Atique Ahmed | Northwestern University (original) (raw)

Papers by Atique Ahmed

Research paper thumbnail of Crossing the boundaries: Stem cells and gene therapy

Discovery medicine

Oncolytic virotherapy is an emerging therapeutic modality for the treatment of cancer. It entails... more Oncolytic virotherapy is an emerging therapeutic modality for the treatment of cancer. It entails construction of viruses with the ability to selectively target and lyse tumor cells. This branch of therapy has significantly advanced in the past decade, heralded by the development of several novel viruses. Despite the initial success of oncolytic virotherapy in the preclinical setting, however, this modality remains hindered by several obstacles. First, failure to achieve effective viral delivery to targeted tumor beds is a well known limitation. Second, the virus-neutralizing mechanisms of the host immune system, which are in place to protect from viral pathogens, may also hinder the therapeutic potential of virotherapy. One approach to tackling these shortcomings is the use of a cellbased carriers to both help with delivery of the virus and shield it from immunosurveillance. Stem cells have recently surfaced as a potential cell-based candidate for delivery of virotherapy. Their unique migratory and immunosuppressive qualities have made them an exciting avenue of investigation. The focus of this review is to discuss the benefits of stem-cell-based delivery of oncolytic virotherapy and its role in cancer treatment.

Research paper thumbnail of ET-29 * an Optimized Oncolytic Adenovirus for Glioma Therapy: Specific Targeting, Efficient Infection, and Restricted Replication in Glioma

Neuro-Oncology, 2014

The dismal clinical context of advanced-grade glioma calls for the development of novel strategie... more The dismal clinical context of advanced-grade glioma calls for the development of novel strategies with the potential for direct patient impact. For this, conditionally replicating adenoviruses (CRAds) represent a potentially effective approach for glioma therapy. In order to maximize the efficiency and safety of CRAds, several modifications may be instituted, including specific and efficient targeting, as well as tumor-restricted replication. A gliomaspecific targeted fiber, which dictates the attachment of an adenoviral vector to a target cell, was developed and generated specific cell-targeting fibers through the incorporation of glioma-specific phage-panned peptides on a Fiber Fibritin-based Ad5 fiber, designated as 'MGFF'. We then generated Ad5MGFF-CMV-GFP (and Survivin-E1) through a homologous recombination with pVK900. Replication-incompetent Ad5MGFF-CMV-GFP was used with 300MOI (vp/cell) to investigate glioma-specific infectivity. Conditionally replicating Ad5MGFF-SurE1 was used to test the specific oncolytic activity on Glioma. The fiber-modified Ad5MGFF shows structural stability and stable viral growth kinetics, indicating that the performed modification had no effect on viral particle formation. This glioma-specific Ad5MGFF-CMVGFP had a mean 68% infection rate in glioma cell lines while showing less than 1% infection in normal (non-neoplastic) cell lines (including normal human astrocytes) as well as other cancer cell lines.

Research paper thumbnail of Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases

Stem cells (Dayton, Ohio), Jan 11, 2015

The treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has... more The treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has been revolutionized by trastuzumab. However, longer survival of these patients now predisposes them to forming HER2 positive brain metastases, as the therapeutic antibodies cannot cross the blood brain barrier. The current oncologic repertoire does not offer a rational, nontoxic targeted therapy for brain metastases. In this study, we used an established human neural stem cell line, HB1.F3 NSCs and generated a stable pool of cells secreting a high amount of functional full-length anti-HER2 antibody, equivalent to trastuzumab. Anti-HER2Ab secreted by the NSCs (HER2Ab-NSCs) specifically binds to HER2 overexpressing human breast cancer cells and inhibits PI3K-Akt signaling. This translates to HER2Ab-NSC inhibition of breast cancer cell growth in vitro. Preclinical in vivo experiments using HER2Ab overexpressing NSCs in a breast cancer brain metastases (BCBM) mouse model demonstrate that in...

Research paper thumbnail of Dendritic Cell-Based Vaccines that Utilize Myeloid Rather than Plasmacytoid Cells Offer a Superior Survival Advantage in Malignant Glioma

Journal of immunology (Baltimore, Md. : 1950), Jan 29, 2015

Dendritic cells (DCs) are professional APCs that are traditionally divided into two distinct subs... more Dendritic cells (DCs) are professional APCs that are traditionally divided into two distinct subsets, myeloid DC (mDCs) and plasmacytoid DC (pDCs). pDCs are known for their ability to secrete large amounts of IFN-α. Apart from IFN-α production, pDCs can also process Ag and induce T cell immunity or tolerance. In several solid tumors, pDCs have been shown to play a critical role in promoting tumor immunosuppression. We investigated the role of pDCs in the process of glioma progression in the syngeneic murine model of glioma. We show that glioma-infiltrating pDCs are the major APC in glioma and are deficient in IFN-α secretion (p < 0.05). pDC depletion leads to increased survival of the mice bearing intracranial tumor by decreasing the number of regulatory T cells (Tregs) and by decreasing the suppressive capabilities of Tregs. We subsequently compared the ability of mDCs and pDCs to generate effective antiglioma immunity in a GL261-OVA mouse model of glioma. Our data suggest that ...

Research paper thumbnail of A Genetically Modified Adenoviral Vector with a Phage Display Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma

Human gene therapy, Jan 25, 2015

The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic... more The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma specific adenovirus by instituting more advanced genetic modifications which can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptides (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as 'GliomaFF.' We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. Additionally, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restr...

Research paper thumbnail of The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence

Expert Review of Neurotherapeutics, 2015

Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glio... more Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glioblastoma. They are able to self-renew, recapitulate a whole tumor, and differentiate into other specific glioblastoma multiforme (GBM) subpopulations. Therefore, they have been held responsible for malignant relapse after primary standard therapy and the poor prognosis of recurrent GBM. The failure of current therapies to eliminate specific GSC subpopulations has been considered a major factor contributing to the inevitable recurrence in GBM patients after treatment. Here, we discuss the molecular mechanisms of chemoresistance of GSCs and the reasons why complete eradication of GSCs is so difficult to achieve. We will also describe the targeted therapies currently available for GSCs and possible mechanisms to overcome such chemoresistance and avoid therapeutic relapse.

Research paper thumbnail of Balyasnikova-et-al-Intranasal delivery of MSCs-Brain tumors-2013-mol research

A c c e p t e d m a n u s c r i p t ACCEPTED ARTICLE PREVIEW A c c e p t e d m a n u s c r i p t ... more A c c e p t e d m a n u s c r i p t ACCEPTED ARTICLE PREVIEW A c c e p t e d m a n u s c r i p t ACCEPTED ARTICLE PREVIEW Abstract Treatment options of glioblastoma multiforme are limited due to the blood brain barrier.

Research paper thumbnail of Advances in stem cells, induced pluripotent stem cells, and engineered cells: delivery vehicles for anti-glioma therapy

Expert Opinion on Drug Delivery, 2014

A limitation of small molecule inhibitors, nanoparticles (NPs) and therapeutic adenoviruses is th... more A limitation of small molecule inhibitors, nanoparticles (NPs) and therapeutic adenoviruses is their incomplete distribution within the entirety of solid tumors such as malignant gliomas. Currently, cell-based carriers are making their way into the clinical setting as they offer the potential to selectively deliver many types of therapies to cancer cells. Here, we review the properties of stem cells, induced pluripotent stem cells and engineered cells that possess the tumor-tropic behavior necessary to serve as cell carriers. We also report on the different types of therapeutic agents that have been delivered to tumors by these cell carriers, including: i) therapeutic genes; ii) oncolytic viruses; iii) NPs; and iv) antibodies. The current challenges and future promises of cell-based drug delivery are also discussed. While the emergence of stem cell-mediated therapy has resulted in promising preclinical results and a human clinical trial utilizing this approach is currently underway, there is still a need to optimize these delivery platforms. By improving the loading of therapeutic agents into stem cells and enhancing their migratory ability and persistence, significant improvements in targeted cancer therapy may be achieved.

Research paper thumbnail of Therapeutic cell carriers: a potential road to cure glioma

Expert review of neurotherapeutics, 2014

Many different experimental molecular therapeutic approaches have been evaluated in an attempt to... more Many different experimental molecular therapeutic approaches have been evaluated in an attempt to treat brain cancer. However, despite the success of these experimental molecular therapies, research has shown that the specific and efficient delivery of therapeutic agents to tumor cells is a limitation. In this regard, cell carrier systems have garnered significant attraction due to their capacity to be loaded with therapeutic agents and carry them specifically to tumor sites. Furthermore, cell carriers can be genetically modified to express therapeutic agents that can directly eradicate cancerous cells or can modulate tumor microenvironments. This review describes the current state of cell carriers, their use as vehicles for the delivery of therapeutic agents to brain tumors, and future directions that will help overcome the present obstacles to cell carrier mediated therapy for brain cancer.

Research paper thumbnail of Nanoparticle-Programmed Self-Destructive Neural Stem Cells for Glioblastoma Targeting and Therapy

Research paper thumbnail of Heme oxygenase-1 protects regulatory T cells from hypoxia-induced cellular stress in an experimental mouse brain tumor model

Journal of Neuroimmunology, 2014

Two characteristic features of malignant gliomas (MG) are the presence of hypoxia and accumulatio... more Two characteristic features of malignant gliomas (MG) are the presence of hypoxia and accumulation of regulatory T cells (Tregs). Heme-oxygenase-1 (HO1) is a cytoprotective enzyme expressed in high level by Tregs in glioma. In this study, we show that higher HO1 expression in Tregs is associated with increased survival under hypoxic conditions and that HO1 inhibitor, tin protoporphyrin (SnPP), abrogates the survival benefits. Moreover, SnPP preferentially eliminates Tregs and treatment with SnPP of tumor bearing mice significantly increases survival (23 to 31days (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05)). Thus HO1 inhibition provides another alternative way of therapeutically targeting Tregs in MG.

Research paper thumbnail of Antiglioma oncolytic virotherapy: unattainable goal or a success story in the making?

Research paper thumbnail of Abstract 1659: Targeting SIAH2-dependent proteolysis downstream of the HER2/EGFR/RAS signaling pathway to inhibit tumorigenesis and metastasis of highly invasive human breast cancer

Research paper thumbnail of Abstract 3487: Distant delivery of glioma-restricted oncolytic adenovirus loaded into a neural stem cell-based carrier prolongs the survival of animals with human glioblastoma

Research paper thumbnail of Abstract A1: SIAH E3 ligase as a novel anticancer drug target to inhibit RAS-mediated tumorigenesis and metastasis in human cancer cells

Research paper thumbnail of Abstract P6-15-14: Inhibit SIAH E3 Ligase, a Downstream Signaling Module Required for the HER2/EGFR/RAS Signal Transduction, To Block Tumorigenesis and Metastasis of Highly Invasive Human Breast Cancers

Research paper thumbnail of Depletion of myeloid-derived suppressor cells during interleukin-12 immunogene therapy does not confer a survival advantage in experimental malignant glioma

Cancer Gene Therapy, 2014

Myeloid-derived suppressor cells (MDSCs) accumulate in the glioma microenvironment during tumor p... more Myeloid-derived suppressor cells (MDSCs) accumulate in the glioma microenvironment during tumor progression and promote immunosuppression. Interleukin-12 (IL-12) immunogene therapy can alter MDSCs toward an antigen-presenting cell phenotype and these mature cells can have a central role in antigen presentation. It remains unclear, however, how MDSC depletion can affect glioma immunotherapy. In this study, we generated a replication-deficient adenoviral vector, Ad.5/3.cRGD-mIL12p70, that transduces the GL261-based murine glioma cell line, resulting in the induction of biologically active, murine IL12p70 expression. Ex vivo, IL-12 expressed by GL261 cells induced interferon-g synthesis in CD8 þ T cells (Po0.001), CD4 þ T cells (P ¼ 0.009) and natural killer cells (P ¼ 0.036). When injected 1 week after tumor implantation, Ad.5/3.cRGD-mIL12p70 successfully prolonged the survival of glioma-bearing mice. Sixty percent of animals treated with IL-12 immunotherapy were long-term survivors over 175 days, whereas all the control group animals expired by 40 days after tumor implantation (P ¼ 0.026). Mice receiving Ad.5/3.cRGD-mIL12p70 also accumulated 50% less MDSCs in the brain than the control group (P ¼ 0.007). Moreover, in the IL-12 group, MDSCs significantly overexpressed CD80 and major histocompatibility complex class II molecules (P ¼ 0.041). Depletion of MDSCs with Gr1 þ antibody had no survival benefit induced by IL-12-mediated immunotherapy. Of note, IL-12 therapy increased the presence of myeloid dendritic cells (mDCs) in the glioma microenvironment (P ¼ 0.0069). Ultimately, the data show that in the context of IL-12 immunogene therapy, MDSCs are dispensable and mDCs may provide the majority of antigen presentation in the brain.

Research paper thumbnail of 46. Upregulation of indoleamine 2,3-dioxygenase in brain tumors is associated with decreased survival through a T cell-dependent mechanism

Brain, Behavior, and Immunity, 2012

ABSTRACT Glioblastoma multiforme (GBM) is a malignant and aggressive primary brain tumor with an ... more ABSTRACT Glioblastoma multiforme (GBM) is a malignant and aggressive primary brain tumor with an average patient survival of 14.6 months following diagnosis. Our laboratory has previously demonstrated that immunosuppressive regulatory T cells (Tregs; CD4+FoxP3+) infiltrate and accumulate in brain tumors, by utilizing mouse models. Importantly, depleting those Tregs is associated with a significant increase in overall survival. To understand the underlying mechanisms that promote Treg recruitment to brain tumors, our laboratory has investigated the enzyme, indoleamine 2,3-dioxygenase 1 (IDO). We have found that the upregulation of IDO in glioma patients (n = 343) is associated with a significantly decreased probability of overall survival (p &lt; 0.005). Utilizing a mouse model that intracranially-injects GL261 (brain tumor) cells, we have confirmed that IDO knockdown (IDOkd), specifically in brain tumor cells, results in decreased Treg recruitment to the tumor, as well as increased long-term survival (p &lt; 0.001). This was accomplished by comparing WT and IDO−/− mice, intracranially-injected control or IDOkd GL261 cells (p &lt; 0.001). Interestingly, the long-term survival mediated through IDO-deficiency was lost in CD4−/−, CD8−/− and Rag1−/− mice, suggesting a contextual role for T cells in mediating brain tumor rejection vs. promotion. These data confirm the importance of IDO1 in brain tumors and provide further support for understanding the mechanism of immune-mediated IDO1-dependent tumor progression.

Research paper thumbnail of Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors

Molecular Therapy, 2014

A c c e p t e d m a n u s c r i p t ACCEPTED ARTICLE PREVIEW A c c e p t e d m a n u s c r i p t ... more A c c e p t e d m a n u s c r i p t ACCEPTED ARTICLE PREVIEW A c c e p t e d m a n u s c r i p t ACCEPTED ARTICLE PREVIEW Abstract Treatment options of glioblastoma multiforme are limited due to the blood brain barrier.

Research paper thumbnail of Stem Cell-Based Cell Carrier for Targeted Oncolytic Virotherapy: Translational Opportunity and Open Questions.

Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus... more Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus to promote cell lysis is harnessed and reprogrammed to selectively destroy cancer cells. Such treatment modalities exhibited antitumor activity in preclinical and clinical settings and appear to be well tolerated when tested in clinical trials. However, the clinical success of oncolytic virotherapy has been significantly hampered due to the inability to target systematic metastasis. This is partly due to the inability of the therapeutic virus to survive in the patient circulation, in order to target tumors at distant sites. An early study from various laboratories demonstrated that cells infected with oncolytic virus can protect the therapeutic payload form the host immune system as well as function as factories for virus production and enhance the therapeutic efficacy of oncolytic virus. While a variety of cell lineages possessed potential as cell carriers, copious investigation has established stem cells as a very attractive cell carrier system in oncolytic virotherapy. The ideal cell carrier desire to be susceptible to viral infection as well as support viral infection, maintain immunosuppressive properties to shield the loaded viruses from the host immune system, and most importantly possess an intrinsic tumor homing ability to deliver loaded viruses directly to the site of the metastasis-all qualities stem cells exhibit. In this review, we summarize the recent work in the development of stem cell-based carrier for oncolytic virotherapy, discuss the advantages and disadvantages of a variety of cell carriers, especially focusing on why stem cells have emerged as the leading candidate, and finally propose a future direction for stem cell-based targeted oncolytic virotherapy that involves its establishment as a viable treatment option for cancer patients in the clinical setting.

Research paper thumbnail of Crossing the boundaries: Stem cells and gene therapy

Discovery medicine

Oncolytic virotherapy is an emerging therapeutic modality for the treatment of cancer. It entails... more Oncolytic virotherapy is an emerging therapeutic modality for the treatment of cancer. It entails construction of viruses with the ability to selectively target and lyse tumor cells. This branch of therapy has significantly advanced in the past decade, heralded by the development of several novel viruses. Despite the initial success of oncolytic virotherapy in the preclinical setting, however, this modality remains hindered by several obstacles. First, failure to achieve effective viral delivery to targeted tumor beds is a well known limitation. Second, the virus-neutralizing mechanisms of the host immune system, which are in place to protect from viral pathogens, may also hinder the therapeutic potential of virotherapy. One approach to tackling these shortcomings is the use of a cellbased carriers to both help with delivery of the virus and shield it from immunosurveillance. Stem cells have recently surfaced as a potential cell-based candidate for delivery of virotherapy. Their unique migratory and immunosuppressive qualities have made them an exciting avenue of investigation. The focus of this review is to discuss the benefits of stem-cell-based delivery of oncolytic virotherapy and its role in cancer treatment.

Research paper thumbnail of ET-29 * an Optimized Oncolytic Adenovirus for Glioma Therapy: Specific Targeting, Efficient Infection, and Restricted Replication in Glioma

Neuro-Oncology, 2014

The dismal clinical context of advanced-grade glioma calls for the development of novel strategie... more The dismal clinical context of advanced-grade glioma calls for the development of novel strategies with the potential for direct patient impact. For this, conditionally replicating adenoviruses (CRAds) represent a potentially effective approach for glioma therapy. In order to maximize the efficiency and safety of CRAds, several modifications may be instituted, including specific and efficient targeting, as well as tumor-restricted replication. A gliomaspecific targeted fiber, which dictates the attachment of an adenoviral vector to a target cell, was developed and generated specific cell-targeting fibers through the incorporation of glioma-specific phage-panned peptides on a Fiber Fibritin-based Ad5 fiber, designated as 'MGFF'. We then generated Ad5MGFF-CMV-GFP (and Survivin-E1) through a homologous recombination with pVK900. Replication-incompetent Ad5MGFF-CMV-GFP was used with 300MOI (vp/cell) to investigate glioma-specific infectivity. Conditionally replicating Ad5MGFF-SurE1 was used to test the specific oncolytic activity on Glioma. The fiber-modified Ad5MGFF shows structural stability and stable viral growth kinetics, indicating that the performed modification had no effect on viral particle formation. This glioma-specific Ad5MGFF-CMVGFP had a mean 68% infection rate in glioma cell lines while showing less than 1% infection in normal (non-neoplastic) cell lines (including normal human astrocytes) as well as other cancer cell lines.

Research paper thumbnail of Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases

Stem cells (Dayton, Ohio), Jan 11, 2015

The treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has... more The treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has been revolutionized by trastuzumab. However, longer survival of these patients now predisposes them to forming HER2 positive brain metastases, as the therapeutic antibodies cannot cross the blood brain barrier. The current oncologic repertoire does not offer a rational, nontoxic targeted therapy for brain metastases. In this study, we used an established human neural stem cell line, HB1.F3 NSCs and generated a stable pool of cells secreting a high amount of functional full-length anti-HER2 antibody, equivalent to trastuzumab. Anti-HER2Ab secreted by the NSCs (HER2Ab-NSCs) specifically binds to HER2 overexpressing human breast cancer cells and inhibits PI3K-Akt signaling. This translates to HER2Ab-NSC inhibition of breast cancer cell growth in vitro. Preclinical in vivo experiments using HER2Ab overexpressing NSCs in a breast cancer brain metastases (BCBM) mouse model demonstrate that in...

Research paper thumbnail of Dendritic Cell-Based Vaccines that Utilize Myeloid Rather than Plasmacytoid Cells Offer a Superior Survival Advantage in Malignant Glioma

Journal of immunology (Baltimore, Md. : 1950), Jan 29, 2015

Dendritic cells (DCs) are professional APCs that are traditionally divided into two distinct subs... more Dendritic cells (DCs) are professional APCs that are traditionally divided into two distinct subsets, myeloid DC (mDCs) and plasmacytoid DC (pDCs). pDCs are known for their ability to secrete large amounts of IFN-α. Apart from IFN-α production, pDCs can also process Ag and induce T cell immunity or tolerance. In several solid tumors, pDCs have been shown to play a critical role in promoting tumor immunosuppression. We investigated the role of pDCs in the process of glioma progression in the syngeneic murine model of glioma. We show that glioma-infiltrating pDCs are the major APC in glioma and are deficient in IFN-α secretion (p < 0.05). pDC depletion leads to increased survival of the mice bearing intracranial tumor by decreasing the number of regulatory T cells (Tregs) and by decreasing the suppressive capabilities of Tregs. We subsequently compared the ability of mDCs and pDCs to generate effective antiglioma immunity in a GL261-OVA mouse model of glioma. Our data suggest that ...

Research paper thumbnail of A Genetically Modified Adenoviral Vector with a Phage Display Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma

Human gene therapy, Jan 25, 2015

The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic... more The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma specific adenovirus by instituting more advanced genetic modifications which can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptides (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as 'GliomaFF.' We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. Additionally, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restr...

Research paper thumbnail of The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence

Expert Review of Neurotherapeutics, 2015

Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glio... more Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glioblastoma. They are able to self-renew, recapitulate a whole tumor, and differentiate into other specific glioblastoma multiforme (GBM) subpopulations. Therefore, they have been held responsible for malignant relapse after primary standard therapy and the poor prognosis of recurrent GBM. The failure of current therapies to eliminate specific GSC subpopulations has been considered a major factor contributing to the inevitable recurrence in GBM patients after treatment. Here, we discuss the molecular mechanisms of chemoresistance of GSCs and the reasons why complete eradication of GSCs is so difficult to achieve. We will also describe the targeted therapies currently available for GSCs and possible mechanisms to overcome such chemoresistance and avoid therapeutic relapse.

Research paper thumbnail of Balyasnikova-et-al-Intranasal delivery of MSCs-Brain tumors-2013-mol research

A c c e p t e d m a n u s c r i p t ACCEPTED ARTICLE PREVIEW A c c e p t e d m a n u s c r i p t ... more A c c e p t e d m a n u s c r i p t ACCEPTED ARTICLE PREVIEW A c c e p t e d m a n u s c r i p t ACCEPTED ARTICLE PREVIEW Abstract Treatment options of glioblastoma multiforme are limited due to the blood brain barrier.

Research paper thumbnail of Advances in stem cells, induced pluripotent stem cells, and engineered cells: delivery vehicles for anti-glioma therapy

Expert Opinion on Drug Delivery, 2014

A limitation of small molecule inhibitors, nanoparticles (NPs) and therapeutic adenoviruses is th... more A limitation of small molecule inhibitors, nanoparticles (NPs) and therapeutic adenoviruses is their incomplete distribution within the entirety of solid tumors such as malignant gliomas. Currently, cell-based carriers are making their way into the clinical setting as they offer the potential to selectively deliver many types of therapies to cancer cells. Here, we review the properties of stem cells, induced pluripotent stem cells and engineered cells that possess the tumor-tropic behavior necessary to serve as cell carriers. We also report on the different types of therapeutic agents that have been delivered to tumors by these cell carriers, including: i) therapeutic genes; ii) oncolytic viruses; iii) NPs; and iv) antibodies. The current challenges and future promises of cell-based drug delivery are also discussed. While the emergence of stem cell-mediated therapy has resulted in promising preclinical results and a human clinical trial utilizing this approach is currently underway, there is still a need to optimize these delivery platforms. By improving the loading of therapeutic agents into stem cells and enhancing their migratory ability and persistence, significant improvements in targeted cancer therapy may be achieved.

Research paper thumbnail of Therapeutic cell carriers: a potential road to cure glioma

Expert review of neurotherapeutics, 2014

Many different experimental molecular therapeutic approaches have been evaluated in an attempt to... more Many different experimental molecular therapeutic approaches have been evaluated in an attempt to treat brain cancer. However, despite the success of these experimental molecular therapies, research has shown that the specific and efficient delivery of therapeutic agents to tumor cells is a limitation. In this regard, cell carrier systems have garnered significant attraction due to their capacity to be loaded with therapeutic agents and carry them specifically to tumor sites. Furthermore, cell carriers can be genetically modified to express therapeutic agents that can directly eradicate cancerous cells or can modulate tumor microenvironments. This review describes the current state of cell carriers, their use as vehicles for the delivery of therapeutic agents to brain tumors, and future directions that will help overcome the present obstacles to cell carrier mediated therapy for brain cancer.

Research paper thumbnail of Nanoparticle-Programmed Self-Destructive Neural Stem Cells for Glioblastoma Targeting and Therapy

Research paper thumbnail of Heme oxygenase-1 protects regulatory T cells from hypoxia-induced cellular stress in an experimental mouse brain tumor model

Journal of Neuroimmunology, 2014

Two characteristic features of malignant gliomas (MG) are the presence of hypoxia and accumulatio... more Two characteristic features of malignant gliomas (MG) are the presence of hypoxia and accumulation of regulatory T cells (Tregs). Heme-oxygenase-1 (HO1) is a cytoprotective enzyme expressed in high level by Tregs in glioma. In this study, we show that higher HO1 expression in Tregs is associated with increased survival under hypoxic conditions and that HO1 inhibitor, tin protoporphyrin (SnPP), abrogates the survival benefits. Moreover, SnPP preferentially eliminates Tregs and treatment with SnPP of tumor bearing mice significantly increases survival (23 to 31days (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05)). Thus HO1 inhibition provides another alternative way of therapeutically targeting Tregs in MG.

Research paper thumbnail of Antiglioma oncolytic virotherapy: unattainable goal or a success story in the making?

Research paper thumbnail of Abstract 1659: Targeting SIAH2-dependent proteolysis downstream of the HER2/EGFR/RAS signaling pathway to inhibit tumorigenesis and metastasis of highly invasive human breast cancer

Research paper thumbnail of Abstract 3487: Distant delivery of glioma-restricted oncolytic adenovirus loaded into a neural stem cell-based carrier prolongs the survival of animals with human glioblastoma

Research paper thumbnail of Abstract A1: SIAH E3 ligase as a novel anticancer drug target to inhibit RAS-mediated tumorigenesis and metastasis in human cancer cells

Research paper thumbnail of Abstract P6-15-14: Inhibit SIAH E3 Ligase, a Downstream Signaling Module Required for the HER2/EGFR/RAS Signal Transduction, To Block Tumorigenesis and Metastasis of Highly Invasive Human Breast Cancers

Research paper thumbnail of Depletion of myeloid-derived suppressor cells during interleukin-12 immunogene therapy does not confer a survival advantage in experimental malignant glioma

Cancer Gene Therapy, 2014

Myeloid-derived suppressor cells (MDSCs) accumulate in the glioma microenvironment during tumor p... more Myeloid-derived suppressor cells (MDSCs) accumulate in the glioma microenvironment during tumor progression and promote immunosuppression. Interleukin-12 (IL-12) immunogene therapy can alter MDSCs toward an antigen-presenting cell phenotype and these mature cells can have a central role in antigen presentation. It remains unclear, however, how MDSC depletion can affect glioma immunotherapy. In this study, we generated a replication-deficient adenoviral vector, Ad.5/3.cRGD-mIL12p70, that transduces the GL261-based murine glioma cell line, resulting in the induction of biologically active, murine IL12p70 expression. Ex vivo, IL-12 expressed by GL261 cells induced interferon-g synthesis in CD8 þ T cells (Po0.001), CD4 þ T cells (P ¼ 0.009) and natural killer cells (P ¼ 0.036). When injected 1 week after tumor implantation, Ad.5/3.cRGD-mIL12p70 successfully prolonged the survival of glioma-bearing mice. Sixty percent of animals treated with IL-12 immunotherapy were long-term survivors over 175 days, whereas all the control group animals expired by 40 days after tumor implantation (P ¼ 0.026). Mice receiving Ad.5/3.cRGD-mIL12p70 also accumulated 50% less MDSCs in the brain than the control group (P ¼ 0.007). Moreover, in the IL-12 group, MDSCs significantly overexpressed CD80 and major histocompatibility complex class II molecules (P ¼ 0.041). Depletion of MDSCs with Gr1 þ antibody had no survival benefit induced by IL-12-mediated immunotherapy. Of note, IL-12 therapy increased the presence of myeloid dendritic cells (mDCs) in the glioma microenvironment (P ¼ 0.0069). Ultimately, the data show that in the context of IL-12 immunogene therapy, MDSCs are dispensable and mDCs may provide the majority of antigen presentation in the brain.

Research paper thumbnail of 46. Upregulation of indoleamine 2,3-dioxygenase in brain tumors is associated with decreased survival through a T cell-dependent mechanism

Brain, Behavior, and Immunity, 2012

ABSTRACT Glioblastoma multiforme (GBM) is a malignant and aggressive primary brain tumor with an ... more ABSTRACT Glioblastoma multiforme (GBM) is a malignant and aggressive primary brain tumor with an average patient survival of 14.6 months following diagnosis. Our laboratory has previously demonstrated that immunosuppressive regulatory T cells (Tregs; CD4+FoxP3+) infiltrate and accumulate in brain tumors, by utilizing mouse models. Importantly, depleting those Tregs is associated with a significant increase in overall survival. To understand the underlying mechanisms that promote Treg recruitment to brain tumors, our laboratory has investigated the enzyme, indoleamine 2,3-dioxygenase 1 (IDO). We have found that the upregulation of IDO in glioma patients (n = 343) is associated with a significantly decreased probability of overall survival (p &lt; 0.005). Utilizing a mouse model that intracranially-injects GL261 (brain tumor) cells, we have confirmed that IDO knockdown (IDOkd), specifically in brain tumor cells, results in decreased Treg recruitment to the tumor, as well as increased long-term survival (p &lt; 0.001). This was accomplished by comparing WT and IDO−/− mice, intracranially-injected control or IDOkd GL261 cells (p &lt; 0.001). Interestingly, the long-term survival mediated through IDO-deficiency was lost in CD4−/−, CD8−/− and Rag1−/− mice, suggesting a contextual role for T cells in mediating brain tumor rejection vs. promotion. These data confirm the importance of IDO1 in brain tumors and provide further support for understanding the mechanism of immune-mediated IDO1-dependent tumor progression.

Research paper thumbnail of Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors

Molecular Therapy, 2014

A c c e p t e d m a n u s c r i p t ACCEPTED ARTICLE PREVIEW A c c e p t e d m a n u s c r i p t ... more A c c e p t e d m a n u s c r i p t ACCEPTED ARTICLE PREVIEW A c c e p t e d m a n u s c r i p t ACCEPTED ARTICLE PREVIEW Abstract Treatment options of glioblastoma multiforme are limited due to the blood brain barrier.

Research paper thumbnail of Stem Cell-Based Cell Carrier for Targeted Oncolytic Virotherapy: Translational Opportunity and Open Questions.

Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus... more Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus to promote cell lysis is harnessed and reprogrammed to selectively destroy cancer cells. Such treatment modalities exhibited antitumor activity in preclinical and clinical settings and appear to be well tolerated when tested in clinical trials. However, the clinical success of oncolytic virotherapy has been significantly hampered due to the inability to target systematic metastasis. This is partly due to the inability of the therapeutic virus to survive in the patient circulation, in order to target tumors at distant sites. An early study from various laboratories demonstrated that cells infected with oncolytic virus can protect the therapeutic payload form the host immune system as well as function as factories for virus production and enhance the therapeutic efficacy of oncolytic virus. While a variety of cell lineages possessed potential as cell carriers, copious investigation has established stem cells as a very attractive cell carrier system in oncolytic virotherapy. The ideal cell carrier desire to be susceptible to viral infection as well as support viral infection, maintain immunosuppressive properties to shield the loaded viruses from the host immune system, and most importantly possess an intrinsic tumor homing ability to deliver loaded viruses directly to the site of the metastasis-all qualities stem cells exhibit. In this review, we summarize the recent work in the development of stem cell-based carrier for oncolytic virotherapy, discuss the advantages and disadvantages of a variety of cell carriers, especially focusing on why stem cells have emerged as the leading candidate, and finally propose a future direction for stem cell-based targeted oncolytic virotherapy that involves its establishment as a viable treatment option for cancer patients in the clinical setting.

Research paper thumbnail of Therapeutic Strategies Targeting Cancer Stem cell.

InTech publisher, Aug 2011

Research paper thumbnail of Maintaining and Loading Neural Stem Cells for Delivery of Oncolytic Adenovirus to Brain Tumors.

Methods Mol Biol, 2012

Despite recent advancements in the treatment of cancer, the prognosis for patients with malignant... more Despite recent advancements in the treatment of cancer, the prognosis for patients with malignant brain tumors remains poor. The success of currently available therapies has been limited in part because of the disseminated nature of these tumors. Furthermore, most of these tumors, when in a high-grade form, are resistant to chemo-and radiotherapy. Taking the above considerations into account, effective treatment of these cancers not only requires the development of new means to target tumor burdens that have dispersed significantly from their site of origin, but also therapeutic approaches which can appropriately discriminate between tumor cell and normal brain.