Sequencing Surgery, Radiotherapy and Chemotherapy: Insights from a Mathematical Analysis

Beil, Damian R.; Wein, Lawrence M.

doi:10.1023/a:1016357311845

Cited by 20 publications

(7 citation statements)

References 25 publications

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“…In the last few years, approaches to combine PD-1 blockade with conventional treatments such as chemotherapy have shown promising results even as first-line treatment in triple-negative metastatic breast cancer [( 8 ), NCT02425891]. It is important to note, that chemotherapy still represents the preferred standard of systemic treatment for metastatic breast cancer and remains one of the most efficient ways to improve patient outcome by decreasing tumor burden and metastasis ( 9 ). However, major limitations of chemotherapy remain, foremost non-specific toxicity, and tumor chemoresistance ( 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Blockade Improves Chemotherapy in the PyMT Mammary Carcinoma Mouse Model

et al. 2020

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Despite the success of immune checkpoint blockade in cancer, the number of patients that benefit from this revolutionary treatment option remains low. Therefore, efforts are being undertaken to sensitize tumors for immune checkpoint blockade, which includes combining immune checkpoint blocking agents such as anti-PD-1 antibodies with standard of care treatments. Here we report that a combination of chemotherapy (doxorubicin) and immune checkpoint blockade (anti-PD-1 antibodies) induces superior tumor control compared to chemotherapy and immune checkpoint blockade alone in the murine autochthonous polyoma middle T oncogene-driven (PyMT) mammary tumor model. Using whole transcriptome analysis, we identified a set of genes that were upregulated specifically upon chemoimmunotherapy. This gene signature and, more specifically, a condensed four-gene signature predicted favorable survival of human mammary carcinoma patients in the METABRIC cohort. Moreover, PyMT tumors treated with chemoimmunotherapy contained higher levels of cytotoxic lymphocytes, particularly natural killer cells (NK cells). Gene set enrichment analysis and bead-based ELISA measurements revealed increased IL-27 production and signaling in PyMT tumors upon chemoimmunotherapy. Moreover, IL-27 signaling improved NK cell cytotoxicity against PyMT cells in vitro. Taken together, our data support recent clinical observations indicating a benefit of chemoimmunotherapy compared to monotherapy in breast cancer and suggest potential underlying mechanisms.

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Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Blockade Improves Chemotherapy in the PyMT Mammary Carcinoma Mouse Model

et al. 2020

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“…Cancer was one of the leading causes of death in the world [1], and chemotherapy, rather than surgery or radiotherapy, remained the most effective strategy for prolonging survival and improving cancer patients' quality of life [2, 3]. Doxorubicin (Dox) was a potential chemotherapeutic agent, and its use was part of several standard regimens for different cancers [4, 5].…”

Section: Introductionmentioning

confidence: 99%

Ocotillol Enhanced the Antitumor Activity of Doxorubicin via p53-Dependent Apoptosis

Wang

Bai

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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The use of doxorubicin (Dox) was severely constrained by dose-dependent side effects, which might be attenuated by combining a “sensitizer” to decrease its cumulative dosage. In this study, it was investigated whether ocotillol could enhance the antiproliferation activity of Dox. MTT assays and xenograft tumor model were firstly conducted to evaluate the effect of ocotillol on the antitumor activity of Dox. Flow cytometry and Hoechst staining assays were then performed to assess cell apoptosis. Western blot and real-time PCR were finally used to detect the expression of p53 and its target genes. Our results showed ocotillol to enhance Dox-induced cell death in p53 wild-type cancer cells. Compared with Dox alone, Dox with ocotillol (Dox-O) could induce much more cell apoptosis and activate p53 to a much greater degree, which in turn markedly increased expression of proapoptosis genes. The enhanced cytotoxic activity was partially blocked by pifithrin-α, which might be through attenuating the increased apoptosis. Furthermore, ocotillol significantly increased the antitumor activity of Dox in A549 xenograft tumor in nude mice. These findings indicated that ocotillol could potentiate the cytotoxic effect of Dox through p53-dependent apoptosis and suggested that coadministration of ocotillol with Dox might be a potential therapeutic strategy.

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“…Breast and hepatocellular carcinoma (HCC) are the second and fifth most prevalent cancers respectively, and leading causes of cancer associated deaths in the entire world 1 2 3 . Although surgical removal of tumor is still the primary treatment of choice, apart from surgery or radiotherapy, chemotherapy remains to be most efficient way for preventing cancer cell growth and metastasis thereby enhancing the survival of cancer patients 4 . One of the major limitations of chemotherapeutic drugs is toxicity due to high dose regimen or improper efficacy of drugs towards tumor cells 5 .…”

mentioning

confidence: 99%

Strategy to enhance efficacy of doxorubicin in solid tumor cells by methyl-β-cyclodextrin: Involvement of p53 and Fas receptor ligand complex

Mohammad

Singh

Malvi

et al. 2015

Sci Rep

107

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Doxorubicin (DOX) is one of the preferred drugs for treating breast and liver cancers. However, its clinical application is limited due to severe side effects and the accompanying drug resistance. In this context, we investigated the effect on therapeutic efficacy of DOX by cholesterol depleting agent methyl-β-cyclodextrin (MCD), and explored the involvement of p53. MCD sensitizes MCF-7 and Hepa1–6 cells to DOX, Combination of MCD and marginal dose of DOX reduces the cell viability, and promoted apoptosis through induction of pro-apoptotic protein, Bax, activation of caspase-8 and caspase-7, down regulation of anti-apoptotic protein Bcl-2 and finally promoting PARP cleavage. Mechanistically, sensitization to DOX by MCD was due to the induction of FasR/FasL pathway through p53 activation. Furthermore, inhibition of p53 by pharmacological inhibitor pifithrin-α (PFT-α) or its specific siRNA attenuated p53 function and down-regulated FasR/FasL, thereby preventing cell death. Animal experiments were performed using C57BL/6J mouse isografted with Hepa1–6 cells. Tumor growth was retarded and survival increased in mice administered MCD together with DOX to as compared to either agent alone. Collectively, these results suggest that MCD enhances the sensitivity to DOX for which wild type p53 is an important determinant.

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Sequencing Surgery, Radiotherapy and Chemotherapy: Insights from a Mathematical Analysis

Cited by 20 publications

References 25 publications

Immune Checkpoint Blockade Improves Chemotherapy in the PyMT Mammary Carcinoma Mouse Model

Immune Checkpoint Blockade Improves Chemotherapy in the PyMT Mammary Carcinoma Mouse Model

Ocotillol Enhanced the Antitumor Activity of Doxorubicin via p53-Dependent Apoptosis

Strategy to enhance efficacy of doxorubicin in solid tumor cells by methyl-β-cyclodextrin: Involvement of p53 and Fas receptor ligand complex

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