Spatiotemporal Heterogeneity Across Metastases and Organ-Specific Response Informs Drug Efficacy and Patient Survival in Colorectal Cancer

Spatiotemporal Response Heterogeneity Across Metastatic Lesions Informs Drug Efficacy and Patient Survival in Colorectal Cancer

10.1101/2020.10.19.20215160 ◽

2020 ◽

Author(s):

Jiawei Zhou ◽

Quefeng Li ◽

Yanguang Cao

Keyword(s):

Colorectal Cancer ◽

Patient Survival ◽

Drug Efficacy ◽

Liver Lesions ◽

Response Dynamics ◽

Metastatic Lesions ◽

Spatiotemporal Heterogeneity ◽

Patient Prognosis ◽

Colorectal Cancer Patients ◽

Spatiotemporal Response

AbstractThe sum of target lesions is routinely used to evaluate patient objective responses to treatment in the RECIST criteria, but it neglects the response heterogeneity across metastases. This study argues that the spatiotemporal response heterogeneity across metastases informs drug efficacy and patient survival. We analyzed the longitudinal data of 11,404 metastatic lesions in 2,802 colorectal cancer patients and examined their response heterogeneity. The response dynamics of metastatic lesions varied broadly across anatomical locations and therapies. High inter-lesion heterogeneity is associated with worse survival (p < 0.001), while targeted therapies (bevacizumab or panitumumab) reduced the inter-lesion heterogeneity (p < 0.05) and elicited more favorable effects on liver lesions (p < 0.001) than chemotherapy alone. The responses of liver lesions predicted patient survival more significantly than the lesions in the lungs and lymph nodes. Altogether, the high spatiotemporal heterogeneity across metastases should be integrated into current methods for treatment evaluation and patient prognosis.SignificanceThe spatiotemporal heterogeneity across metastases in response to first-line therapies in colorectal cancer is informative for drug efficacy and patient survival, particularly in targeted therapy. Our findings provide evidence to support the inclusion of individual lesion response in the RECIST to improve the assessment of drug efficacy and patient survival.

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Faculty Opinions recommendation of Association between molecular subtypes of colorectal cancer and patient survival.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.719131045.793502499 ◽

2014 ◽

Author(s):

Noam Harpaz ◽

Alexandros Polydorides

Keyword(s):

Colorectal Cancer ◽

Patient Survival ◽

Molecular Subtypes

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The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

Oncogene ◽

10.1038/s41388-021-01815-4 ◽

2021 ◽

Author(s):

Jian Chen ◽

Risi Na ◽

Chao Xiao ◽

Xiao Wang ◽

Yupeng Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Patient Survival ◽

Serine Hydroxymethyltransferase ◽

First Line ◽

Xenograft Models ◽

Potential Opportunity ◽

First Line Treatment ◽

Novel Therapeutic

Abstract5-Fluorouracil (5-FU)-based chemotherapy is the first-line treatment for colorectal cancer (CRC) but is hampered by chemoresistance. Despite its impact on patient survival, the mechanism underlying chemoresistance against 5-FU remains poorly understood. Here, we identified serine hydroxymethyltransferase-2 (SHMT2) as a critical regulator of 5-FU chemoresistance in CRC. SHMT2 inhibits autophagy by binding cytosolic p53 instead of metabolism. SHMT2 prevents cytosolic p53 degradation by inhibiting the binding of p53 and HDM2. Under 5-FU treatment, SHMT2 depletion promotes autophagy and inhibits apoptosis. Autophagy inhibitors decrease low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, the lethality of 5-FU treatment to CRC cells was enhanced by treatment with the autophagy inhibitor chloroquine in patient-derived and CRC cell xenograft models. Taken together, our findings indicate that autophagy induced by low SHMT2 levels mediates 5-FU resistance in CRC. These results reveal the SHMT2–p53 interaction as a novel therapeutic target and provide a potential opportunity to reduce chemoresistance.

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Targeting vitamin E TPGS–cantharidin conjugate nanoparticles for colorectal cancer therapy

RSC Advances ◽

10.1039/c5ra08154h ◽

2015 ◽

Vol 5 (66) ◽

pp. 53846-53856 ◽

Cited By ~ 3

Author(s):

Shihou Sheng ◽

Tao Zhang ◽

Shijie Li ◽

Jun Wei ◽

Guangjun Xu ◽

...

Keyword(s):

Colorectal Cancer ◽

Drug Delivery ◽

Vitamin E ◽

Chinese Medicine ◽

Side Effects ◽

Cancer Therapy ◽

Traditional Chinese Medicine ◽

Drug Efficacy ◽

Vitamin E Tpgs ◽

Colorectal Cancer Cells

A traditional Chinese medicine cantharidin which was previously found to be effective on colorectal cancer cells was translated into nanoparticles for drug delivery to reduce its side effects and enhance its drug efficacy.

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Relationship between colorectal cancer glutathione levels and patient survival

Diseases of the Colon & Rectum ◽

10.1007/bf02236562 ◽

2000 ◽

Vol 43 (8) ◽

pp. 1133-1140 ◽

Cited By ~ 21

Author(s):

Sam C. Barranco ◽

Roger R. Perry ◽

Mary E. Durm ◽

Mohammed Quraishi ◽

Alice L. Werner ◽

...

Keyword(s):

Colorectal Cancer ◽

Patient Survival

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The Clinical and Prognostic Significance of Protein Arginine Deiminases 2 and 4 in Colorectal Cancer

Pathobiology ◽

10.1159/000518414 ◽

2021 ◽

pp. 1-11

Author(s):

Mohamed Gijon ◽

Rachael L. Metheringham ◽

Michael S. Toss ◽

Samantha J. Paston ◽

Lindy G. Durrant

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Survival Time ◽

Patient Survival ◽

Prognostic Significance ◽

High Expression ◽

Related Protein ◽

Post Translational Modification

Introduction: Protein arginine deiminases (PADIs) are a family of enzymes that catalyse the post-translational modification of proteins. Association between PADI expression and clinicopathology, protein expression, and outcome was determined. Methods: PADI2 and PADI4 expression was assessed immunohistochemically in a cohort of colorectal cancer (CRC) patients. Results: CRC tissues expressed variable levels of PADI2 which was mainly localised in the cytoplasm and correlated with patient survival (p = 0.005); high expression increased survival time from 43.5 to 67.6 months. Expression of cytoplasmic PADI2 correlated with the expression of nuclear β catenin, PADI4, and alpha-enolase. In contrast, expression of nuclear PADI2 correlated with a decrease in survival (p = 0.010), with high expression decreasing survival from 76.4 to 42.9 months. CRC tissues expressed variable levels of PADI4 in both the nucleus and cytoplasm. Expression of cytoplasmic PADI4 correlated with survival (p = 0.001) with high expression increasing survival time from 48.1 to 71.8 months. Expression of cytoplasmic PADI4 correlated with expression of nuclear β catenin, alpha-enolase (p ≤ 0.0001, p = 0.002), and the apoptotic related protein, Bcl-2. Expression of nuclear PADI4 also correlated with survival (p = 0.011), with high expression of nuclear PADI4 increasing survival time from 55.4 to 74 months. Expression of nuclear PADI4 correlated with p53, alpha-enolase, and Bcl-2. Multivariate analysis showed that TNM stage, cytoplasmic PADI2, and PADI4 remained independent prognostic factors in CRC. Both PADI2 and PADI4 are good prognostic factors in CRC. Conclusion: High expression of cytoplasmic PADI2, PADI4, and nuclear PADI4 were associated with an increase in overall survival.

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500P Local lymphatic reaction in colorectal cancer: The relationship to patient survival, systemic inflammatory markers, MSI and KRAS mutations to tumour

Annals of Oncology ◽

10.1016/j.annonc.2020.08.610 ◽

2020 ◽

Vol 31 ◽

pp. S452

Author(s):

Y. Ma ◽

P. Lu ◽

X. Liang ◽

S. Wei

Keyword(s):

Colorectal Cancer ◽

Inflammatory Markers ◽

Patient Survival ◽

Kras Mutations ◽

The Relationship

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Improvement of Metastatic Colorectal Cancer Patient Survival: Single Institution Experience

Cancers ◽

10.3390/cancers11030369 ◽

2019 ◽

Vol 11 (3) ◽

pp. 369 ◽

Cited By ~ 4

Author(s):

Elisabetta Fenocchio ◽

Federica Colombi ◽

Maria Grazia Calella ◽

Roberto Filippi ◽

Ilaria Depetris ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Patient Survival ◽

Colorectal Cancer Patient ◽

Survival Rates ◽

Integrated Approach ◽

Metastatic Tumour ◽

Single Institution ◽

Significant Difference ◽

Metastatic Colorectal Cancer Patient

The survival rates of patients with metastatic colorectal cancer (mCRC) have improved in recent years. We analysed the survival of mCRC patients followed at a single institution over the last 17 years. We retrospectively collected data from 899 mCRC patients treated from 2001 to 2016. Patients were divided into two groups based on the year of diagnosis: Cohort A (2001–2006) and Cohort B (2007–2014). A total of 788 patients were analysed. The median survival of the whole population was 32.0 months with a significant difference between Cohort A and B (29.2 vs. 33.5 months; p = 0.041). Surgical procedures significantly increased in Cohort B, however, no significant changes in survival were observed in patients undergoing surgery (58.9 months Cohort A vs. 58.2 months Cohort B, p = 0.822). Similarly, we did not demonstrate survival improvement in patients treated with systemic therapy alone (18.9 months Cohort A vs. 20.7 months Cohort B; p = 0.948). At the multivariate analysis, right-sided primary and synchronous metastatic tumour were found to be independent unfavorable prognostic factors. Improvements of mCRC patient survival might relate to integrated approach, with more patients undergoing extra-hepatic surgery. The medical approach seems to have had a more favourable impact on subgroups characterized by a worse prognosis.

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