Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

Sun, Jessica; Liu, Qian; Ahluwalia, Dharmendra; Li, Wenwu; Meng, Fanying; Wang, Yan; Bhupathi, Deepthi; Ruprell, Ayesha S.; Hart, Charles P.

doi:10.1080/15384047.2014.1003005

Cited by 48 publications

(38 citation statements)

References 44 publications

(52 reference statements)

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“…A similar result was found with a combination of a chemopreventive agent (silibinin) and doxorubicin in which specific drug concentrations of 100 × 10 −6 m silibinin/25 × 10 −9 m doxorubicin produced a synergistic effect in breast cancer cells . Our result is also consistent with a few other studies, including a phase II clinical trial, that demonstrated synergistic effects of TH‐302 combined with chemotherapy and radiotherapy treatments against cancer cells . The enhanced efficacy of doxorubicin at a low concentration of 100 × 10 −9 m by addition of 10 × 10 −6 m TH‐302 is also advantageous from a practical standpoint to prevent/reduce cardiotoxic side effects .…”

Section: Resultssupporting

confidence: 90%

“…We used a hypoxia activated prodrug, TH‐302, that has progressed to clinical studies . TH‐302 is reduced under hypoxic conditions, releasing a DNA crosslinker bromo‐isophosphoramide mustard . This mechanism of TH‐302 allows selective drug activation in hypoxic cells in a tumor and has shown hypoxia‐induced cytotoxicity against 32 human cancer cell lines .…”

Section: Resultsmentioning

confidence: 99%

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Engineered Breast Cancer Cell Spheroids Reproduce Biologic Properties of Solid Tumors

Ham

Joshi

Luker

et al. 2016

Adv Healthcare Materials

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Solid tumors develop as three-dimensional tissue constructs. As tumors grow larger, spatial gradients of nutrients and oxygen and inadequate diffusive supply to cells distant from vasculature develops. Hypoxia initiates signaling and transcriptional alterations to promote survival of cancer cells and generation of cancer stem cells (CSCs) that have self-renewal and tumor-initiation capabilities. Both hypoxia and CSCs are associated with resistance to therapies and tumor relapse. Here, we conduct a systematic study to demonstrate that 3D cancer cell models, known as tumor spheroids, generated with a polymeric aqueous two-phase system (ATPS) technology capture these important biological processes. Similar to solid tumors, spheroids of triple negative breast cancer (TNBC) cells deposit major extracellular matrix proteins. Our molecular analysis establishes presence of hypoxic cells in the core region and expression of CSC gene and protein markers including CD24, CD133, and Nanog. Importantly, these spheroids resist treatment with chemotherapy drugs. We successfully target drug resistant spheroids through a combination treatment approach using a hypoxia-activated prodrug, TH-302, and a chemotherapy drug, doxorubicin. This study demonstrates that ATPS spheroids recapitulate important biological and functional properties of solid tumors and provide a unique model for studies in cancer research.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Engineered Breast Cancer Cell Spheroids Reproduce Biologic Properties of Solid Tumors

Ham

Joshi

Luker

et al. 2016

Adv Healthcare Materials

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“…We reasoned that if tumour-initiating cells (TIC) reside in a hypoxic microenvironment, then they would be sensitive to the hypoxia-activated prodrug TH-302 but relatively resistant to ionizing radiation. TH-302 (evofosfamide) is a 2-nitroimidazole [24-27] whose reductive metabolism produces an alkylating species that causes DNA damage in quiescent as well as proliferating cells. It was recently tested in combination with gemcitabine in a large randomized clinical trial, MAESTRO, treating patients with advanced pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302

et al. 2016

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Previous reports have suggested that the hypoxic microenvironment provides a niche that supports tumor stem cells, and that this might explain clinical observations linking hypoxia to metastasis. To test this, we examined the effects of a hypoxia-activated prodrug, TH-302, on the tumor-initiating cell (TIC) frequency of patient-derived pancreatic xenografts (PDX).The frequencies of TIC, measured by limiting dilution assay, varied widely in 11 PDX models, and were correlated with rapid growth but not with the levels of hypoxia. Treatment with either TH-302 or ionizing radiation (IR), to target hypoxic and well-oxygenated regions, respectively, reduced TIC frequency, and the combination of TH-302 and IR was much more effective in all models tested. The combination was also more effective than TH-302 or IR alone controlling tumor growth, particularly treating the more rapidly-growing/hypoxic models. These findings support the clinical utility of hypoxia targeting in combination with radiotherapy to treat pancreatic cancers, but do not provide strong evidence for a hypoxic stem cell niche.

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“…In a xenograft model of pancreatic cancer, TH-302 showed promising activity with gemcitabine, decreasing the frequency of tumor-initiating cells from patient-derived xenografts in combination with ionizing radiation (37). TH-302 also improved the efficacy of a gemcitabine and nab-paclitaxel combination in mouse xenograft models of human pancreatic ductal adenocarcinoma (PDAC) (51). The addition of TH-302 to topotecan improved tumor response and prolonged survival in neuroblastoma and rhabdomyosarcoma xenograft models (52).…”

Section: Clinical–translational Advancesmentioning

confidence: 99%

Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy

Baran

Konopleva

2017

Clinical Cancer Research

111

123

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Hypoxia is a known feature of aggressive solid tumors as well as a critical hallmark of the niche in aggressive hematologic malignances. Hypoxia is associated with insufficient response to standard therapy, resulting in disease progression and curtailed patients’ survival through maintenance of noncycling cancer stem-like cells. A better understanding of the mechanisms and signaling pathways induced by hypoxia is essential to overcoming these effects. Recent findings demonstrate that bone marrow in the setting of hematologic malignancies is highly hypoxic and that progression of the disease is associated with expansion of hypoxic niches and stabilization of the oncogenic hypoxia-inducible factor-1alpha (HIF-1α). Solid tumors have also been shown to harbor hypoxic areas, maintaining survival of cancer cells via the HIF-1α pathway. Developing new strategies for targeting hypoxia has become a crucial approach in modern cancer therapy. The number of preclinical and clinical trials targeting low-oxygen tumor compartments or the hypoxic bone marrow niche via hypoxia-activated prodrugs is increasing. This review discusses the development of the hypoxia-activated prodrugs and their applicability in treating both hematologic malignancies and solid tumors.

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Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

Abstract: (2015) Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer, Cancer Biology & Therapy, 16:3,[438][439][440][441][442][443][444][445][446][447][448][449]

Cited by 48 publications

References 44 publications

Engineered Breast Cancer Cell Spheroids Reproduce Biologic Properties of Solid Tumors

Engineered Breast Cancer Cell Spheroids Reproduce Biologic Properties of Solid Tumors

Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302

Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy

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