Ferroptosis contributes to the progression of female-specific neoplasms, from breast cancer to gynecological malignancies in a manner regulated by non-coding RNAs: Mechanistic implications

Review

作者: Nabavi, Noushin ; Bonyadi, Mojtaba ; Klionsky, Daniel J ; Reiter, Russel J ; Aref, Amir Reza ; Hushmandi, Kiavash ; Salimimoghadam, Shokooh ; Saadat, Seyed Hassan

Ferroptosis, a recently identified type of non-apoptotic cell death, triggers the elimination of cells in the presence of lipid peroxidation and in an iron-dependent manner. Indeed, ferroptosis-stimulating factors have the ability of suppressing antioxidant capacity, leading to the accumulation of reactive oxygen species (ROS) and the subsequent oxidative death of the cells. Ferroptosis is involved in the pathophysiological basis of different maladies, such as multiple cancers, among which female-oriented malignancies have attracted much attention in recent years. In this context, it has also been unveiled that non-coding RNA transcripts, including microRNAs, long non-coding RNAs, and circular RNAs have regulatory interconnections with the ferroptotic flux, which controls the pathogenic development of diseases. Furthermore, the potential of employing these RNA transcripts as therapeutic targets during the onset of female-specific neoplasms to modulate ferroptosis has become a research hotspot; however, the molecular mechanisms and functional alterations of ferroptosis still require further investigation. The current review comprehensively highlights ferroptosis and its association with non-coding RNAs with a focus on how this crosstalk affects the pathogenesis of female-oriented malignancies, from breast cancer to ovarian, cervical, and endometrial neoplasms, suggesting novel therapeutic targets to decelerate and even block the expansion and development of these tumors.

2024-08-01·The Journal of Nutritional Biochemistry

Natural product/diet-based regulation of macrophage polarization: Implications in treatment of inflammatory-related diseases and cancer

Review

作者: Aref, Amir Reza ; Ertas, Yavuz Nuri ; Ashrafizadeh, Milad ; Sethi, Gautam ; Wang, Lu

Macrophages are phagocytic cells with important physiological functions, including the digestion of cellular debris, foreign substances, and microbes, as well as tissue development and homeostasis. The tumor microenvironment (TME) shapes the aggressiveness of cancer, and the biological and cellular interactions in this complicated space can determine carcinogenesis. TME can determine the progression, biological behavior, and therapy resistance of human cancers. The macrophages are among the most abundant cells in the TME, and their functions and secretions can determine tumor progression. The education of macrophages to M2 polarization can accelerate cancer progression, and therefore, the re-education and reprogramming of these cells is promising. Moreover, macrophages can cause inflammation in aggravating pathological events, including cardiovascular diseases, diabetes, and neurological disorders. The natural products are pleiotropic and broad-spectrum functional compounds that have been deployed as ideal alternatives to conventional drugs in the treatment of cancer. The biological and cellular interactions in the TME can be regulated by natural products, and for this purpose, they enhance the M1 polarization of macrophages, and in addition to inhibiting proliferation and invasion, they impair the chemoresistance. Moreover, since macrophages and changes in the molecular pathways in these cells can cause inflammation, the natural products impair the pro-inflammatory function of macrophages to prevent the pathogenesis and progression of diseases. Even a reduction in macrophage-mediated inflammation can prevent organ fibrosis. Therefore, natural product-mediated macrophage targeting can alleviate both cancerous and non-cancerous diseases.

2024-04-05·Cancer Research

Abstract LB218: Advanced ex vivo platform for drug response analysis: Evaluating the potent effects of NMC-521 mAb on mouse-and patient-derived organotypic tumor spheroids

作者: Aref, Amir ; Sarafraz-Yazdi, Ehsan ; Khardenavis, Kirti ; Perricone, Michael A. ; Adler, Victor ; Martin, Alyssa ; Krzesaj, Patryk ; Aboulkheyr Es, Hamidreza

AbstractIn response to the high failure rate of new drugs in clinical trials, we have developed an innovative organotypic tumor spheroids platform, designed to mitigate the risks associated with advancing drugs to clinical stages. Utilizing patient-derived organotypic tumor spheroids (PDOTS), this platform uniquely captures both the phenotype and genotype of individual patient tumor microenvironments. This approach not only enhances the precision of preclinical models but also bridges the gap between laboratory research and clinical applicability. In this study, we assess the effectiveness of the first-in-class monoclonal antibody NMC-521 (NomoCan Pharmaceuticals, NY) using our ex vivo platform. Targeting the novel cancer-specific antigen NMC-1, NMC-521 exhibited significant growth inhibition of CT-26 tumors in syngeneic BALB/c mice, reducing tumor size by approximately 55% compared to the control. Similarly, in ex vivo settings with freshly excised CT-26 tumors (n=18), NMC-521 demonstrated a dose-dependent cytotoxic effect, achieving about a 65% reduction in tumor viability with an effective dose (ED50) of 10 µg/ml. Further insights were gained into NMC-521's mechanism of action using our ex vivo platform. The drug’s ability to induce tumor cell death in CT26 ex vivo was significantly reversed (p<0.01) when co-treated with α-NKG2D but not α-CD8, indicating a critical role for natural killer (NK) cells in its therapeutic effect. Complementing these findings, our analyses on freshly excised patient tumors (n=15) corroborated the cytotoxic effects of this drug on colorectal cancer but not to the same magnitude as in the CT-26 model. Furthermore, unlike the syngeneic murine tumor model, the response rate was (8 of 15 responsive patient tumors. Gene expression profiling indicated that NK cell-associated RNAs were elevated in NMC-521 treated PDOTS. Additionally, combination therapy studies using NMC-521 and nivolumab within our platform mirrored murine in vivo results, enhancing our understanding of the drug's potential in clinical settings. Intriguingly, an observed elevation in IL-15 levels in patient tumors treated with NMC-521 suggests an increased presence of NK cell activity when compared to treatments with nivolumab. This research underscores the potential of our organotypic tumor spheroids platform as a transformative tool in cancer drug development, offering an accurate and patient-specific method to evaluate new therapies, thereby increasing the likelihood of successful translation from the laboratory to patient care.Citation Format: Amir Aref, Alyssa Martin, Hamidreza Aboulkheyr Es, Patryk Krzesaj, Victor Adler, Kirti Khardenavis, Ehsan Sarafraz-Yazdi, Michael A. Perricone. Advanced ex vivo platform for drug response analysis: Evaluating the potent effects of NMC-521 mAb on mouse-and patient-derived organotypic tumor spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB218.

项与 Xsphera Biosciences, Inc. 相关的新闻（医药）

2023-11-14

·BioSpace

Xsphera Biosciences and NEX-I Collaborate to Advance Oncology Drug Research

Boston, MA – Xsphera Biosciences, a leading biotechnology company specializing in ex vivo testing of oncology therapeutics on patient-excised tumor tissue, is pleased to announce the formalization of a Memorandum of Understanding (MOU) with NEX-I, a Seoul-based pioneer in immune-oncology therapeutics. This partnership represents a significant step forward in oncology drug research and development. At the heart of this partnership lies Xsphera's innovative technology, exclusively licensed from the Dana-Farber Cancer Institute. Xsphera’s technology maintains each patient’s tumor microenvironment in an ex vivo platform directly from a fresh excisional tumor biopsy. Over the past year, Xsphera has played a pivotal role in advancing NEX-I’s pipeline by assessing the performance of NEX-I mono and combination therapies on patient tumor samples. Additionally, the companies have leveraged Xsphera’s cloud analytics platform to jointly explore molecular pathways modulated by the multiple therapeutic treatments, aiming to comprehend the mechanisms of action and resistance for each treatment across a diverse set of patient samples. NEX-I is advancing the development of 'NXI-101', a notable first-in-class antibody drug targeting 'ONCOKINE-1', a factor produced by cancer cells that contributes to the resistance of cancer cells to cancer immunotherapy. With treatments like NXI-101 designed to counter these resistance factors, NEXI aims to bolster the efficacy of cancer immunotherapy. Furthermore, NEX-I is diligently working to expedite its entry into global clinical markets. Stephen Remondi, CEO of Xsphera Biosciences, remarked, "This MOU underscores our shared commitment to deepen our collaboration. We are excited to further our understanding of immune modulation in response to NEX-I therapeutics as well as to discover new therapeutic targets in oncology that is enabled by comparing the modulated responses of different therapeutics on tumor tissue from the same patient. " Importantly, this partnership is set to deliver tangible benefits to cancer patients by tailoring treatments to their unique biological responses, thereby improving treatment outcomes and personalizing the battle against cancer." CEO, Kyoung Wan Yoon, stated, “NXI-101 is on the verge of entering clinical trials next year. On top of our animal data, validating the efficacy and mechanism of NXI-101 through our collaborative research with Xsphera increases our likelihood of clinical success, and will deliver real-world value to patients. Furthermore, through this research collaboration, we aim to verify the possibility of developing companion diagnostic biomarkers for the NXI-101 treatment and accelerate the pace of technological and business growth globally." About Xsphera Biosciences: Xsphera Biosciences is a biotechnology company dedicated to bridging the translational gap between animal models and human clinical trials for oncology therapeutics. Through collaboration with Dana-Farber, Xsphera has developed a revolutionary fresh human tumor tissue-based platform that enables the assessment of therapeutic efficacy across various cancer indications and drug modalities. Integrating this ex vivo biology capability with its AI-powered cloud analytics platform, Xsphera can reveal the underlying mechanisms of action and resistance in the tumor microenvironment, providing invaluable insights into human biology and clinical trial strategy. For more information, please visit the Xsphera website at . About NEX-I: NEX-I is breaking ground in the fight against cancer with its next-generation therapies targeting immunotherapy-resistant cancers. Leveraging its proprietary platform, NEX-I has developed robust models for immunotherapy-refractory cancers to analyze their characteristics and identify novel therapeutic targets comprehensively. This unique and dedicated research has led to the discovery of a series of soluble targets, ONCOKINE, which highly expresses and plays a critical role in refractory cellular mechanisms through the proprietary screening platform. NEX-I proposes a new standardized solution to inhibit cancer cell growth and metastasis by suppressing them. Learn more at . A copy of the White Paper describing NXI-101 and the results from Xsphera platform can be found here: For further information, please contact: Xsphera Biosciences Inc. Kazuhito Ishikawa Vice President, Sales and Business development kazu@xspherabio.com

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