311. In Vivo Anti-TumorActivity of Oncolytic Adenoviruses That Express GM-CSF in Xenograft Tumor Models

Abstract Background Chemotherapy is a widely used treatment for cancer. However, the development of acquired multidrug resistance (MDR) is a serious issue. Emerging evidence has shown that the extracellular vesicles (EVs) mediate MDR, but the underlying mechanism remains unclear, especially the effects of chemotherapeutic agents on this process. Methods Extracellular vesicles isolation was performed by differential centrifugation. The recipient cells that acquired ATP-binding cassette sub-family B member 1 (ABCB1) proteins were sorted out from co-cultures according to a stringent multi-parameter gating strategy by fluorescence-activated cell sorting (FACS). The transfer rate of ABCB1 was measured by flow cytometry. The xenograft tumor models in mice were established to evaluate the transfer of ABCB1 in vivo. Gene expression was detected by real-time PCR and Western blotting. Results Herein, we show that a transient exposure to chemotherapeutic agents can strikingly increase Rab8B-mediated release of extracellular vesicles (EVs) containing ABCB1 from drug-resistant cells, and accelerate these EVs to circulate back onto plasma membrane of sensitive tumor cells via the down-regulation of Rab5. Therefore, intercellular ABCB1 transfer is significantly enhanced; sensitive recipient cells acquire a rapid but unsustainable resistance to evade the cytotoxicity of chemotherapeutic agents. More fascinatingly, in the xenograft tumor models, chemotherapeutical drugs also locally or distantly increase the transfer of ABCB1 molecules. Furthermore, some Non-small-cell lung carcinoma (NSCLC) patients who are undergoing primary chemotherapy have a rapid increase of ABCB1 protein in their monocytes, and this is obviously associated with poor chemotherapeutic efficacy. Conclusions Chemotherapeutic agents stimulate the secretion and recycling of ABCB1-enriched EVs through the dysregulation of Rab8B and Rab5, leading to a significant increase of ABCB1 intercellular transfer, thus assisting sensitive cancer cells to develop an urgent resistant phenotype. Our findings provide a new molecular mechanism of how chemotherapeutic drugs assist sensitive cancer cells in acquiring an urgent resistance.

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1111. Anti-Tumor Studies of an Oncolytic Adenovirus That Expresses GM-CSF in Human Xenograft Tumor Models

Molecular Therapy ◽

10.1016/s1525-0016(16)41553-4 ◽

2003 ◽

Vol 7 (5) ◽

pp. S428

Keyword(s):

Oncolytic Adenovirus ◽

Xenograft Tumor ◽

Tumor Models ◽

Gm Csf ◽

Tumor Studies

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The Impact of the Low Molecular Weight Heparin Tinzaparin on the Sensitization of Cisplatin-Resistant Ovarian Cancers—Preclinical In Vivo Evaluation in Xenograft Tumor Models

Molecules ◽

10.3390/molecules22050728 ◽

2017 ◽

Vol 22 (5) ◽

pp. 728 ◽

Cited By ~ 9

Author(s):

Thomas Mueller ◽

Daniel Pfankuchen ◽

Kathleen Wantoch von Rekowski ◽

Martin Schlesinger ◽

Franziska Reipsch ◽

...

Keyword(s):

Molecular Weight ◽

Low Molecular Weight Heparin ◽

Low Molecular Weight ◽

Xenograft Tumor ◽

Tumor Models ◽

In Vivo Evaluation ◽

Ovarian Cancers ◽

The Impact

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TAK-573, an anti-CD38-targeted attenuated interferon alpha (IFNα) fusion protein, showed anti-myeloma tumor responses in combination with standard of care (SOC) agents in multiple myeloma (MM) xenograft tumor models in vivo

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2019.09.192 ◽

2019 ◽

Vol 19 (10) ◽

pp. e116 ◽

Cited By ~ 2

Author(s):

Marjan Fatholahi ◽

Miriam Valencia ◽

Armanini Mark ◽

Mingying Bi ◽

Sakeena Syed ◽

...

Keyword(s):

Multiple Myeloma ◽

Fusion Protein ◽

Interferon Alpha ◽

Standard Of Care ◽

Xenograft Tumor ◽

Tumor Models

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317. InVivo Spread of Oncolytic Adenoviruses in Xenograft Tumor Models

Molecular Therapy ◽

10.1016/s1525-0016(16)43147-3 ◽

2002 ◽

Vol 5 (5) ◽

pp. S105

Keyword(s):

Xenograft Tumor ◽

Tumor Models ◽

Oncolytic Adenoviruses

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Linked Tumor-Selective Virus Replication and Transgene Expression from E3-Containing Oncolytic Adenoviruses

Journal of Virology ◽

10.1128/jvi.79.9.5455-5465.2005 ◽

2005 ◽

Vol 79 (9) ◽

pp. 5455-5465 ◽

Cited By ~ 12

Author(s):

Mingzhu Zhu ◽

J. Andrew Bristol ◽

Yuefeng Xie ◽

Mervat Mina ◽

Hong Ji ◽

...

Keyword(s):

Simian Virus 40 ◽

Simian Virus ◽

T Antigen ◽

Cell Pair ◽

Gm Csf ◽

Oncolytic Adenoviruses ◽

E3 Region ◽

Tumor Selective

ABSTRACT Historically, the adenoviral E3 region was found to be nonessential for viral replication in vitro. In addition, adenoviruses whose genome was more than approximately 105% the size of the native genome were inefficiently packaged. These profound observations were used experimentally to insert transgenes into the adenoviral backbone. More recently, however, the reintroduction of the E3 region into oncolytic adenoviruses has been found to positively influence antitumor efficacy in preclinical models and clinical trials. In the studies reported here, the granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA sequence has been substituted for the E3-gp19 gene in oncolytic adenoviruses that otherwise retained the E3 region. Five viruses that differed slightly in the method of transgene insertion were generated and compared to Ar6pAE2fGmF (E2F/GM/ΔE3), a previously described E3-deleted oncolytic adenovirus encoding GM-CSF. In all of the viruses, the human E2F-1 promoter regulated E1A expression and GM-CSF expression was under the control of the adenoviral E3 promoter and the packaging signal was relocated immediately upstream from the right terminal repeat. The E3-gp19-deleted viruses had similar cytolytic properties, as measured in vitro by cytotoxicity assays, but differed markedly in their capacity to express and secrete GM-CSF. Ar15pAE2fGmF (E2F/GM/E3b), the virus that produced the highest levels of GM-CSF and retained the native GM-CSF leader sequence, was selected for further analysis. The E2F/GM/E3b and E2F/GM/ΔE3 viruses exhibited similar cytotoxic activity and GM-CSF production in several tumor cell lines in vitro. However, when compared in vivo in nude mouse xenograft tumor models, E2F/GM/E3b spread through tumors to a greater extent, resulted in higher peak GM-CSF and total exposure levels in both tumor and serum, and was more efficacious than the E3-deleted virus. Using the matched WI-38 (parental) and WI-38-VA13 (simian virus 40 large T antigen transformed) cell pair, GM-CSF was shown to be selectively produced in cells expressing high levels of E2F, indicating that the tumor-selective E2F promoter controlled E1A and GM-CSF expression.

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Evaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models

10.26434/chemrxiv.7877987.v1 ◽

2019 ◽

Author(s):

Daniel Sun ◽

Soumya Poddar ◽

Roy D. Pan ◽

Juno Van Valkenburgh ◽

Ethan Rosser ◽

...

Keyword(s):

Solid Tumor ◽

Small Cell Lung Carcinoma ◽

Single Agent ◽

Resistance Mechanisms ◽

Tumor Models ◽

Cell Lung Carcinoma ◽

Adaptive Resistance ◽

Cancer Models ◽

Nanomolar Range

The lead compound, an ⍺-N-heterocyclic carboxaldehyde thiosemicarbazone HCT-13, was highly potent against a panel of pancreatic, small cell lung carcinoma, and prostate cancer models, with IC90 values in the low-to-mid nanomolar range. We show that the cytotoxicity of HCT-13 is copper-dependent, that it acts as a copper ionophore, induces production of reactive oxygen species (ROS), and promotes mitochondrial dysfunction and S-phase arrest. Lastly, DNA damage response/replication stress response (DDR/RSR) pathways, specifically Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (ATR), were identified as actionable adaptive resistance mechanisms following HCT-13 treatment. Taken together, HCT-13 is potent against solid tumor models and warrants in vivo evaluation against aggressive tumor models, either as a single agent or as part of a combination therapy.

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