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Article Published in the Author Account = of

Hong Jiang

Eradication of Brain Tumor Stem Cells with an Oncolytic=20 Adenovirus

Published on July 5, 2010

Author: Hong = Jiang

Specialty: Oncol= ogy,=20 C= ell=20 Biology, Molecular=20 Biology, Virol= ogy
Institution:=20 Department of Neuro-Oncology, The University of Texas M.D. Anderson = Cancer=20 Center
Address: Houston, Texas, 77030, United States

Author: = Juan = Fueyo

Abstract: Malignant gliomas, the most = common=20 type of primary brain tumors, are one of the most deadly cancers. Even = when=20 given the best available treatment, patients with these tumors face a = poor=20 prognosis, a situation that has changed little in the past several = decades.=20 Recently, researchers identified brain tumor stem cells that are = responsible for=20 tumors' resistance to therapy and recurrence. Since conventional = radiotherapy=20 and chemotherapy have had limited success in the treatment of malignant = gliomas,=20 we developed an oncolytic adenovirus, Delta-24-RGD, that is able to = efficiently=20 eradicate both brain tumor bulk and stem cells, indicating its potential = to=20 induce complete tumor remission in patients with malignant gliomas. = Currently,=20 this novel agent is being tested in a phase I clinical trial at the = Brain Tumor=20 Center, The University of Texas MD Anderson Cancer Center.

Introduction

Malignant gliomas are the most common and most lethal of all primary=20 intracranial tumors (Furnari et al., 2007), accounting for approximately = 70% of=20 the 22,500 new cases of malignant primary brain tumors diagnosed in = adults in=20 the United States each year (Wen and Kesari, 2008). Although relatively = uncommon=20 compared with cancers at other anatomic sites, malignant gliomas are = associated=20 with disproportionately high morbidity and mortality rates. Despite=20 implementation of intensive therapeutic strategies and supportive care, = the=20 median survival of patients with these cancers has remained at 12 months = for the=20 past decade (Furnari et al., 2007). According to research presented at = the CRS=20 Brain & CNS Cancers Workshop in June 2007, high rates of mortality = make=20 malignant glioma=20 the leading cause of cancer-related death in children, the third most = frequent=20 cause of cancer-related death in men ages 15-54 years, and the fourth = most=20 frequent cause of cancer-related death in women ages 15-34 years.

Malignant gliomas are highly resistant to conventional therapies = (i.e.,=20 surgery, radiotherapy,=20 and chemotherapy),=20 and tumor recurrence is usually followed by difficult-to-treat = progression.=20 Recently, brain=20 tumor stem cells (BTSCs), which are responsible for therapy = resistance and=20 tumor recurrence, have been identified in malignant gliomas (Hemmati et = al.,=20 2003; Ignatova et al., 2002; Singh et al., 2004). This discovery raises = the=20 possibility of developing therapies that will eradicate the BTSC = population in=20 order to achieve complete tumor remission. To this end, oncolytic = adenoviruses=20 are emerging as a promising agent for glioma therapy. Delta-24-RGD, an = E1A = mutant oncolytic=20 adenovirus developed in our laboratory, has shown remarkable = efficacy in=20 glioma cell lines and intracranial glioma models as well as in other = types of=20 tumors (Alonso et al., 2008; Bauerschmitz et al., 2004; Bauerschmitz et = al.,=20 2002; Fueyo et al., 2003; Lamfers et al., 2002; Page et al., 2007; = Suzuki et=20 al., 2001; Witlox et al., 2004). This adenovirus=20 is currently being tested in the clinical setting. Recently, we reported = that=20 Delta-24-RGD was an efficient agent against BTSCs and BTSC-derived = intracranial=20 gliomas (Jiang et al., 2007).

In this review, we discuss BTSCs and oncolytic adenoviruses, the = mechanism of=20 oncolysis by adenoviruses, and the application and future direction of = oncolytic=20 adenoviruses in cancer therapy.

Brain Tumor Stem Cells

For decades, researchers have observed that tumors are capable of = growing and=20 spreading by repopulating distinct cell types within the tumor (Huntly = and=20 Gilliland, 2005). The process resembled the function of normal stem = cells; thus,=20 the concept of cancer stem cells was proposed (Huntly and Gilliland, = 2005).=20 Cancer stem cells are thought to share many of the properties of normal = stem=20 cells that provide for a long life span, including relative quiescence,=20 resistance to drugs and toxins through the expression of several ABC=20 transporters (ATP-binding cassette transporters), active DNA repair = capacity,=20 and resistance to apoptosis = (Dean et=20 al., 2005). However, cancer stem cells are not subject to the same = intrinsic and=20 extrinsic controls as normal stem cells (Huntly and Gilliland, 2005). = Several=20 groups of researchers identified stem-like cells in brain tumors = (Hemmati et=20 al., 2003; Ignatova et al., 2002; Singh et al., 2004). BTSCs isolated = from human=20 brain tumors exhibited stem=20 cell properties in vitro and the capacity for self renewal and exact = recapitulation of the original tumor in the brains of immune deficient = mice=20 (Singh et al., 2004). Although accounting for only a small population of = a=20 tumor=E2=80=99s cells, BTSCs are thought to be responsible for the = initiation of new=20 tumors and for the tumors=E2=80=99 resistance to therapies (Bao et al., = 2006; Singh et=20 al., 2004). BTSCs have been reported to contribute to glioma = radioresistance=20 through preferential activation of the DNA damage checkpoint response = and an=20 increase in DNA repair capacity (Bao et al., 2006). Thus, failure to = eliminate=20 BTSCs during treatment will result in tumor recurrence. For this reason, = therapies that can efficiently eradicate BTSCs are urgently needed to = improve=20 the prognosis for glioma patients.

Oncolytic Adenovirus Delta-24-RGD

Cancer cells differ from normal cells in that cancer cells exhibit=20 uncontrolled cellular proliferation, prevention of apoptosis, and = resistance to=20 the host immune-effector mechanisms (Thorne et al., 2005). These = properties may=20 be exploitable for anticancer therapies (Jiang et al., 2006; Roberts et = al.,=20 2006). Virology=20 studies revealed that, in order to replicate themselves, adenoviruses = express=20 early genes to reprogram their host cells, resulting in phenotypes that = resemble=20 those of cancer cells (Thorne et al., 2005). This finding gives us the=20 opportunity to develop oncolytic adenoviruses that can selectively = replicate in=20 cancer cells. After infecting a cancer cell, adenoviruses immediately = express an=20 early viral protein called E1A (Berk, 2007). This protein binds and = inactivates=20 cellular proteins, such as the retinoblastoma=20 (RB) protein that acts as a brake in controlling the cell cycle (Berk, = 2007). In=20 cancer cells, the RB protein has been inactivated (Nevins, 2001), = resulting in=20 uncontrolled cell proliferation. Since cancer cells already have the = environment=20 for viral replication, even a mutation in the E1A gene that = abrogates=20 the interaction between the RB and E1A protein will not affect viral = replication=20 within the cancer cell. However, the mutant adenovirus is unable to = replicate in=20 normal cells that have functional RB protein. This was the rationale = behind our=20 development of the oncolytic adenovirus Delta-24-RGD, in which a 24-bp = region=20 coding for RB binding was deleted from the E1A gene (Fueyo et = al.,=20 2000). Delta-24-RGD also contains an inserted RGD motif in the HI loop = of the=20 fiber protein (Fueyo et al., 2003). This modification allows the virus = to enter=20 the cells by attachment to integrins, the expression of which is = relatively high=20 in glioma cells, instead of CAR (Coxsackie virus and adenovirus = receptor), which=20 is the native receptor for adenoviruses and the expression of which is=20 relatively low in glioma cells (Fueyo et al., 2003). These two = modifications=20 ensure that the oncolytic adenovirus Delta-24-RGD efficiently infects = glioma=20 cells and selectively replicates in cancer cells but not in normal = cells. When=20 Delta-24-RGD underwent in vitro and in vivo testing in prostate and lung = cancers, Delta-24-RGD demonstrated CAR-independent transduction, = enhancing viral=20 propagation and an oncolytic effect (Suzuki et al., 2001). In gliomas, = the virus=20 efficiently induced a cytopathic effect in both low- and = high-CAR-expressing=20 glioma cells (Fueyo et al., 2003).

Eradication of Brain Tumor Stem Cells with = Delta-24-RGD

Brain tumors usually encompass many genetic alterations. Viruses have = been=20 used as vectors to transfer therapeutic genes into cancer cells to = target these=20 defects. However, the strategy of targeting one aberrant gene or pathway = at a=20 time is inefficient in tackling heterogeneous glioblastomas, the most = malignant=20 form of gliomas. In addition, replication-deficient viral vectors cannot = reach=20 enough cancer cells to induce a significant anticancer effect. = Therefore,=20 investigators wanted to develop strategies that target the universal = defects in=20 cancer cells and improve agents that have expandable cytotoxic power = only in the=20 cancer cell population.

The replication-competent oncolytic adenovirus Delta-24-RGD may = achieve both=20 objectives. Instead of targeting a single molecule or pathway, = Delta-24-RGD is=20 capable of hijacking the entire cellular system within a cancer cell for = its own=20 replication (Berk, 2007). Even in BTSCs that are resistant to other = therapies,=20 Delta-24-RGD induces robust efficacy (Jiang et al., 2007). These BTSCs = express=20 high levels of integrins and CAR on the cell surface, which makes them=20 susceptible to adenoviral infection. The defective RB pathway in BTSCs=20 distinguishes them from normal brain cells and allows Delta-24-RGD to=20 selectively replicate in and kill these malignant cells while sparing = normal=20 brain cells. We found that, after infecting the BTSCs, Delta-24-RGD = caused a=20 large amount of autophagic vacuoles in the cytoplasm, which accompanied = the cell=20 lysis process (Jiang et al., 2007). Atg5, a key protein in the = autophagic=20 machinery, was upregulated dramatically at the late stage of viral = infection=20 (Jiang et al., 2007), suggesting the involvement of autophagy = in cell=20 lysis and the release of viral progenies. In vivo, Delta-24-RGD = significantly=20 improved the survival time of mice bearing gliomas derived from BTSCs = (Jiang et=20 al., 2007). The virus induced drastic upregulation of Atg5 in the tumor = as well,=20 suggesting that the Atg5 level can serve as a surrogate marker to = monitor the=20 therapeutic effect of Delta-24-RGD in clinical trials. A phase I = clinical trial=20 began at the Brain Tumor Center, The University of Texas MD Anderson = Cancer=20 Center in December 2008 to test Delta-24-RGD in patients with recurrent=20 malignant gliomas.

Perspectives

Figure 1. A schematic = illustration=20 shows the therapeutic effect of Delta-24-RGD. Brain tumor bulk cells are = sensitive to conventional radiotherapy and chemotherapy while BTSCs are=20 resistant to these therapies. Conventional therapies may cause tumor = regression=20 by killing the tumor bulk cells, but the surviving BTSCs will renew = themselves=20 and regenerate new tumor cells. However, both types of cells are = susceptible to=20 Delta-24-RGD, which may result in complete tumor remission.

Oncolytic adenoviruses are designed to selectively target defective = molecules=20 or pathways in cancer cells (Jiang et al., 2006). In our study, the = newly=20 identified BTSCs were found to be susceptible to the oncolytic = adenovirus=20 Delta-24-RGD (Jiang et al., 2007), which has the potential to eradicate = both=20 tumor bulk and cancer stem cells efficiently (Fueyo et al., 2003; Jiang = et al.,=20 2007). Thus, this adenovirus might be able to overcome malignant = gliomas=E2=80=99=20 resistance to conventional radiotherapy and chemotherapy to achieve = complete=20 tumor remission in glioma patients (Figure 1). Also, = because of=20 the infiltrative nature of gliomas, complete remission of the tumor = largely=20 depends on the efficient delivery of therapeutic agents to the cancerous = cells=20 that have infiltrated normal brain tissue. Replication-competent = oncolytic=20 adenoviruses, such as Delta-24-RGD, may be able to bridge the vector gap = in cancer = gene=20 therapies since the viruses replicate and spread their progeny to = adjacent=20 cancer cells.

Although preclinical studies of oncolytic adenoviruses have been very = successful, this type of therapy will face challenges in clinical = application,=20 such as anatomic barriers to the tumor and clearance of the viruses by = the=20 host=E2=80=99s initial innate immune responses (Chiocca, 2008; Jiang et = al., 2006). The=20 anatomic barriers may be addressed by stereotactic techniques and the protease = expression by=20 the viruses (aiding the viruses to spread in tissue) (Jiang et al., = 2006).=20 Host=E2=80=99s immunity might be modulated by using cyclo= phosphamide=20 to suppress immune response prior to oncolytic=20 virus inoculation; this strategy has been shown to significantly = improve the=20 efficacy of the virus in glioma-bearing mice (Kambara et al., 2005). = However,=20 the development of antitumor immunity later in gene=20 therapy should help eliminate remaining malignant cells (Barba et = al.,=20 1994). For example, oncolytic viruses expressing the immune-enhancing = gene IL-12 have=20 demonstrated increased efficacy in part because of the antitumor actions = of=20 immune-related infiltrating cells (Hellums et al., 2005; Parker et al., = 2000).=20 Thus, a better understanding of the interaction between oncolytic = viruses and=20 the host immune system will help develop strategies for modulating the = immune=20 response, thereby minimizing the antiviral immunity against oncolytic=20 adenoviruses while maximizing antitumor immunity.

Acknowledgments

This work was supported by a grant from the National Cancer Institute = (R01-CA-090879 to J. Fueyo).

(Corresponding author: Hong Jiang, Ph.D., Department of=20 Neuro-Oncology, Unit 1002, The University of Texas M.D. Anderson Cancer = Center,=20 1515 Holcombe Blvd., Houston, TX 77030, USA.)

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[Discovery Medicine; ISSN: 1539-6509; eISSN: = 1944-7930.=20 Discov Med 10(50):24-28, July 2010.]

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