Viruses with Deletions in Antiapoptotic Genes As Potential Oncolytic Agents

Oncogene (2005) 24, 6069–6079 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc REVIEW Viruses with deletions in antiapoptotic genes as potential oncolytic agents Ta-Chiang Liu*,1 and David Kirn*,2,3 1Molecular Neurosurgery Laboratory, Massachusetts General Hospital and Harvard Medical School, MA, USA; 2Department of Clinical Pharmacology, University of Oxford, UK; 3Jennerex Biotherapeutics, Inc., Mountain View, CA, USA Replication-selective oncolytic viruses have emerged as a defects present in almost all cancer cells (Heise et al., new treatment platform for cancers. However, selectivity 2000). However, clinical trials with dl1520 to date show and potency need to be improved before virotherapy can limited efficacy when used as a single agent despite become a standard treatment modality. In addition, selectivity (Kirn, 2001a). mechanisms that can be incorporated to enable targeting Other approaches include the use of transcriptional a broad range of cancer types are highly desirable. Cancer control by placing essential immediate early viral genes cells are well known to have multiple blocks in apoptosis under the control of tumor- and/or tissue-specific pathways. On the other hand, viruses have evolved to promoter/enhancer elements (Kirn et al., 2001), the express numerous antiapoptotic genes to antagonize use of inherently tumor-selective viruses (e.g. Reovirus, apoptosis induced upon infection. Viruses with deletions NDV, VSV, etc.), and engineering ligands for tumor- in antiapoptotic genes can therefore be complemented by selective receptors into the virus coat (Coffey et al., antiapoptotic genetic changes in cancer cells for efficient 1998; Lorence et al., 1988; Stojdl et al., 2000; Wickham, replication and oncolysis. In this review, we summarize the 2003). These are interesting approaches and are subject recent development of this concept, the potential ob- to extensive reviews elsewhere (Kirn, 2000; Wickham, stacles, and future directions for optimization. 2003). Oncogene (2005) 24, 6069–6079. doi:10.1038/sj.onc.1208734 As mentioned above, the currently utilized gene deletions conferring selectivity also frequently result in Keywords: oncolytic; virus; cancer; apoptosis; virology; significantly reduced potency of the virus in tumors due gene therapy to the multifunctional nature of many viral proteins. The deletion mutant dl1520 showed an overall response rate of 14% in patients with refractory locally recurrent head and neck cancers when given as a single agent by Introduction intratumoral injection. Similar results have been re- ported with gene-deleted herpes viruses (e.g. G207, Although the term ‘oncolytic virus’ was first described 1716) in Phase I trials. Therefore, new approaches early in the 20th century, it was not until last decade that targeting ubiquitous tumor-specific pathways that can the genetic mechanisms to achieve/improve tumor enhance the potency and efficacy while maintaining (or selectivity were first described (Kirn et al., 2001). The improving) the selectivity are eagerly awaited. This will first engineered replication-selective virus was published presumably require identification of viral gene muta- in 1991; Martuza et al. (1991) described a HSV mutant tions resulting in selectivity but not attenuation in with deletion in the thymidine kinase (tk) gene that cancer cells. replicates specifically in dividing tumor cells. The first replication-selective adenovirus dl1520 (also known as Apoptosis: ubiquitously inhibited in cancer cells Onyx-015) had a deletion in the E1B-55K gene and at least partially targeted the p53 pathway that is Apoptosis, or ‘programmed cell death’, is a form of frequently abnormal in cancers (Barker and Berk, cellular suicide that is widely observed in nature. This 1987; Bischoff et al., 1996). The development of dl1520 process can be triggered by a variety of stimuli, was based on our understanding of tumor biology and including cytokines, hormones, viruses, mutagenic virology that the replication of DNA viruses and the chemicals, or irradiation. Apoptosis can be induced by carcinogenesis involve inactivating similar cellular de- two different mechanisms, namely the mitochondrial fense mechanisms (Kirn, 2000). This led to the (intrinsic) signaling pathway and the death-receptor subsequent discovery of an adenoviral mutant with (extrinsic) signaling pathway (Hengartner, 2000). The deletion in the E1A-CR2 region (dl922–947), which mitochondrial pathway, activated via a variety of achieved tumor selectivity by targeting Rb pathway intracellular stresses, including cytokine deprivation, serum starvation, UV and g-irradiation, oncogenic *Correspondence: T-C Liu; E-mail: [email protected] or stimuli such as c-MYC overexpression, is triggered by D Kirn; E-mail: [email protected] proapoptotic members of the Bcl-2 family, initially by a Viruses with deletions in antiapoptotic genes T-C Liu and D Kirn 6070 subset of these called the ‘BH3-only subfamily’ proteins (Liu et al., 1996). FADD recruits the upstream DED- because they possess only one of the Bcl-2 homology containing procaspase-8to the receptor via homophilic (BH) domains. These include Bid, Bim, Harikari, Noxa, DED–DED interactions. DED is a specific example of a and a number of others. In response to environmental more global homophilic interaction domain termed cues, these proteins engage another set of proapoptotic CARD (caspase recruitment domain), which is found Bcl-2 members, the Bax subfamily (which includes Bax, in several caspases with large prodomains, including Bak, and Bok), loosely residing on the mitochondrial caspases-2, -8, -9, and -10 (Hofmann et al., 1997). outer membranes or in the cytosol. The interaction Procaspase-8within this newly formed death-inducing causes the latter to oligomerize and insert into the signalling complex (DISC; composed of death ligands, mitochondrial membrane. Here the complex acts to death receptors, FADD, TRADD, and Procaspase-8or trigger the sudden and complete release of cytochrome c -10) then proteolytically autocleaves itself to the active and other proteins from all of the mitochondria in the form and initiates apoptosis by subsequent cleavage of cell (Green and Reed, 1998). downstream effector caspases (caspase-3, -6, and -7) The released cytochrome c binds to Apaf-1, a (Hirata et al., 1998). cytosolic protein (Li et al., 1997). This induces Apaf-1 However, the intrinsic and extrinsic apoptosis signal- oligomerization, and the Apaf-1 ‘apoptosome’ recruits ing pathways do not necessarily function individually and activates procaspase-9. The active caspase-9 now and independently. Crosstalk between the two pathways recruits and activates the effector procaspase-3. Bcl-2 is common and can ensure that the apoptosis process is and Bcl-xL (and probably other antiapoptotic members carried out efficiently (Roth and Reed, 2002). For of this family) block cell death by preventing the instance, the activation of caspase-8or -10 through the mitochondrial release of the intermembrane proteins, extrinsic pathway can cleave Bid (a proapoptotic including cytochrome c (Yang et al., 1997). Once the member of the Bcl2 family). Truncated Bid (tBid) then process has achieved the mitochondrial step, these translocates to mitochondria, where it induces confor- antiapoptotic proteins have no effect. mational changes of Bax and Bak with subsequent In mammals, Bcl-2 has at least 20 relatives, all of oligomerization and formation of pores in the mem- which share at least one conserved BH domain. The brane, causing the release of cytochrome c and Smac/ antiapoptotic branch includes four other proteins: Bcl- DIABLO, activating caspase-9 and -3. This amplifies xL, Bcl-w, Mcl-1, and A1. These proteins function by apoptosis induction through the extrinsic pathway. In binding to Apaf-1 and thereby preventing cytochrome c contrast, DNA damage can induce transcriptional release and procaspase-9 activation. There are two upregulation of some death receptors, such as Fas and groups of Bcl-2 proteins that promote apoptosis: the death receptor 5 (DR5), through p53-dependent as well Bax and the BH3-only families. Both types of proapop- as p53-independent mechanisms (Ozoren and El-Deiry, totic protein are required to initiate apoptosis: the BH3- 2003). This upregulation increases cellular sensitivity to only proteins act as damage sensors and direct death receptor ligands. Thus, crosstalk exists between antagonists of the prosurvival proteins, whereas the the intrinsic and extrinsic apoptosis signaling pathways. Bax-like proteins act further downstream in mitochon- A simplified summary of the intrinsic and extrinsic drial disruption (Huang and Strasser, 2000). pathways of apoptosis is shown in Figure 1. Apoptosis can also be triggered from outside of the Cancer cells are well known to have dysregulated cell, generally following cell–cell contact, by a family of apoptosis pathways. Disruption of the intrinsic apopto- transmembrane proteins – called death receptors – sis pathway is extremely common in cancer cells. Indeed, which belong to the tumor necrosis factor (TNF) family the p53 tumor suppressor gene is the most frequent of receptors. For Fas (CD95; Apo 1) and TNF mutated gene in human tumors, and loss of p53 function signaling, the two most well-studied pathways, the can both disable apoptosis and accelerate tumor engagement of cognate ligands of the TNF superfamily development in knockout mice (Vogelstein et al., members (e.g. TNF-a, FasL, TRAIL, etc.) induces 2000). Moreover,

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