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1.
Mol Ther Oncolytics ; 30: 316-319, 2023 Sep 21.
Article in English | MEDLINE | ID: mdl-37732297

ABSTRACT

Oncolytic viruses are being heavily investigated as novel methods to treat cancers; however, predicting their therapeutic efficacy remains challenging. The most commonly used predictive tests involve determining the in vitro susceptibility of a tumor's malignant cells to infection with an oncolytic agent. Whether these tests are truly predictive of in vivo efficacy, however, remains unclear. Here we demonstrate that a recombinant, oncolytic myxoma virus shows efficacy in two murine models of triple negative breast cancer despite extremely low permissivity of these models to viral infection. These data demonstrate that in vitro infectivity studies are not an accurate surrogate for therapeutic efficacy and suggest that other tests need to be developed.

2.
J Immunother Cancer ; 10(4)2022 04.
Article in English | MEDLINE | ID: mdl-35414592

ABSTRACT

Surgical removal of tumors remains a front-line therapy for many types of cancer. However, this treatment often fails to eradicate disease due to either recurrence of the original tumor or development of distant micrometastases. To address these challenges, patients are often given non-curative treatments presurgery with the intent of improving surgical outcomes. These treatments, collectively known as neoadjuvant therapies, have traditionally focused on the presurgical use of chemotherapeutics. Recently, however, a variety of immunotherapies have also been identified as potentially effective in the neoadjuvant setting. One of these immunotherapies is oncolytic virotherapy, whose clinical use has exploded with the Food and Drug Administration approval of Talimogene Laherparepvec. This review summarizes both the preclinical and clinical literature examining the use of oncolytic virotherapy in the neoadjuvant setting for different types of cancers and discusses some of the major questions that still need to be addressed in order for this unique use of immunotherapy to become clinically viable.


Subject(s)
Melanoma , Oncolytic Virotherapy , Oncolytic Viruses , Humans , Immunotherapy , Melanoma/therapy , Neoadjuvant Therapy , Oncolytic Viruses/genetics
3.
Sci Signal ; 10(502)2017 Oct 24.
Article in English | MEDLINE | ID: mdl-29066540

ABSTRACT

Signaling by the transforming growth factor-ß (TGF-ß) receptors I and II (TßRI/II) and the primary cilia-localized sonic hedgehog (Shh) pathway promote cell migration and, consequently, tumor metastasis. In contrast, the sphingolipid ceramide inhibits cell proliferation and tumor metastasis. We investigated whether ceramide metabolism inhibited TßRI/II trafficking to primary cilia to attenuate cross-talk between TßRI/II and the Shh pathway. We found that ceramide synthase 4 (CerS4)-generated ceramide stabilized the association between TßRI and the inhibitory factor Smad7, which limited the trafficking of TßRI/II to primary cilia. Expression of a mutant TßRI that signals but does not interact with Smad7 prevented the CerS4-mediated inhibition of migration in various cancer cells. Genetic deletion or knockdown of CerS4 prevented the formation of the Smad7-TßRI inhibitory complex and increased the association between TßRI and the transporter Arl6 through a previously unknown cilia-targeting signal (Ala31Thr32Ala33Leu34Gln35) in TßRI. Mutating the cilia-targeting signal abolished the trafficking of TßRI to the primary cilia. Localization of TßRI to primary cilia activated a key mediator of Shh signaling, Smoothened (Smo), which stimulated cellular migration and invasion. TßRI-Smo cross-talk at the cilia in CerS4-deficient 4T1 mammary cancer cells induced liver metastasis from orthotopic allografts in both wild-type and CerS4-deficient mice, which was prevented by overexpression of Smad7 or knockdown of intraflagellar transport protein 88 (IFT88). Overall, these data reveal a ceramide-dependent mechanism that suppresses cell migration and invasion by restricting TßRI/II-Shh signaling selectively at the plasma membrane of the primary cilium.


Subject(s)
Cell Movement , Ceramides/metabolism , Cilia/metabolism , Neoplasm Metastasis/pathology , Receptors, Transforming Growth Factor beta/metabolism , A549 Cells , Animals , Cell Line, Tumor , Cell Proliferation , Ceramides/genetics , Cilia/genetics , Disease Models, Animal , Gene Knockdown Techniques , Humans , Mice , Mice, Knockout , Receptors, Transforming Growth Factor beta/genetics , Smad7 Protein/metabolism , Sphingosine N-Acyltransferase/genetics , Sphingosine N-Acyltransferase/metabolism
4.
EMBO Mol Med ; 9(8): 1030-1051, 2017 08.
Article in English | MEDLINE | ID: mdl-28606997

ABSTRACT

Human papillomavirus (HPV) infection is linked to improved survival in response to chemo-radiotherapy for patients with oropharynx head and neck squamous cell carcinoma (HNSCC). However, mechanisms involved in increased HNSCC cell death by HPV signaling in response to therapy are largely unknown. Here, using molecular, pharmacologic and genetic tools, we show that HPV early protein 7 (E7) enhances ceramide-mediated lethal mitophagy in response to chemotherapy-induced cellular stress in HPV-positive HNSCC cells by selectively targeting retinoblastoma protein (RB). Inhibition of RB by HPV-E7 relieves E2F5, which then associates with DRP1, providing a scaffolding platform for Drp1 activation and mitochondrial translocation, leading to mitochondrial fission and increased lethal mitophagy. Ectopic expression of a constitutively active mutant RB, which is not inhibited by HPV-E7, attenuated ceramide-dependent mitophagy and cell death in HPV(+) HNSCC cells. Moreover, mutation of E2F5 to prevent Drp1 activation inhibited mitophagy in HPV(+) cells. Activation of Drp1 with E2F5-mimetic peptide for inducing Drp1 mitochondrial localization enhanced ceramide-mediated mitophagy and led to tumor suppression in HPV-negative HNSCC-derived xenograft tumors in response to cisplatin in SCID mice.


Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Ceramides/metabolism , Cisplatin/administration & dosage , Membrane Proteins/metabolism , Mitophagy , Papillomavirus E7 Proteins/metabolism , Sphingosine N-Acyltransferase/metabolism , Animals , Antineoplastic Agents/metabolism , Carcinoma, Squamous Cell/pathology , Cell Death , Cell Line, Tumor , Cisplatin/metabolism , Disease Models, Animal , Heterografts , Humans , Mice, SCID , Neoplasm Transplantation , Papillomavirus E7 Proteins/genetics , Treatment Outcome
5.
Blood ; 128(15): 1944-1958, 2016 10 13.
Article in English | MEDLINE | ID: mdl-27540013

ABSTRACT

Signaling pathways regulated by mutant Fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD), which mediate resistance to acute myeloid leukemia (AML) cell death, are poorly understood. Here, we reveal that pro-cell death lipid ceramide generation is suppressed by FLT3-ITD signaling. Molecular or pharmacologic inhibition of FLT3-ITD reactivated ceramide synthesis, selectively inducing mitophagy and AML cell death. Mechanistically, FLT3-ITD targeting induced ceramide accumulation on the outer mitochondrial membrane, which then directly bound autophagy-inducing light chain 3 (LC3), involving its I35 and F52 residues, to recruit autophagosomes for execution of lethal mitophagy. Short hairpin RNA (shRNA)-mediated knockdown of LC3 prevented AML cell death in response to FLT3-ITD inhibition by crenolanib, which was restored by wild-type (WT)-LC3, but not mutants of LC3 with altered ceramide binding (I35A-LC3 or F52A-LC3). Mitochondrial ceramide accumulation and lethal mitophagy induction in response to FLT3-ITD targeting was mediated by dynamin-related protein 1 (Drp1) activation via inhibition of protein kinase A-regulated S637 phosphorylation, resulting in mitochondrial fission. Inhibition of Drp1 prevented ceramide-dependent lethal mitophagy, and reconstitution of WT-Drp1 or phospho-null S637A-Drp1 but not its inactive phospho-mimic mutant (S637D-Drp1), restored mitochondrial fission and mitophagy in response to crenolanib in FLT3-ITD+ AML cells expressing stable shRNA against endogenous Drp1. Moreover, activating FLT3-ITD signaling in crenolanib-resistant AML cells suppressed ceramide-dependent mitophagy and prevented cell death. FLT3-ITD+ AML drug resistance is attenuated by LCL-461, a mitochondria-targeted ceramide analog drug, in vivo, which also induced lethal mitophagy in human AML blasts with clinically relevant FLT3 mutations. Thus, these data reveal a novel mechanism which regulates AML cell death by ceramide-dependent mitophagy in response to FLT3-ITD targeting.


Subject(s)
Benzimidazoles/pharmacology , Ceramides , Drug Resistance, Neoplasm , Leukemia, Myeloid, Acute , Mitophagy , Mutation , Piperidines/pharmacology , RNA, Small Interfering/pharmacology , Signal Transduction , fms-Like Tyrosine Kinase 3 , Animals , Ceramides/genetics , Ceramides/metabolism , Cyclic AMP-Dependent Protein Kinases/genetics , Cyclic AMP-Dependent Protein Kinases/metabolism , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Dynamins , GTP Phosphohydrolases/genetics , GTP Phosphohydrolases/metabolism , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Male , Mice , Mice, Inbred NOD , Microtubule-Associated Proteins/antagonists & inhibitors , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Mitochondria/genetics , Mitochondria/metabolism , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Mitophagy/drug effects , Mitophagy/genetics , Phosphorylation/drug effects , Phosphorylation/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/metabolism
6.
EMBO Mol Med ; 5(1): 105-21, 2013 01.
Article in English | MEDLINE | ID: mdl-23180565

ABSTRACT

Mechanisms that alter protein phosphatase 2A (PP2A)-dependent lung tumour suppression via the I2PP2A/SET oncoprotein are unknown. We show here that the tumour suppressor ceramide binds I2PP2A/SET selectively in the nucleus and including its K209 and Y122 residues as determined by molecular modelling/simulations and site-directed mutagenesis. Because I2PP2A/SET was found overexpressed, whereas ceramide was downregulated in lung tumours, a sphingolipid analogue drug, FTY720, was identified to mimick ceramide for binding and targeting I2PP2A/SET, leading to PP2A reactivation, lung cancer cell death, and tumour suppression in vivo. Accordingly, while molecular targeting of I2PP2A/SET by stable knockdown prevented further tumour suppression by FTY720, reconstitution of WT-I2PP2A/SET expression restored this process. Mechanistically, targeting I2PP2A/SET by FTY720 mediated PP2A/RIPK1-dependent programmed necrosis (necroptosis), but not by apoptosis. The RIPK1 inhibitor necrostatin and knockdown or genetic loss of RIPK1 prevented growth inhibition by FTY720. Expression of WT- or death-domain-deleted (DDD)-RIPK1, but not the kinase-domain-deleted (KDD)-RIPK1, restored FTY720-mediated necroptosis in RIPK1(-/-) MEFs. Thus, these data suggest that targeting I2PP2A/SET by FTY720 suppresses lung tumour growth, at least in part, via PP2A activation and necroptosis mediated by the kinase domain of RIPK1.


Subject(s)
Antineoplastic Agents/pharmacology , Histone Chaperones/antagonists & inhibitors , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Propylene Glycols/pharmacology , Protein Phosphatase 2/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Sphingosine/analogs & derivatives , Transcription Factors/antagonists & inhibitors , Animals , Cell Line, Tumor , DNA-Binding Proteins , Fingolimod Hydrochloride , Gene Knockdown Techniques , Histone Chaperones/chemistry , Histone Chaperones/genetics , Histone Chaperones/metabolism , Humans , Lung Neoplasms/pathology , Mice , Mice, SCID , Models, Molecular , Necrosis , Phosphorylation , Propylene Glycols/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Sphingosine/metabolism , Sphingosine/pharmacology , Transcription Factors/chemistry , Transcription Factors/genetics , Transcription Factors/metabolism , Xenograft Model Antitumor Assays
7.
EMBO Mol Med ; 4(2): 78-92, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22180294

ABSTRACT

Histone deacetylases (HDACs) and microRNAs (miRs) have pro-survival roles, but the mechanism behind this is unclear. Repression of ceramide synthase 1 (CerS1), altering C(18) -ceramide generation, was linked to drug resistance and metastasis. Here we report that the CerS1 promoter was repressed by HDAC1-dependent inhibition of Sp1 recruitment to two specific GC-boxes spanning the -177 and -139 region. Moreover, an alternatively spliced variant CerS1 mRNA (CerS1-2) was detected mainly in cancer cells or primary tumour tissues compared to controls, which was targeted by miR-574-5p for degradation. A specific 3'UTR-targeting site, localized within the retained intron between exons 6 and 7, was identified, and its mutation, or miR-574-5p knockdown prevented the degradation of CerS1-2 mRNA. Interference with HDAC1 and miR-574-5p reconstituted CerS1-2 expression and C(18) -ceramide generation in multiple human cancer cell lines, which subsequently inhibited proliferation and anchorage-independent growth. Accordingly, knockdown of CerS1 partially protected cancer cells from MS-275/miR-574-5p siRNA-mediated growth inhibition. Thus, these data suggest that the HDAC1/miR-574-5p axis might provide a novel therapeutic target to reconstitute tumour suppressor CerS1/ceramide signalling.


Subject(s)
Gene Expression Regulation, Neoplastic , Histone Deacetylase 1/genetics , Membrane Proteins/genetics , MicroRNAs/genetics , Neoplasms/genetics , Sphingosine N-Acyltransferase/genetics , 3' Untranslated Regions , Alternative Splicing , Cell Line, Tumor , Cell Proliferation , Humans , Membrane Proteins/metabolism , Neoplasms/pathology , Signal Transduction/genetics , Sphingosine N-Acyltransferase/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
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