Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside

Lizardo, Darleny Y.; Kuang, Chaoyuan; Hao, Suisui; Yu, Jian; Huang, Yi; Zhang, Lin

doi:10.1016/j.bbcan.2020.188447

Cited by 119 publications

(96 citation statements)

References 98 publications

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“…However, it is often followed by tumour relapse and acquired chemotherapy-resistance. An effective drug for therapy and prognosis after surgery still does not exist [2][3][4] .…”

Section: Introductionmentioning

confidence: 99%

“…It should be emphasised that compounds with the 1,2,4-triazine nucleus condensed with five-membered heterocycles have received considerable attention because they are bioisosteric with a purine core. Among the fused 1,2,4-triazine derivatives with one heterocycle, compounds bearing a pyrrole ring, such as pyrrolo[2,1-c][1, 2,4]triazine and pyrrolo[2,1-f][1, 2,4]triazine, represent the most abundant class of triazine with antitumor activity 5 . Derivatives bearing this heterocyclic system are widely described as potent kinase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…Derivatives bearing this heterocyclic system are widely described as potent kinase inhibitors. Pyrrolo[2,1-f][1, 2,4] triazine scaffold, miming the adenine ring of ATP, was also employed to afford other kinase inhibitors such as Met kinase inhibitors 10 .…”

Section: Introductionmentioning

confidence: 99%

“…Bernat et al reported that pyrazolo triazine derivates show increased antiproliferative and apoptotic effects in cancerous cell lines, as compared to normal tissue 13 . Another group is pyrazolo [4,3-e][1, 2,4]triazine sulphonamides prepared as inhibitors of carbonic anhydrase hCA IX and XII with antitumor activity 14,15 . Moreover, some previously described pyrazolotriazine sulphonamides were found to have dose-dependent antiproliferative effects against two Bcr-Abl positive cancer cell lines, K562 and BV173.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous study, we described synthesis and characterisation of novel pyrazolo [4,3- 2,4]triazine sulphonamides differing in the structure of the sulphonamide group 19 . Screening results revealed that compound MM-129 presented in Figure 1 exhibited strong inhibition activity towards DLD-1 and HT-29 (two of the cell lines of CRC).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer

Hermanowicz

Szymanowska

Sieklucka

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in men and in women. The impact of the new pyrazolo [4,3-e]tetrazolo [1,5-b][1,2,4]triazine sulphonamide (MM-129) was evaluated against human colon cancer in vitro and in zebrafish xenografts. Our results show that this new synthesised compound effectively inhibits cell survival in BTK-dependent mechanism. Its effectiveness is much higher at a relatively low concentration as compared with the standard chemotherapy used for CRC, i.e. 5fluorouracil (5-FU). Flow cytometry analysis after annexin V-FITC and propidium iodide staining revealed that apoptosis was the main response of CRC cells to MM-129 treatment. We also found that MM-129 effectively inhibits tumour development in zebrafish embryo xenograft model, where it showed a markedly synergistic anticancer effect when used in combination with 5-FU. The above results suggest that this novel heterofused 1,2,4-triazine derivative may be a promising candidate for further evaluation as chemotherapeutic agent against CRC.

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“…However, it is often followed by tumour relapse and acquired chemotherapy-resistance. An effective drug for therapy and prognosis after surgery still does not exist [2][3][4] .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer

Hermanowicz

Szymanowska

Sieklucka

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

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Total Neoadjuvant Therapy With PD-1 Blockade for High-Risk Proficient Mismatch Repair Rectal Cancer

Li,

Pan,

Gao

et al. 2024

JAMA Surg

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ImportanceTotal neoadjuvant therapy (TNT) is the standard treatment for locally advanced rectal cancer, especially for patients with high-risk factors. However, the efficacy of TNT combined with immunotherapy for patients with proficient mismatch repair (pMMR) rectal cancer is unknown.ObjectivesTo evaluate the safety and efficacy of TNT with induction chemoimmunotherapy followed by long-course chemoradiation in patients with high-risk, pMMR rectal cancer and to identify potential molecular biomarkers associated with treatment efficacy.Design, Setting, and ParticipantsThis cohort study was a single-arm phase 2 trial conducted at Gastrointestinal Cancer Center, Peking University Cancer Hospital &amp; Institute, from June 2020 to October 2021. Biopsies and plasma were collected before treatment for whole-exome sequencing and cell-free DNA sequencing, respectively. Data were analyzed from May 2022 to September 2022.InterventionsParticipants received 3 cycles of induction oxaliplatin and capecitabine combined with camrelizumab and radiotherapy (50.6 Gy in 22 fractions) with concurrent capecitabine. Patients without disease progression received 2 cycles of consolidation oxaliplatin/capecitabine.Main Outcomes and MeasuresThe primary end point was pathologic complete response rate.ResultsOf 25 patients enrolled (19 men [76%]; 6 women [24%]; median [IQR] age, 58 [48-64] years), 22 patients (88%) completed the TNT schedule. The pathologic complete response rate was 33.3% (7/21). Twelve patients (48%) achieved clinical complete response, and 4 patients (16%) chose to watch and wait. R0 resection was achieved in 21 of 21 patients, and the major pathologic response rate was 38.1% (8/21). The most common adverse event was nausea (80%, 20/25); grade 3 toxic effects occurred in 9 of 25 patients (36%). Patients with tumor shrinkage of 50% or greater after induction oxaliplatin/capecitabine and camrelizumab or clinical complete response had higher percentages of LRP1B mutation. Mutation of LRP1B was associated with high tumor mutation burden and tumor neoantigen burden. Patients with high tumor mutation burden all benefited from therapy.Conclusions and RelevanceThis study found that TNT with induction chemoimmunotherapy followed by long-course chemoradiation was safe and effective for patients with high-risk rectal cancer with pMMR status. Longer follow-up and larger clinical studies are needed to validate this innovative regimen. There is also an urgent need to further validate the predictive value of LRP1B and discover other novel biomarkers with potential predictive value for rectal cancer.

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Construction of a prognostic glycolysis‐related lncRNA signature for patients with colorectal cancer

Zhong

Wang

et al. 2022

Cancer Medicine

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Aerobic glycolysis is a common metabolic phenotype in tumors that helps cancer cells adjust to severe living conditions and can aid metastasis in several types of carcinomas, including colorectal cancer (CRC). Long non‐coding RNAs (lncRNAs) can influence tumor biology and have been previously used to assess patients' outcomes and to identify potential therapeutic targets. However, despite the importance of glycolysis‐related lncRNAs (GRLs) in the development of CRC, studies on their use as prognostic markers are still limited. Herein, we applied a series of bioinformatic analyses to screen potential prognostic lncRNAs for colorectal cancer. Out of all lncRNAs screened, nine GRLs were selected to constitute a prognostic signature. Based on the signature, two molecular subtypes were classified with distinct prognostic outcomes and excellent diagnostic accuracy (The 1‐, 3‐ and 5‐year AUC are 0.756, 0.716, and 0.721, respectively). The prognostic value of this signature was further validated using another cohort. The enriched molecular pathways, immune infiltration, and mutation landscape were also significantly different between the two groups. The different drug sensitivity results between the two groups suggest a potential strategy for precise treatment. Furthermore, we confirmed that AFAP1‐AS1 could regulate aerobic glycolysis and metastasis of CRC cells. Overall, we developed a glycolysis‐related lncRNA (GRL) signature and suggested that this signature could offer a predictive value and identify potential therapeutic targets for cancer therapy.

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Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside

Cited by 119 publications

References 98 publications

Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer

Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer

Total Neoadjuvant Therapy With PD-1 Blockade for High-Risk Proficient Mismatch Repair Rectal Cancer

Construction of a prognostic glycolysis‐related lncRNA signature for patients with colorectal cancer

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