Browsing by Author "Singh, Naresh"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
  • Thumbnail Image
    Item
    Inhibition of Glutamate-to-Glutathione Flux Promotes Tumor Antigen Presentation in Colorectal Cancer Cells
    (Wiley, 2025) Yu, Tao; Van der Jeught, Kevin; Zhu, Haiqi; Zhou, Zhuolong; Sharma, Samantha; Liu, Sheng; Eyvani, Haniyeh; So, Ka Man; Singh, Naresh; Wang, Jia; Sandusky, George E.; Liu, Yunlong; Opyrchal, Mateusz; Cao, Sha; Wan, Jun; Zhang, Chi; Zhang, Xinna; Medical and Molecular Genetics, School of Medicine
    Colorectal cancer (CRC) cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro-tumor microenvironment, and therapeutic resistance. One such metabolic change occurs in glutamine metabolism. Colorectal tumors with high glutaminase (GLS) expression exhibited reduced T cell infiltration and cytotoxicity, leading to poor clinical outcomes. However, depletion of GLS in CRC cells has minimal effect on tumor growth in immunocompromised mice. By contrast, remarkable inhibition of tumor growth is observed in immunocompetent mice when GLS is knocked down. It is found that GLS knockdown in CRC cells enhanced the cytotoxicity of tumor-specific T cells. Furthermore, the single-cell flux estimation analysis (scFEA) of glutamine metabolism revealed that glutamate-to-glutathione (Glu-GSH) flux, downstream of GLS, rather than Glu-to-2-oxoglutarate flux plays a key role in regulating the immune response of CRC cells in the tumor. Mechanistically, inhibition of the Glu-GSH flux activated reactive oxygen species (ROS)-related signaling pathways in tumor cells, thereby increasing the tumor immunogenicity by promoting the activity of the immunoproteasome. The combinatorial therapy of Glu-GSH flux inhibitor and anti-PD-1 antibody exhibited a superior tumor growth inhibitory effect compared to either monotherapy. Taken together, the study provides the first evidence pointing to Glu-GSH flux as a potential therapeutic target for CRC immunotherapy.
  • Thumbnail Image
    Item
    Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions
    (Baishideng, 2024) Sharma, Samantha; Singh, Naresh; Turk, Anita Ahmed; Wan, Isabella; Guttikonda, Akshay; Dong, Julia Lily; Zhang, Xinna; Opyrchal, Mateusz; Medical and Molecular Genetics, School of Medicine
    Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
  • Thumbnail Image
    Item
    Photo-activated microtubule targeting drugs: Advancing therapies for colorectal cancer
    (Baishideng, 2024) Singh, Naresh; Sharma, Samantha; Medical and Molecular Genetics, School of Medicine
    Over the years immunotherapy has demonstrably improved the field of cancer treatment. However, achieving long-term survival for colorectal cancer (CRC) patients remains a significant unmet need. Combination immunotherapies incorporating targeted drugs like MEK or multi-kinase inhibitors have offered some palliative benefit. Nevertheless, substantial gaps remain in the current therapeutic armamentarium for CRC. In recent years, there has been a surge of interest in exploring novel treatment strategies, including the application of light-activated drugs in conjunction with optical devices. This approach holds promise for achieving localized and targeted delivery of cytotoxic agents, such as microtubule-targeting drugs, directly to cancerous cells within the colon.