bluuebunny/crossref_metadata_2025_split huggingface dataset:
D3S-001, a highly potent, selective, and differentiated covalent inhibitor of KRAS G12C: Human dose prediction and first‐in‐human (FIH) trial design.
Authors: Lu Jingtao , Zhang Jing , Zheng Zhiqiang , Chen Cheng , Wang Jia , Chen Janet , Lu Jiang , Rui Haopeng , Wang Allison , Chen Zhi Jian 
Published: June 2022

e15087 Background: Effective inhibition of G12C mutated KRAS is believed to be critical for anti-tumor efficacy in KRAS-driven cancers. D3S-001 is a potent and highly differentiated KRAS G12C inhibitor, which demonstrates rapid and near complete target inhibition and strong anti-tumor activity in preclinical cell line and animal models [Preclinical characterization of D3S-001, a highly potent, selective, and differentiated covalent inhibitor of KRAS G12C, ASCO 2022 Abstract #378099]. The current study utilizes pharmacokinetic (PK) modeling to predict the extent of KRAS G12C target inhibition at the proposed clinical dose range. Methods: Allometric scaling and non-linear fixed effect modeling were used to predict human PK profiles from DMPK data in animals. Human in vivo target inhibition was calculated based on human PK predictions, free drug fraction and results from in vitro target engagement assay. A First-in-Human (FIH) study was designed to investigate D3S-001 monotherapy in subjects with advanced solid tumors having a KRAS G12C mutation. Six dose escalation cohorts will be investigated, starting from 50mg QD. Results: Based on a GLP toxicology study in dogs, the highest non-severely toxic dose (HNSTD) was determined to be 20 mg/kg/day. Per ICH S9, a 20 mg/kg/day dose in dog supports a FIH starting dose of 110 mg. To ensure an additional safety margin, a lower starting dose of 50 mg was proposed. At 50 mg QD, the predicted human exposure (Cmax 60 nM, Caverage 49 nM, Ctrough 31 nM) is expected to achieve ̃70% target inhibition at 2 hours after dosing. In NCI-H358 mouse xenograft model, this exposure is associated with 94% tumor growth inhibition (TGI). Safety margins based on Cmax and AUC comparing to dog HNSTD are 17-fold and 9-fold, respectively. At 100 mg QD, the predicted human exposure (Cmax 120 nM, Caverage 98 nM, Ctrough 63 nM) is expected to achieve ̃95% target inhibition. This exposure is associated with tumor regression of 72% in the NCI-H358 mouse xenograft model. At dose levels higher than 100 mg QD, predicted human exposures are expected to consistently achieve >95% target inhibition starting 1 hour after dosing. These exposures are associated with deeper levels of tumor regression of 97%. Moreover, even at 400 mg QD, predicted human plasma concentrations are still below dog plasma concentration of 443 nM, Caverage at HNSTD. Conclusions: D3S-001 is predicted to achieve rapid and consistently efficacious KRAS G12C target inhibition in humans at proposed clinical dose range. This high degree of KRAS G12C inhibition over the dosing interval may translate into greater clinical benefit to patients with KRAS G12C mutations comparing with other clinical-stage KRAS G12C inhibitors. Clinical data from the FIH study will be evaluated and compared to preclinical predictions.
Selective inhibition of METTL3 enhanced anticancer activity via targeting the c-Myc pathway.
Authors: Arumugam Paramasivam , Jayaseelan Vijayashree Priyadharsini 
Published: June 2022

e15089 Background: Methyltransferase-like 3 (METTL3) is a master regulator enzyme in the N6-methyladenosine (m6A) methyltransferase system, that not only plays a crucial role in cancer but has become a promising therapeutic target for the same. This study was aimed to discover molecular mechanisms underlying the potential anticancer effects of a novel and selective METTL3 inhibitor named STM2457 against oral squamous cell carcinoma (OSCC). Methods: OSCC patient-derived organoids (PDOs) and the corresponding 2D cell lines were established from the patients who have increased expression of METTL3 and c-Myc. The pharmacological activity of STM2457 was extensively studied with organoids and primary OSCC cells. Cell proliferation, wound healing and colony formation assays were used to detect STM2457 anticancer activity in vitro. Patient-Derived tumor Xenograft (PDX) model of OSCC was used to detect STM2457 anticancer activity in vivo. m6A level of mRNA was measured by an m6A-RNA methylation quantification kit. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was used to screen the target genes of METTL3. RNA stability assay was used to detect the half-lives of METTL3 target genes. Real-time quantitative PCR was used for gene expression and western blot was used for protein expression analysis. Results: We found that STM2457 treatment exerted potential anticancer activity in PDOs and primary OSCC cells. MeRIP-seq revealed that c-Myc was the downstream gene of METTL3. Functionally, knockdown or pharmacological inhibition of METTL3 by STM2457 reduced stability and expression of c-Myc. This eventually, results in significant attenuation of migration, invasion, tumorsphere formation, and colony formation abilities of OSCC cells. Moreover, STM2457-treated OSCC cells showed reduced tumorigenic activity in vivo. Furthermore, STM2457 treatment reduced m6A level in PDOs and OSCC cells by blocking METTL3 activity thereby elucidating the importance of personalized approach for effective cancer treatment. Conclusions: Altogether, the revelation of anticancer effect of STM2457 exerted by blocking of METTL3-c-Myc signaling pathway opens novel avenues into the field of epitranscriptomics.
FAT4 mutation as a potential predictive biomarker for immunotherapy combined with anti-angiogenic therapy in MSS metastatic colorectal cancer.
Authors: Chen Mifen , Zhang Qi , Chen Hui , Wang Zhenghang , Xu Ting , QI Changsong , Chen Shiqing , Zhao Xiaochen , Bai Yuezong , Peng Zhi , Wang Xicheng , Zhang Xiaotian , Gong Jifang , Shen Lin , Li Jian 
Published: June 2022

e15504 Background: Microsatellite stable (MSS) metastatic colorectal cancer (CRC) lacks effective treatments and has a poor prognosis. The aim of this study was to identify patients who could benefit from immunotherapy combined with anti-angiogenic therapy. Exploration of predictive biomarkers could help to maximize the clinical benefits. Methods: In total, FFPE tissues samples before immunotherapy combined with anti-angiogenic therapy of 21 patients were successfully tested for tumor microenvironments (TMEs) by multiple immunofluorescence, of which 11 of them were successfully detected by 733-gene NGS panel in a CLIA-certified laboratory. The correlation between gene variations and clinical durable benefit (DCB: PR, or SD≥6 months), PFS and TMEs were analyzed by Fisher's test, K-M survival curve analysis and Mann Whitney analysis respectively. Results: Significant difference was detected between FAT4 mutation (FAT4-MUT) and FAT4 wildtype (FAT4-WT) regarding DCB (100%, 4/4 vs 17%, 1/7, P = 0.0152) and progress-free survival (median PFS, 13.8 months vs 2.8 months, LogRank P = 0.003). There was no significant difference in TMB level between DCB and NDB (SD＜6 months, or PD) groups (12 mut/Mb vs 6 mut/Mb, P = 0.0823) or between FAT4-MUT and FAT4-WT (11 mut/Mb vs 6 mut/Mb, P = 0.3697). TMEs analyses revealed that the CD3+CD4+ T cell proportion was tended to be higher in FAT4-MUT (0.7% vs 0.3%, P = 0.054). Further TIMER2.0 data showed FAT4-MUT was significantly associated with higher Immune infiltration of four immune cells, including CD4+ T cell in both colon and rectal adenocarcinoma, CD8+ central memory T cell, B cell, and Macrophage in colon adenocarcinoma. Conclusions: Our findings indicated that FAT4 mutation serves as a potential novel biomarker correlated with a better response to immunotherapy combined with anti-angiogenic therapy in MSS metastatic CRC, which may be related to the activation of CD4 T cell infiltration. However, these need to be validated by further cohort expansion.
Recurrence risk stratification model for patients with stage I-III colorectal cancer based on clinicopathological and postoperative ctDNA predictors.
Authors: Gu Jin , Lei Fuming , Wang Xiaodong , Chen Hui , Huang Wensheng , He Xiaomang , Hong Yuming , Zeng Qingmin , Wang Yanzhao , Gao Qingkun , Yuan Zheping , Niu Pengfei , Huang Dandan , Gao Zhaoya , Ding Changming , Zhai Zhichao , An Ke , Chen Shiqing , Zhao Xiaochen , Bai Yuezong 
Published: June 2022

e15511 Background: The aim of this study was to propose a new kind of recurrence risk classification and further establish a prognostic model for resected stage I-III colorectal cancer (CRC). Methods: From 2017 to 2020, 142 patients diagnosed with stage I-III CRC at Peking University Shougang Hospital were recruited for this study. Tissues and paired white blood cells were analyzed with a 733-gene NGS panel, and peripheral plasma obtained 7-10 days after surgery was analyzed with a 127-gene ultra-deep target panel in a CLIA-certified laboratory. The relationship between the postoperative ctDNA status, clinicopathological features and recurrence-free survival (RFS) was identified by log-rank test and Cox regression analysis. Results: In total, 108 patients successfully completed both tissue and postoperative plasma NGS tests, of which 17 patients were postoperatively positive for ctDNA (tumor-informed, ≥1 somatic mutation). Postoperative ctDNA positivity was independently associated with poorer RFS (HR = 8.4, P < 0.0001). Postoperative recurrence rates were significantly higher in ctDNA-positive patients than ctDNA-negative patients (76.5% vs 16.5%, P < 0.0001). Univariate analysis showed that, in addition to ctDNA status, stage, vascular invasion, neural invasion, and preoperative CEA were all significantly associated with worse RFS (P < 0.05). Furthermore, in a COX regression model, the contribution of these clinicopathological factors to RFS has been adjusted. The model showed good discrimination [the concordance index (c-index): 0.811] of recurrence. Clinically high-risk groups according to clinicopathological risk model had significantly poorer RFS than low-risk groups (HR = 10.6, P < 0.001). In the clinicopathological high-risk group, ctDNA-positive patients can still further differentiate the higher risk of recurrence (HR = 3.7, P = 0.0012). There were similar trends in the clinicopathological low-risk group (HR = 6.1, P = 0.066). Combining the clinicopathological model and ctDNA, patients with either clinicopathological high-risk or ctDNA-positive had a significantly poorer RFS, compared with both clinicopathological low-risk and ctDNA-negative (HR = 12.9, P < 0.0001). Conclusions: Postoperative ctDNA can independently predict the risk of recurrence in stage I-III CRC. Combining clinicopathological factors and ctDNA showed superiority for recurrence risk stratification over either alone. This recurrence risk stratification model may serve as a useful clinical tool to help clinicians determine individualized treatment plans for stage I-III CRC patients. However, the model still needs further external cohort validation.
Racial parity in rectal cancer treatment and outcomes within an integrated healthcare system.
Authors: Kwak Hyunjee V. , Hsu Diana S. , Chae Andrew , Douaiher Jeffrey , Chang Ching-Kuo 
Published: June 2022

e15538 Background: This study evaluates survival outcomes of rectal adenocarcinoma patients treated at a large, integrated health system and whether there are differences in survival based on race. Methods: We conducted a retrospective study of patients at Kaiser Permanente Northern California (KPNC) who were treated between 2010-2019. Self-reported racial ethnic groups included Caucasian, African American, Hispanic, Asian, and Other. Kaplan Meier and Cox regression analyses were used to evaluate differences in race, age, stage, and treatment utilization in relation to overall survival. Results: A total of 3,589 patients were diagnosed with rectal adenocarcinoma from 2010-2019. There was a significant difference between race groups in stage at the time of diagnosis (p < .001) with more African Americans having localized disease (58.4%) compared to Hispanics (45.5%). Overall survival was longest for African American at 70.9 months but shortest for Hispanic at 60.6 months (p = 0.007). Hispanic patients were more likely to be male, younger, and with nodal disease. Conclusions: This study identified racial parity in survival outcomes for rectal cancer patients who were treated at a large, integrated healthcare system where patients have equal access to care. Improvement in outreach and screening should be tailored to the ethnic groups at higher risk for earlier age and more advanced disease at presentation.
A single center phase 2 study of anti-PD-1 antibody plus bevacizumab and FOLFIRI as second-line treatment for patients with MSI-H metastatic colorectal cancer.
Authors: Li Hongli , Ning Tao , Zhang Le , Ge Shaohua , Yang Yuchong , Bai Ming , Wang Xia , Ji Zhi , Liu Rui , Deng Ting , Ba Yi 
Published: June 2022

e15541 Background: The therapeutic efficacy of second-line chemotherapy for metastatic colorectal cancer (mCRC) is low. Immunotherapy is suitable for MSI-H mCRC, but the efficacy of single-drug immunotherapy is still unsatisfactory. We investigated to combine immunotherapy with bevacizumab and FOLFIRI as second-line treatment for these patients. Methods: This single center exploratory phase 2 study enrolled adults patient with histologically confirmed metastatic colorecal adenocarcinoma, who were failure of oxaliplatin-based chemotherapy as first-line therapy. Patients receive FOLFIRI (iritecan 180mg/m2, leucovorin 400mg/m2, fluorouracil 400mg/m2 bolus, fluorouracil 2400mg/m2 46-48 hours), anti-PD-1 antibody (Nivolumab 240mg, or Pembromab 200mg, or Terriprizumab 240mg), and bevacizumab (5mg/kg). Maintenance therapy was allowed using PD-1, bevacizumab and/or fluorouracil. An-PD-1 antibody is given for up to 24 months. Results: Between November 29,2018 and January 15, 2021, a tolal of 8 patients were enrolled in our study. There were 3 femles and 5 males, and the median age was 39.5 years old. Among 8 patients who were evaluated, complete resonse (CR) was obtained in 3 cases, partial response (PR) was observed in 3 cases, and stable disease (SD) in 2 cases. Objective response rate was 75%, and disease control rate was 100%. The median PFS and the median overal survival have not yet been reached. The most common adverse events (AE) were alopecia (87.5%), nausea (75%), vomit (50%), hypothyroidism (50%), leukopenia (37.5%), hypertension (25%) and proteinuria (25%). Most of the AEs were grade 1 or 2, and the most common grade 3 or 4 treatment-related AE was hypertension (25%). Conclusions: Anti-PD-1 antibody plus bevacizumab and FOLFIRI demonstrated promising activity as second-line treatment for patients with MSI-H metastatic colorectal cancer. Clinical trial information: NCT05035381.
Immune landscape of colorectal cancer lung metastasis.
Authors: Lee Song-Yi , An Minae , Lee Jeeyun 
Published: June 2022

e15542 Background: Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death worldwide. What makes CRC treatment a challenge is synchronous or metachronous recurrence at distant organs; metastasis. Approximately half of CRC patients develop metastases in the course of the disease and the most prevalent metastatic site is liver, followed by lung and peritoneum. A 5-year survival rate metastatic CRC is much poorer than that of patients with regional and localized CRC. Methods: From 2019 to 2020, 9 metastatic CRC patients who had recurrence to lung oligo-metastases were enrolled. These patients were eligible for lung metastatectomy of curative intent. The surgically resected lung metastases were collected and whole exome sequencing/RNA sequencing,10x chromium single cell RNA sequencing analysis were performed. The purpose of this study was to uncover distinctive tumor microrenvironment (TME) of the lung metastases from CRC, we compared these results with those from public available primary CRC data. Results: We successfully analyzed all 9 metastatic lung samples. Compared to primary CRC, we found that lung metastasis had more immune-suppressive TMEs, represented by downregulation of TCR signaling, innate/adaptive immune system and antigen presentation. In addition, there were higher expression levels of immune checkpoint molecules, such as PD-1, LAG-3 and TIGIT in metastatic lung samples when compared to primary colon cancer public database. Macrophage polarization of lung metastases toward alternatively activated M2 subset, rather than classically activated M1 subset, resulting in low M1/M2 ratio, was also thought to attribute to immune suppressive environments of the lung metastases and successful colonization of primary tumors. Conclusions: This study identified different TMEs of lung metastasis specimens from primary CRCs. Our study underscores the importance of the tumor microenvironment and the anatomic location of the tumor cells for optimized immunotherapeutic strategies.
Impact of perioperative chemotherapy on survival outcome of advanced colorectal cancer patients treated with cytoreduction and hyperthermic intraperitoneal chemotherapy: A retrospective study.
Authors: Elsamany Shereef Ahmed , Alzahrani Saleh , Alzahrani Abdulaziz , Bukhari Ammar , Arbaein Amr , Hassanin Fayza , Elkhatib Hani 
Published: June 2022

e15570 Background: Colorectal cancer (CRC) with peritoneal carcinomatosis (PC) is generally associated with poor prognosis. The present study aims to assess potential value of perioperative systemic chemotherapy in patients treated with cytoreductive surgery with HIPEC (CRS/HIPEC) in a single institute in Saudi Arabia. Methods: We included CRC with PC who underwent CRS/ HIPEC from January 2012 till December 2019. Different clinicopathological, treatment-related factors and dates of relapse/death, were retrospectively assessed. We checked the distribution of these factors in addition to survival outcome in those who received perioperative chemotherapy vs. none. Results: We recruited 127 eligible patients (79 patients [62.2%] received systemic chemotherapy). Patients with no perioperative chemotherapy were more likely to have grade 1 tumours (62.5% vs. 25.3%, p < 0.0001), mucinous adenocarcinoma (41.7% vs. 12.7%, p = 0.002), normal CEA ≤5 ng/dl (70.2% vs. 47.4%, p = 0.016) and peritoneal-only metastasis (66.7% vs. 45.6%, p = 0.021). Median PFS and OS were 34 and 62.2 months, respectively. Patients with no perioperative systemic chemotherapy had significantly better PFS and OS (median PFS: not reached vs. 19 months, HR = 0.29, 95% CI = 0.15-0.59, p < 0.0001, OS :HR = 4.3, 95% CI 1.3-14.3, p = 0.009). After adjustment of different prognostic factors, there was no significance difference in OS between the two groups (HR = 3.8, 95% CI = 0.98-14.71, p = 0.053), while PFS was still significantly better in the no chemotherapy group (HR = 2.52, 95% CI = 1.13-5.63, p = 0.024). Conclusions: CRS/HIPEC provided favourable survival outcome in our study cohort especially in patients with more favourable prognostic features. No survival benefit with perioperative chemotherapy could be demonstrated.
Toripalimab with Fruquintinib as the third-line treatment for refractory advanced metastatic colorectal cancer: Results of a single-arm, single-center, prospective, phase II clinical study.
Authors: Ma Shoucheng , Chen Rui , Hou Xiaoming , Duan Lin , Li Chunmei , Yang Tianning , Ling Xiaoling , Zhao Da 
Published: June 2022

e15573 Background: The most effective treatment of immune checkpoint inhibitors (ICIs) is restricted in microsatellite instability (MSI-H) subsets of advanced colorectal cancer, but MSI-H only accounts for 4-5% among them. Currently, Fruquintinib/ Regorafenib is the standard third-line treatment for metastatic colorectal cancer (mCRC) with microsatellite stable (MSS), which efficacy remains limited in pre-clinical trials. According to the published literature, ICIs has little efficacy in the treatment of refractory advanced mCRC patients with MSS. However, there may be a good synergistic mechanism in the combination of ICIs and anti-VEGFR drugs, which can improve the tumor microenvironment (TME). Our study aimed to evaluate the efficacy and safety of Fruquintinib plus Toripalimab as third-line treatment for refractory advanced mCRC. Methods: This was a single-arm, single-center, phase II clinical trial with 30 patients. Pts received toripalimab (240mg, i.v., Q3W), combined with Fruquintinib (5mg, p.o., 3 weeks on/ 1 week off) until the disease progresses/unacceptable toxicity or receiving the above two drugs as maintenance treatment. The primary endpoint was objective response rate (ORR); the secondary endpoints were disease control rate (DCR), 1-year progression-free survival (PFS) rate, overall survival (OS) and safety. Results: As of Feb 5, 2022, 24 mCRC pts (female: 29.2%, median age: 52.1 years) with ECOG PS ≤ 2 who failed to at least 2 previous lines of therapy containing fluoropyrimidine, oxaliplatin or irinotecan combined with Bevacizumab or Cetuximab were enrolled. The ORR was 16.7% (95% CI：59.7%-94.8%). The DCR was 54.1%, including 4 patients with PR and 9 patients with SD, respectively. 16 patients were alive and the study treatments for 6 patients were still ongoing. Median PFS was 6.0 months (95% CI：3.511-12.489), the 1-year PFS rate was 18%; median OS was 8.0 months (95% CI：1.452-10.548). Overall, 24 pts were enrolled for safety analysis, The most frequent treatment related adverse events were fatigue (50%), hepatocyte dysfunction (36.3%), hypertension (29.1%) and abdominal pain (27.0%). 6 patients (25%) experienced grade 3/4 TRAE (including hypertension, liver enzyme elevation, and immune-associated pneumonia). No treatment-related death was reported. TRAEs leading to either Fruquintinib or Toripalimab discontinuation occurred in 3 (12.5%) pts each. Conclusions: Fruquintinib plus Toripalimab showed certain efficacy and favorable safety profile in refractory advanced mCRC with MSS. It may provide a new choice for mCRC patients who are receiving third-line treatment. The results supported ongoing combined treatment in mCRC patients with MSS and more data will being updated subsequently. Clinical trial information: ChiCTR2000028965.