Targeting the Untargetable: Oncolytic Virotherapy for the Cancer Stem Cell

The biological and therapeutic importance of cancer stem cells has become increasingly clear over the past several years.1Jordan C Guzman M Noble M Cancer stem cells.N Engl J Med. 2006; 355: 1253-1261Crossref PubMed Scopus (1347) Google Scholar The success or failure of cancer treatment approaches may be influenced greatly by the presence and treatment sensitivity of these cells. Cancer cures may therefore require effective targeting and destruction of the cancer stem cell population. For therapeutics to be effective against such cells, they must be effective against quiescent, apoptosis-resistant, and drug transporter–overexpressing cells. Further complicating this challenge, normal stem cells share many of these same features, to the extent that selectively targeting the cancer stem cell while leaving the normal stem cells unharmed is a difficult proposition. In this issue of Molecular Therapy, Eriksson and colleagues report proof-of-concept studies for the efficacy of oncolytic virotherapy against cancer stem cells.2Eriksson M Guse K Bauerschmitz G Virkkunen P Tarkkanen M Tanner M et al.Oncolytic adenoviruses kill breast cancer initiating CD44+CD24–/Low cells.Mol Ther. 2007; 15: 2088-2093Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Cancer stem cells are believed to be critical for the initiation, progression, and persistence of both leukemias and solid tumors. For example, cancer stem cells have been identified in chronic myelogenous leukemia, glioblastoma multiforme (brain) tumors, and breast cancers.3Brabletz T Jung A Spaderna S Hlubek F Kirchner T Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression.Nat Rev Cancer. 2005; 5: 744-749Crossref PubMed Scopus (1168) Google Scholar Cancer stem cells purportedly have three key properties that they share with normal tissue stem cells.1Jordan C Guzman M Noble M Cancer stem cells.N Engl J Med. 2006; 355: 1253-1261Crossref PubMed Scopus (1347) Google Scholar First, all stem cells have a self-renewal capacity, meaning that each of the daughter cells resulting from mitosis retains the parent cell's properties. Second, these cells have the capability to differentiate into multiple lineages within the normal tissue or the tumor. Finally, they are able to proliferate extensively. These self-renewing cells have unclear, and perhaps numerous, origins.4Bjerkvig R Tysnes BB Aboody KS Najbauer J Terzis AJ Opinion: the origin of the cancer stem cell: current controversies and new insights.Nat Rev Cancer. 2005; 5 (Erratum in Nat Rev Cancer 5 995): 899-904Crossref PubMed Scopus (489) Google Scholar They may arise from mutations in either normal tissue stem cells or progenitor cells, for example. Despite great interest in this area, controversy exists regarding which cell subpopulations may play the greatest role in tumor initiation and propagation for each tumor type. Many investigators now believe that many tumor cell relapses following cytoreductive treatments may be due to the inherent resistance and subsequent outgrowth of cancer stem cell clones.5Dean M Fojo T Bates S Tumour stem cells and drug resistance.Nat Rev Cancer. 2005; 5: 275-284Crossref PubMed Scopus (3097) Google Scholar These cells may be more resistant to many standard chemotherapeutics because of their relatively quiescent state; as a result, cell cycle–dependent chemotherapies would be relatively ineffective. In addition, these cells typically overexpress cell membrane drug transporters of the ATP-binding cassette class; one example is the multidrug resistance transporter p-glycoprotein that pumps out chemotherapeutics, including paclitaxel and doxorubicin. Therefore, cancer stem cells are frequently resistant to the chemotherapeutics that are transported by these molecules. Finally, survival pathways that are activated in these cells (e.g., the hedgehog-patched pathway) can make them resistant to apoptosis induction. Oncolytic viruses may represent an effective therapeutic approach to target cancer stem cells.6Parato KA Senger D Forsyth PA Bell JC Recent progress in the battle between oncolytic viruses and tumors.Nat Rev Cancer. 2005; 5: 965-976Crossref PubMed Scopus (456) Google Scholar,7Liu TC Galanis E Kirn D Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress.Nat Clin Pract Oncol. 2007; 4: 101-117Crossref PubMed Scopus (388) Google Scholar These agents are inherently or genetically targeted to replicate in and selectively kill cancer cells. The resulting “oncolysis” is a novel mechanism of action (MOA) that is effective against apoptosis-resistant cells. In addition to this primary MOA, oncolytic viruses can demonstrate complementary secondary MOAs such as induction of tumor-specific cytotoxic T lymphocytes (CTLs),8Kim JH Oh JY Park BH Lee DE Kim JS Park HE et al.Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF.Mol Ther. 2006; 14: 361-370Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar tumor vascular shutdown,9Breitbach CJ Paterson JM Lemay CG Falls TJ McGuire A Parato KA et al.Targeted inflammation during oncolytic virus therapy severely compromises tumor blood flow.Mol Ther. 2007; 15: 1686-1693Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar and chemosensitization.10Khuri FR Nemunaitis J Ganly I Arseneau J Tannock IF Romel L et al.A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer.Nat Med. 2000; 6: 879-885Crossref PubMed Scopus (1010) Google Scholar The next generation of oncolytic viruses have additional MOAs through therapeutic transgene “arming.” These therapeutic payloads are expressed selectively in cancer cells during replication, resulting in complementary MOAs. Examples include JX-594 (targeted vaccinia-expressing granulocyte-macrophage colony-stimulating factor; Jennerex Biotherapeutics, San Francisco, CA) and measles virus expressing the sodium-iodide symporter gene (Mayo Clinic, Rochester, MN).11Dingli D Peng KW Harvey JE Greipp PR O'Connor MK Cattaneo R et al.Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter.Blood. 2004; 103: 1641-1646Crossref PubMed Scopus (282) Google Scholar Of note for the treatment of cancer stem cells, many oncolytic virus species have the potential to replicate in quiescent target cells; this can result in direct cell lysis, avascular necrosis, or the induction of tumor-specific CTLs. Targeted and armed oncolytic viruses therefore wage a multipronged attack against cancers, and these MOAs have the potential to theoretically overcome the stem cell resistance mechanisms outlined above. In the new work reported in this issue, Eriksson et al. treated breast cancer stem cells isolated directly from patients (defined by CD44+/CD24−/Low phenotype) both in vitro and in vivo with E1A-CR2 gene region–deleted adenoviruses with modified capsids.2Eriksson M Guse K Bauerschmitz G Virkkunen P Tarkkanen M Tanner M et al.Oncolytic adenoviruses kill breast cancer initiating CD44+CD24–/Low cells.Mol Ther. 2007; 15: 2088-2093Abstract Full Text Full Text PDF PubMed Scopus (85) Google ScholarThe CD44+CD24–/low cell population found in breast cancer patients exhibits many stem cell characteristics, such as the ability to initiate tumor growth in mice with low cell numbers and resistance to many conventional therapies. The capsids were engineered to allow coxsackievirus adenovirus receptor (CAR)–independent infection, because the investigators hypothesized that cancer stem cells might have low levels of CAR expression. As demonstrated in previous publications, the deletion in the pRB-binding region of the E1A gene results in a virus that is attenuated in normal quiescent cells, but replication-competent in cells with a disrupted pRB pathway.12Heise C Hermiston T Kirn D An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy.Nat Med. 2000; 6: 1134-1141Crossref PubMed Scopus (511) Google Scholar They report that significant efficacy was demonstrated both in vitro and in vivo. In vivo experiments studied efficacy of infection before injection of tumor cells into the mouse host and of injection of viruses into established tumors. The authors conclude that both putative breast cancer stem cells and committed breast cancer cells can be destroyed with E1A-CR2 capsid–modified adenoviruses. Notably, Jiang and colleagues have recently shown that a similar virus has the ability to kill brain tumor stem cells through autophagy, both in vitro and in vivo. 13Jiang H Gomez-Manzano C Aoki H Alonso MM Kondo S McCormick F et al.Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death.J Natl Cancer Inst. 2007; 99: 1410-1414Crossref PubMed Scopus (238) Google ScholarIn this issue Skog et al. show that human adenovirus 16 and chimpanzee adenovirus CV23 can both infect low-passage human brain tumor cells and cancer stem cells more efficiently than human adenovirus.14Skog J Edlund K Bergenheim AT Wadell G Adenoviruses 16 and CV23 efficiently transduce human low-passage brain tumor and cancer stem cells.Mol Ther. 2007; 15: 2140-2145Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Future work should focus on some of the questions raised, but not fully addressed, by this paper. First, although such E1A-CR2 adenovirus mutants have been shown to be effective against proliferating established tumors,12Heise C Hermiston T Kirn D An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy.Nat Med. 2000; 6: 1134-1141Crossref PubMed Scopus (511) Google Scholar this virus was an unlikely choice for targeting quiescent cancer stem cells. The relative resistance of the tumor xenografts to these viruses may be partially explained by the quiescent nature of the stem cells. Future studies should explore the efficacy of other oncolytic viruses that are not dependent on cell cycling for their efficient replication. Also, the relative contribution of the E1A mutation and the capsid modification to the behavior of the engineered viruses could not be determined, because controls for these specific alterations were not evaluated. Finally, the selectivity of oncolytic viruses for cancer stem cells vs. normal cells (including normal stem cells) should be assessed in the future. Some stem cells may be relatively expendable (e.g., breast stem cells after mastectomy), whereas others may not be (e.g., hematopoietic). Answers to these questions will have important implications for this approach and for the field. Nevertheless, because of their unique and multiple MOAs, targeted oncolytic viruses hold promise for the treatment of cancer, and specifically for the treatment of the putative cancer stem cell.

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