Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate Cancer

Ghosh, Taraswi Mitra; White, Jason; Davis, Joshua; Mazumder, Suman; Kansom, Teeratas; Skarupa, Elena; Barnett, Grafton S.; Piazza, Gary A.; Bird, Richard M.; Mitra, Amit; Yates, Clayton; Cummings, Brian S.; Arnold, Robert D.

doi:10.3389/fphar.2021.736951

Cited by 8 publications

(16 citation statements)

References 67 publications

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“…Interestingly, metronomic Cyclophosphamide application also induced an immune reaction (in terms of T cell reactivation) in patients with biochemical recurrence ( 105 ). Although the mode of action of metronomic therapies is not completely understood, a recent study identified key genes which were associated with (metronomic) Topotecan dosing in PCa cell lines ( 106 ).…”

Section: Discussionmentioning

confidence: 99%

Angiogenesis as Therapeutic Target in Metastatic Prostate Cancer – Narrowing the Gap Between Bench and Bedside

2022

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Angiogenesis in metastatic castration-resistant prostate cancer (mCRPC) has been extensively investigated as a promising druggable biological process. Nonetheless, targeting angiogenesis has failed to impact overall survival (OS) in patients with mCRPC despite promising preclinical and early clinical data. This discrepancy prompted a literature review highlighting the tumor heterogeneity and biological context of Prostate Cancer (PCa). Narrowing the gap between the bench and bedside appears critical for developing novel therapeutic strategies. Searching clinicaltrials.gov for studies examining angiogenesis inhibition in patients with PCa resulted in n=20 trials with specific angiogenesis inhibitors currently recruiting (as of September 2021). Moreover, several other compounds with known anti-angiogenic properties – such as Metformin or Curcumin – are currently investigated. In general, angiogenesis-targeting strategies in PCa include biomarker-guided treatment stratification – as well as combinatorial approaches. Beyond established angiogenesis inhibitors, PCa therapies aiming at PSMA (Prostate Specific Membrane Antigen) hold the promise to have a substantial anti-angiogenic effect – due to PSMA´s abundant expression in tumor vasculature.

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Section: Discussionmentioning

confidence: 99%

Angiogenesis as Therapeutic Target in Metastatic Prostate Cancer – Narrowing the Gap Between Bench and Bedside

2022

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“…Metronomic, very low-dose chemotherapy promotes a continuous pattern of stress responses [ 55 , 123 , 124 , 125 ]. The present clinical data reveal that metronomic chemotherapy at ‘very’ low-doses limits tumor tissue plasticity by stress response, probably decreasing phenotypic heterogeneity of tumor cell niches as tissue stress generally induces a tighter phenotype [ 123 , 126 , 127 , 128 , 129 , 130 , 131 ]. Thus, metronomic chemotherapy might induce phenotypic integration of inflammation control or differentiation by editing techniques and, consecutively, may serve as an enhancer of pro-anakoinotic effects mediated by added transcriptional modulators [ 55 , 123 ].…”

Section: Specific Therapeutic Access To M-crac With Tumor Tissue Edit...mentioning

confidence: 99%

Addressing Genetic Tumor Heterogeneity, Post-Therapy Metastatic Spread, Cancer Repopulation, and Development of Acquired Tumor Cell Resistance

Harrer,

Lüke,

Pukrop

et al. 2023

Cancers

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The concept of post-therapy metastatic spread, cancer repopulation and acquired tumor cell resistance (M-CRAC) rationalizes tumor progression because of tumor cell heterogeneity arising from post-therapy genetic damage and subsequent tissue repair mechanisms. Therapeutic strategies designed to specifically address M-CRAC involve tissue editing approaches, such as low-dose metronomic chemotherapy and the use of transcriptional modulators with or without targeted therapies. Notably, tumor tissue editing holds the potential to treat patients, who are refractory to or relapsing (r/r) after conventional chemotherapy, which is usually based on administering a maximum tolerable dose of a cytostatic drugs. Clinical trials enrolling patients with r/r malignancies, e.g., non-small cell lung cancer, Hodgkin’s lymphoma, Langerhans cell histiocytosis and acute myelocytic leukemia, indicate that tissue editing approaches could yield tangible clinical benefit. In contrast to conventional chemotherapy or state-of-the-art precision medicine, tissue editing employs a multi-pronged approach targeting important drivers of M-CRAC across various tumor entities, thereby, simultaneously engaging tumor cell differentiation, immunomodulation, and inflammation control. In this review, we highlight the M-CRAC concept as a major factor in resistance to conventional cancer therapies and discusses tissue editing as a potential treatment.

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“…METRO is an emerging treatment option that has shown promise for various cancer types, including prostate cancer ( 20–23 ). In our previous study, we reported that metronomic topotecan treatment (METRO-TOPO) was 2.4- to 18-fold more potent ( P < 0.05) compared with conventional topotecan (CONV-TOPO) treatment in prostate cancer cell lines ( 22 ). We then performed animal study with METRO-TOPO versus CONV-TOPO and demonstrated that by day 17, METRO-TOPO treatment resulted in significantly ( P ≤ 0.05) smaller tumor volume (65.4% ± 11.2%) compared with control (136% ± 14%) and CONV-TOPO–treated animals (138% ± 10%) in an aggressive xenograft tumor model of human prostate cancer implanted in male NCr athymic mice ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

“…In our previous study, we reported that metronomic topotecan treatment (METRO-TOPO) was 2.4- to 18-fold more potent ( P < 0.05) compared with conventional topotecan (CONV-TOPO) treatment in prostate cancer cell lines ( 22 ). We then performed animal study with METRO-TOPO versus CONV-TOPO and demonstrated that by day 17, METRO-TOPO treatment resulted in significantly ( P ≤ 0.05) smaller tumor volume (65.4% ± 11.2%) compared with control (136% ± 14%) and CONV-TOPO–treated animals (138% ± 10%) in an aggressive xenograft tumor model of human prostate cancer implanted in male NCr athymic mice ( 22 ). This overall antitumor activity of METRO-TOPO was maintained through the end of the study, animals receiving METRO-TOPO dosing regimens had significantly ( P ≤ 0.05) smaller tumor volumes (54.8% ± 16.5%) than animals receiving CONV-TOPO dosing (144% ± 11%) or the control group (207% ± 26%; ref.…”

Section: Introductionmentioning

confidence: 99%

“…This overall antitumor activity of METRO-TOPO was maintained through the end of the study, animals receiving METRO-TOPO dosing regimens had significantly ( P ≤ 0.05) smaller tumor volumes (54.8% ± 16.5%) than animals receiving CONV-TOPO dosing (144% ± 11%) or the control group (207% ± 26%; ref. 22 ). To further investigate the impact of low-dose therapy, the effect of METRO-TOPO, CONV-TOPO intravenous administration on tumor volume was compared with implantation of ALZET micro-osmotic pumps in nude mice after tumor xenografts reached 200–300 mm 3 ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

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Metronomic Administration of Topotecan Alone and in Combination with Docetaxel Inhibits Epithelial–mesenchymal Transition in Aggressive Variant Prostate Cancers

Mitra Ghosh,

Mazumder,

Davis

et al. 2023

Cancer Research Communications

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Prostate cancer (PCa) is the second leading cause of non-cutaneous cancer-related deaths in American men. Androgen deprivation therapy (ADT), radical prostatectomy, and radiation therapy remain the primary treatment for early-stage PCa patients (castration-sensitive: CSPC). Following ADT, many patients ultimately develop metastatic castration-resistant PCa (mCRPC). Standard chemotherapy options for CRPC are Docetaxel (DTX) and Cabazitaxel (CBZ), which increase median survival, although the development of resistance is common. Cancer-stem-like cells possess mesenchymal phenotypes (EMT) and play crucial roles in tumor initiation and progression of mCRPC. We have shown that low-dose continuous administration of topotecan (METRO-TOPO) inhibits PCa growth by interfering with key cancer-pathway genes. This study utilized bulk and single-cell or whole-transcriptome analysis (RNA-sequencing and scRNAseq), and we observed greater expression of several EMT markers, including VIM, HAS3, S100A6, TGFB1, CD44, CD55, and CD109 in European American and African American aggressive variant PCa (AVPC) subtypes - mCRPC, neuroendocrine variant (NEPC), and taxane-resistant. The taxane-resistant gene FSCN1 was also expressed highly in single-cell sub-clonal populations in mCRPC. Further, metronomic-topotecan single-agent and combinations with DTX downregulated these EMT markers as well as CD44+ and CD44+/CD133+ “stem-like” cell populations. A microfluidic chip-based cell invasion assay revealed that METRO-TOPO treatment as a single-agent or in combination with DTX was potentially effective against invasive PCa spread. Our RNAseq and scRNAseq analysis were supported by in silico and in vitro studies, suggesting METRO-TOPO combined with DTX may inhibit oncogenic progression by reducing cancer stemness in AVPC through the inhibition of EMT markers and multiple oncogenic factors/pathways.

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Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate Cancer

Cited by 8 publications

References 67 publications

Angiogenesis as Therapeutic Target in Metastatic Prostate Cancer – Narrowing the Gap Between Bench and Bedside

Angiogenesis as Therapeutic Target in Metastatic Prostate Cancer – Narrowing the Gap Between Bench and Bedside

Addressing Genetic Tumor Heterogeneity, Post-Therapy Metastatic Spread, Cancer Repopulation, and Development of Acquired Tumor Cell Resistance

Metronomic Administration of Topotecan Alone and in Combination with Docetaxel Inhibits Epithelial–mesenchymal Transition in Aggressive Variant Prostate Cancers

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