Ock, Hyo-Song Kim. Genomic and transcriptomic analyses of desmoid tumor reveals enrichment of transforming growth factor beta responsive signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2250.

11551 Background: Based on the central role played by the vascular endothelial growth factor receptor (VEGFR) in immunosuppression, we assessed the activity and safety of VEGFR inhibitor pazopanib plus anti-PD-L1 blockade durvalumab in soft tissue sarcoma (STS). Methods: We did a single-arm, single-center, phase 2 study that enrolled patients with metastatic or locally advanced STS aged 19 years or older, ECOG PS 0-1, with at least one measurable lesion, and received at least one previous line of systemic therapy. Patient were given pazopanib 800 mg orally daily and durvalumab 1500 mg intravenously for 60 min every 3 weeks. The primary endpoint was investigator-assessed objective response. Results: Between September 2019 and October 2020, 47 participants were enrolled, of whom 46 (97.9%) were evaluable for the efficacy analyses. With a median follow up of 12.3 months, complete and partial response (PR) was achieved in 1 (2.2%) and 12 (26.1%) patients, resulting in 28.3 % of objective response rate. Median time to achieve PR was 1.4 months and median duration of response was 11.0 months. The most common treatment-related adverse events of any grade include fatigue (20 [42.6%]), anorexia (17 [36.2%]), diarrhea (17 [36.2%]), and AST elevation (16, [34.0%]). Thirty-one patients (67.3%) had progressive disease, and the median progression free survival was 8.6 months (95% CI 3.6-13.6). Conclusions: Durvalumab and pazopanib showed encouraging activity in patients with advanced STS. Molecular predictors with whole exome and RNA sequencing will be presented. Clinical trial information: NCT03798106.

Radiotherapy (RT), along with surgery and chemotherapy, is a major modality of cancer therapy. Nevertheless, insufficient deposition of radiation energy in tumors and hypoxia-associated radioresistance remain the greatest challenges in RT. Here, we propose porous platinum nanoparticles as a new nanomedicine platform for solving these two problems at the same time using a single agent. Because of the combined advantages of a high-Z element and oxygen generation capability, porous platinum nanoparticles can significantly increase radiation-induced DNA damage, ROS stress, and cell cycle arrest by effectively depositing X-ray radiation energy within the cancer cells. Further, porous platinum nanoparticles increase tumor oxygenation by converting endogenic H2O2 to O2, thus greatly enhancing RT with no apparent in vivo toxicity to animals. This study presents a new nanomedicine strategy based on the use of porous high-Z metal nanoparticles with oxygen generation function for the synergistic enhancement of RT in cancer treatment.

Korea Institute of Ceramic Engineering & TechnologyReceived July 15, 2013, Accepted July 23, 2013Irradiation of gold nanorods (GNRs) with laser light corresponding to the longitudinal surface plasmonoscillation results in rapid conversion of electromagnetic energy into heat, a phenomenon commonly known asthe photothermal effect of GNRs. Herein, we propose a facile strategy for increasing the photothermalconversion efficiency of GNRs by integration to form graphene oxide (GO) nanocomposites. Moreover,conjugation of iron oxide (IO) with the GO-GNR nanohybrid allowed magnetic enrichment at a specific targetsite and the separated GO-IO-GNR assembly was rapidly heated by laser irradiation. The present GO-IO-GNRnanocomposites hold great promise for application in various biomedical fields, including surface enhancedRaman spectroscopy imaging, photoacoustic tomography imaging, magnetic resonance imaging, andphotothermal cancer therapy.Key Words : Photothermal effect, Longitudinal plasmon resonance, Gold nanorods, Iron oxide, Graphene oxideIntroductionThe recent rapid evolution of nanoscience and nano-technology has propelled the development of various multi-functional solid nanoparticles with unique chemical andphysical properties for biomedical applications as multi-modal molecular imaging probes and therapeutic agents.

We report on a one-step progressive modification of imprinted nanopatterns for the induction of a structural and physicochemical gradient in a single chip with the use of gradually attenuated oxygen plasma. Imprinted line patterns could be easily tapered off to up to 60% of their original line width, which was found to be dependent upon the rate of plasma attenuation. Gradually modified nanopatterns are believed to have a continuous variation of physicochemical properties along the pattern gradient, which in this study was exemplified in contact angle variation, which was observed to be more than a factor of about 5 in 2 cm separation on a sample surface. It was also demonstrated for modified patterns used as replica molds for pattern reversal in consecutive processes. Furthermore, it was also proven that this gradual modification method is applicable to various imprint patterns of different structures and resist materials.