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Background: HER2-targeted therapies combined with chemotherapy have improved survival outcomes for patients with metastatic HER2-positive breast cancer. However, for patients progressed after several lines of anti-HER2 combinational therapies, the overall survival (OS) remained unfavorable. Prior studies showed that immunotherapy in combination with chemotherapy or targeted therapy could significantly prolong OS of metastatic breast cancer patients, especially in patients with triple-negative breast cancer. Reports of immunotherapy combined with HER2-targeted therapy are still limited. Here we reported the preliminary results from an ongoing phase II trial assessing the safety and efficacy for KN046 (a bispecific antibody blocks both PD-L1 interaction with PD-1/CD80 and CTLA-4 interaction with CD80/CD86) in combination with KN026 (a bispecific antibody that binds to two different HER2 epitopes shared by trastuzumab and pertuzumab) in HER2-positive metastatic breast cancer patients, who have progressed after prior anti-HER2 combinational therapies.Methods: Female patients with metastatic HER2-positive breast cancer who were previously treated with at least one line of HER2-targeted combinational therapy were enrolled from multiple academic hospitals in China to receive KN046 (iv. 5 mg/kg Q3W) plus KN026 (iv. 30 mg/kg Q3W) until progression, unacceptable toxicities or patient withdrawal. Efficacy was evaluated Q6W per RECIST 1.1. The primary endpoint was objective response rate (ORR). Results: As of the June 20th, 2021, 36 patients with the median age of 53 years (range: 33-67) were enrolled. 30 of 36 patients (83.3%) received ≥3 lines of HER2-targeted combinational therapies in the metastatic setting. 22 patients were evaluable for overall response and all 36 for safety. The ORR was 50.0% (11 of 22, 95% CI: 28.2-71.8), and one patient achieved complete response (CR). And the disease control rate (DCR) was 81.8% (18 of 22, 95% CI 59.7-94.8). The median progression-free survival (PFS) was 5.6 (95%CI 2.5-not reached) months. 34 of 36 (94.4%) patients had treatment-related adverse events (TRAEs) of any grade, while 4 of 36 (11.1%) patients had experienced ≥grade 3 TRAEs. The most common (≥10%) TEAEs were infusion related reaction (36.1%), rash (16.7%), alanine aminotransferase increased (13.9%), diarrhea (13.9%), pruritus (13.9%), aspartate aminotransferase increased (11.1%), and hypokalemia (11.1%). No treatment-related deaths were observed.Conclusions: The combination of KN046 and KN026, as a chemo free regimen, has shown favorable clinical efficacy with manageable side effects in heavily pre-treated patients with metastatic HER2-positive breast cancer. This trial is currently ongoing. ClinicalTrials.gov number, NCT04521179. Citation Format: Jieqiong Liu, Chuangui Song, Xiangcai Wang, Mingli Ni, Xujuan Wang, Lei Chen, Hongwei Yang, Rusen Zhao, Ting Xu, Lin Shen. Preliminary safety and efficacy results of KN046 (an anti-PD-L1/CTLA-4 bispecific antibody) in combination with KN026 (a HER2-targeted bispecific antibody) in patients with metastatic HER2-positive breast cancer: A phase II trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-04.

Background & aims Hepatocellular carcinoma (HCC) is one of the main types of primary liver cancer with high morbidity and mortality, and poor treatment effect. Tripartite motif-containing protein 11 (TRIM11) has been shown to promote tumor formation in lung cancer, breast cancer, gastric cancer, and so on. However, the specific function and mechanism of TRIM11 in HCC have not been elucidated. Approach & results Through clinical analysis, we found that the expression of TRIM11 was upregulated in HCC tissues and was associated with high tumor node metastasis (TNM) stages, advanced histological grade and poor patient survival. Then, by gain- and loss-of-function investigations, we demonstrated that TRIM11 promoted cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, RNA sequencing and mass spectrometry analysis showed that TRIM11 interacted with PH domain leucine rich repeats protein phosphatase 1 (PHLPP1) and promoted K48-linked ubiquitination degradation of PHLPP1, thus promoted activation of protein kinase B (AKT) signaling pathway. Moreover, overexpression of PHLPP1 blocked the promotional effect of TRIM11 on HCC function. Conclusions Our study confirmed that TRIM11 plays an oncogenic role in hepatocellular carcinoma through the PHLPP1/AKT signaling pathway, suggesting that targeting TRIM11 may be a promising target for the treatment of hepatocellular carcinoma.

Glioma is one of the most common and deadly malignant brain tumors originating from glial cells. For personalized treatment, an accurate preoperative prognosis for glioma patients is highly desired. Recently, various machine learning-based approaches have been developed to predict the prognosis based on preoperative magnetic resonance imaging (MRI) radiomics, which extract quantitative features from radiographic images. However, major challenges remain for methodologic developments to optimize feature extraction and provide rapid information flow in clinical settings. This study investigates two machine learning-based prognosis prediction tasks using radiomic features extracted from preoperative multimodal MRI brain data: (i) prediction of tumor grade (higher-grade vs. lower-grade gliomas) from preoperative MRI scans and (ii) prediction of patient overall survival (OS) in higher-grade gliomas ( 12 months) from preoperative MRI scans. Specifically, these two tasks utilize the conventional machine learning-based models built with various classifiers. Moreover, feature selection methods are applied to increase model performance and decrease computational costs. In the experiments, models are evaluated in terms of their predictive performance and stability using a bootstrap approach. Experimental results show that classifier choice and feature selection technique plays a significant role in model performance and stability for both tasks; a variability analysis indicates that classification method choice is the most dominant source of performance variation for both tasks.

To overcome the limitations of conventional breast screening methods based on digital mammography, a quasi-3D imaging technique, digital breast tomosynthesis (DBT) has been developed in the field of breast cancer screening in recent years. In this work, a computer-aided architecture for mass regions segmentation in DBT images using a dilated deep convolutional neural network (DCNN) is developed. First, to improve the low contrast of breast tumour candidate regions and depress the background tissue noise in the DBT image effectively, the constraint matrix is established after top-hat transformation and multiplied with the DBT image. Second, input image patches are generated, and the data augmentation technique is performed to create the training data set for training a dilated DCNN architecture. Then the mass regions in DBT images are preliminarily segmented; each pixel is divided into two different kinds of labels. Finally, the postprocessing procedure removes all false-positives regions with less than 50 voxels. The final segmentation results are obtained by smoothing the boundaries of the mass regions with a median filter. The testing accuracy (ACC), sensitivity (SEN), and the area under the receiver operating curve (AUC) are adopted as the evaluation metrics, and the ACC, SEN, as well as AUC are 86.3%, 85.6%, and 0.852 for segmenting the mass regions in DBT images on the entire data set, respectively. The experimental results indicate that our proposed approach achieves promising results compared with other classical CAD-based frameworks.

Intracranial aneurysms are local dilations of the cerebral blood vessels; people with intracranial aneurysms have a high risk to cause bleeding in the brain, which is related to high mortality and morbidity rates. Accurate detection and segmentation of intracranial aneurysms from Magnetic Resonance Angiography (MRA) images are essential in the clinical routine. Manual annotations used to assess the intracranial aneurysms on MRA images are substantial interobserver variability for both aneurysm detection and assessment of aneurysm size and growth. Many prior automated segmentation works have focused their efforts on tackling the problem, but there is still room for performance improvement due to the significant variability of lesions in the location, size, structure, and morphological appearance. To address these challenges, we propose a novel One-Two-One Fully Convolutional Networks (OTO-Net) for intracranial aneurysms automated segmentation in MRA images. The OTO-Net uses full convolution to achieve intracranial aneurysms automated segmentation through the combination of downsampling, upsampling, and skip connection. In addition, loss ensemble is used as the objective function to steadily improve the backpropagation efficiency of the network structure during the training process. We evaluated the proposed OTO-Net on one public benchmark dataset and one private dataset. Our proposed model can achieve the automated segmentation accuracy with 98.37% and 97.86%, average surface distances with 1.081 and 0.753, dice similarity coefficients with 0.9721 and 0.9813, and Hausdorff distance with 0.578 and 0.642 on these two datasets, respectively.

Except breast cancer and gastric cancer, HER2 gene amplification or overexpression is also expressed in other solid tumors, including but not limited to colorectal cancer (CRC), non-small cell lung cancer (NSCLC), gallbladder cancer, renal pelvis cancer and pancreatic cancer. The reports of immunotherapy combined with HER2-targeted therapy are limited. KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD-1 and CTLA4 interaction with CD80/CD86. KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. Here the preliminary safety and efficacy results of KN046 in combination KN026 were reported in patients with locally advanced unresectable or metastatic other solid tumors who received ≥ 1 line prior systemic therapy. Methods: HER2-positive locally advanced unresectable or metastatic other solid tumors with progression after ≥ 1 line of prior systemic therapy were recruited, including 14 CRC patients, 4 NSCLC patients, 4 gallbladder cancer patients, 1 renal pelvis cancer patient and 1 pancreatic cancer patient. These patients were by KN046 (iv. 5 mg/kg Q3W) plus KN026 (iv. 30 mg/kg Q3W, loading on C1D1, D8) until progression, unacceptable toxicity, or patient withdrawal. Efficacy was assessed according to RECIST 1.1 Q6W. The primary endpoint was objective response rate (ORR). Results: As of the August 10th, 2021, 24 non-breast or non-gastric cancer patients with the median age of 56 years (range: 37-66) were enrolled. 20 and 24 patients were evaluable for overall response and safety, respectively. The ORR was 55.0% (11 of 20, 95% CI: 31.5-76.9). And the disease control rate (DCR) was 85.0% (17 of 20, 95% CI 62.1-96.8). The 6-month progression-free survival (PFS) rate was 84.1%. 11 CRC patients were evaluable for overall response. The ORR and DCR in CRC was 45.5% (5 of 11, 95% CI: 16.7-76.6) and 90.9% (10 of 11, 95% CI 58.7-99.8), respectively. Twenty of total 24(87.9%) patients suffered from treatment-related adverse events (TRAEs) of any grade. Total 4 of 24 (16.7%) patients had experienced ≥grade 3 TRAEs, including 4 cases related to KN046 and 3 cases related to KN026. The most common (≥10%) TRAEs were infusion related reaction (29.2%), diarrhea (19.4%), alanine aminotransferase increased (16.7%), aspartate aminotransferase increased (16.7%), vomiting(12.5%) and decreased appetite (12.5%). No treatment-related deaths were observed. Conclusion: This chemotherapy-free regimen of KN046 in combination with KN026 has shown promising clinical efficacy and manageable toxicity in HER2-positive non-breast and non-gastric solid tumors with ≥ 1 line prior systemic therapy. The trial is currently ongoing. ClinicalTrials.gov Number, NCT04521179 Citation Format: Jifang Gong, Lei Chen, Meili Sun, Yanming Zhang, Jieer Ying, Xiangcai Wang, Mingli Ni, Zhixiang Zhuang, Baohong Guo, Long Xiao, Summer Xia, Lin Shen. Preliminary safety and efficacy results of KN046 in combination with KN026 in patients with locally advanced unresectable or metastatic HER2-positive solid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT542.

2526 Background: This phase III study compared clinical efficacy, safety of the first biosimilar QL1206 with denosumab in solid tumor patients with bone metastases. Methods: Patients aged 18-80 years, with bone metastatic solid tumors and ECOG performance status of 0-2 were randomly assigned 1:1 to receive subcutaneous QL1206 or denosumab (120 mg Q4W, both) based on stratification factors (tumor types, previous skeletal-related event [SRE], and current systemic anti-tumor therapy). The primary efficacy endpoint was the percentage changes from baseline to week 13 in urinary N-telopeptide/creatinine ratio (uNTX/uCr); Clinical equivalence would be confirmed if the two-sided 90% confidence intervals (CI) of the least-squares mean (LSM) difference of natural log-transformed ratio of week 13 uNTX/uCr to baseline calculated by analysis of covariance were within the margins of ±0.135. The secondary endpoints included the percentage changes from baseline to week 25 and 53 in uNTX/uCr, the percentage changes from baseline to week 13, 25 and 53 in serum bone-specific alkaline phosphatase (s-BALP) and the time to on-study SRE. Adverse events (AE), immunogenicity (IG) and pharmacokinetics (PK) were also assessed. Population PK was analyzed using nonlinear mixed effects model. Results: 717 patients were randomized to the QL1206 (n = 357) and denosumab (n = 360) groups, respectively. The median percentage changes at week 13 in uNTX/uCr were -75.2% for QL1206 and -75.8% for denosumab. LSM of natural log-transformed ratio of week 13 uNTX/uCr to baseline were -1.429 (standard error 0.130) and -1.441 (0.130) in the two groups. The LSM difference between the two groups was 0.012 (90% CI -0.078 to 0.103; P = 0.8208), within the equivalence margins. Analyses for subgroups of sex, age, and randomization strata showed almost no significant differences. The secondary endpoints were also similar between the two groups (median percentage changes in s-BALP from baseline to week 13: -38.0% vs -37.1%; hazard ratio of time to SRE: 1.264 [95% CI 0.670 to 2.383]; both P > 0.05). In the safety set, treatment-emergent AE occurred in 332 of 356 patients (93.3%) in the QL1206 group and 348 of 361 (96.4%) in the denosumab group. The proportions of positive anti-drug antibody (14/345 [4.1%] vs 16/352 [4.5%]), neutralizing antibody (three [0.9%], each), and PK characteristics were similar between the two groups. Conclusions: The results suggest that QL1206, the first biosimilar denosumab, is similar to denosumab with respect to clinical efficacy, acceptable safety, IG, and PK characteristics. The totality of evidence supports clinical equivalence of QL1206 and denosumab. Clinical trial information: NCT04550949.

Colorectal cancer (CRC) is a common cancer worldwide, and its treatment strategies are limited. The underlying mechanism of CRC progression remains to be determined. Telomere maintenance 2 (TELO2) is a mTOR-interacting protein. Both the role and molecular mechanism of TELO2 in cancer progression remain unknown. In this study, the gene expression database of normal and tumor tissue, in addition to western blot analysis, and immunohistochemistry (IHC) were used to determine the expression and location of TELO2 in CRC and normal tissues. Clinical features of a tissue array were collected and analyzed. WST-1, soft agar, flow cytometry, wound healing, and invasion assays were employed to verify the role of TELO2 in the growth, cell cycle, migration, and invasion of CRC cells. The correlation between TELO2 and RICTOR (rapamycin-insensitive companion of mTOR) was analyzed by bioinformatics, IHC, and immunoprecipitation. Normal and serum-deprived cells were collected to detect the protein level of TELO2 and its downstream effectors. The results revealed that TELO2 was significantly upregulated in CRC, and TELO2 inhibition significantly restrained the growth, cell cycle, and metastasis of CRC cells. TELO2 overexpression correlated with age, lymph node metastasis, and TNM stage of CRC patients. In addition, TELO2 was positively correlated with RICTOR in CRC and induced tumor progression mainly via RICTOR with serum in culture. RICTOR induced the degradation of TELO2 upon serum deprivation in an mTOR-independent manner. These findings indicate that TELO2 promotes tumor progression via RICTOR in a serum-dependent manner, which may be a potential therapeutic target for CRC.

Cancer is a major cause of death worldwide, and its incidence and mortality continuously increase in China. Nowadays, cancer heavily influences our health and constitutes enormous burden on society and families. Although there are many tools for cancer treatment, but the overall therapeutic effect is poor. In addition, cancer cells often develop resistance to therapy due to defective cell death or immune escape mechanisms. Therefore, it is a promising way for cancer treatment to effectively activate apoptosis and conquer immunosuppression. RIG-I-like receptors (RLRs) belong to RNA-sensing pattern recognition receptors (PRRs), one of the major subsets of PRRs, and play a critical role in sensing RNA viruses and initiate host antiviral responses such as the production of type I interferons (IFNs), proinflammatory cytokines, and other immune response molecules. Recent studies have demonstrated that tumor cells could mimic viral infection to activate viral recognition of immune system and the activation of interferon response pathway. RIG-I and MDA5, two members of RLRs family, could induce growth inhibition or apoptosis of multiple types of cancer cells on the activation by RNA ligands in IFN-dependent or IFN-independent approach. Previous studies have reviewed PRRs as promising immunotherapy targets for colorectal cancer and pancreatic cancer. However, until now, a comprehensive review on the role of RLRs in the development and treatment of various cancers is still lacking. In this article, we reviewed the latest studies on the roles as well as the mechanisms of RIG-I and MDA5 in the development of various cancers and therapeutic potentials of targeting RIG-I and MDA5 for cancer treatment.

Colorectal cancer (CRC) is one of the major health threats in developed countries. Changes in dietary components, such as more protein and lipid intake, can increase the risk of CRC. Diet affects CRC in many ways. They regulate the composition and function of gut microbiota, which have an amazing metabolic capacity and can produce short chain fatty acids (SCFAs), such as propionate, acetate, and butyrate. Butyrate is a principal energy source for colonic epithelial cells and plays an important role in maintaining the stability of gut microbiota and the integrity of intestinal epithelium. However, there are few studies reviewing the anti-CRC potentials of butyrate. This review summarizes the recent research progresses in the effect of gut microbiota imbalance and the decrease in intestinal microbial metabolite butyrate caused by unbalanced diet on CRC development, and discusses the mechanisms of butyrate-induced anti-CRC activities, which may guide people to prevent CRC by improving diet structures.