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The article by Nayar et al underscores the astonishing capacity of KSHV to pirate vital cellular mechanisms and corroborates previous findings that demonstrate an important role for Hsp90 in controlling expression of viral genes and maintenance of latent infection, both critical processes for the oncogenic virus and cell transformation.4,5 Cells infected with an oncogenic virus are often addicted to both viral and mutated or aberrantly expressed cellular proteins, making them critically reliant on Hsp90. KSHV uses Hsp90 to protect and sustain the activity of viral proteins. However, this clever engagement makes the virus-infected cells vulnerable by sensitizing them to inhibition of the chaperone. Destabilization of viral latent proteins following Hsp90 inhibition provides of powerful and specific way to interfere with the virus-driven deregulation of proliferation and cell intrinsic control mechanisms. In their article, Nayar et al combined Hsp90 inhibition with targeting of antiapoptotic Bcl-2, one of the key players in pathways identified in the Hsp90 oncoproteome, which further augmented the antitumor potency of the Hsp90 inhibitor. Other cancer critical pathways discovered in the proteomic approach, such as nuclear factor kB and phosphatidylinositol 3-kinase/ mammalian target of rapamycin, represent additional targets to be tested in combination with PU-H71. Other oncogenic viruses are exploiting Hsp90-mediated chaperoning to control virus-induced signal transduction and virus–host protein interactions.6 It is therefore tempting to speculate that Hsp90 inhibition would also represent an attractive novel therapeutic strategy for other viral cancers. The study by Nayar et al highlights the now widely recognized, strong potential of combinatorial therapeutic strategies in combating cancer. Because tumor cells often develop resistance to even the most potent single targeted therapy, the chances for successfully eradicating the tumor are significantly higher when the treatment modality is directed against two pathways critical for cancer cell survival. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Nayar U, Lu P, Goldstein RL, et al. Targeting the Hsp90-associated viral oncoproteome in


gammaherpesvirus-associated malignancies. Blood. 2013;122(16):2837-2847.

LANA, of the viral co-receptor EphA2 as well as other client proteins. PLoS Pathog. 2012;8(11):e1003048.

2. Moulick K, Ahn JH, Zong H, et al. Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat Chem Biol. 2011;7(11):818-826.

5. Qin Z, DeFee M, Isaacs JS, Parsons C. Extracellular Hsp90 serves as a co-factor for MAPK activation and latent viral gene expression during de novo infection by KSHV. Virology. 2010;403(1):92-102.

3. Breinig M, Caldas-Lopes E, Goeppert B, et al. Targeting heat shock protein 90 with non-quinone inhibitors: a novel chemotherapeutic approach in human hepatocellular carcinoma. Hepatology. 2009;50(1): 102-112. 4. Chen W, Sin SH, Wen KW, Damania B, Dittmer DP. Hsp90 inhibitors are efficacious against Kaposi Sarcoma by enhancing the degradation of the essential viral gene

6. Defee MR, Qin Z, Dai L, Isaacs JS, Parsons CH. Interactions between Hsp90 and oncogenic viruses: implications for viral cancer therapeutics. Am J Cancer Res. 2011;1(6):763-772. © 2013 by The American Society of Hematology


Comment on Larocca et al, page 2799

“A fortuitous combination of circumstances” ----------------------------------------------------------------------------------------------------Sagar Lonial1



In this issue of Blood, Larocca et al report encouraging data on the 3-drug combination of cyclophosphamide, pomalidomide, and prednisone among relapsed myeloma patients, for a “fortuitous combination,” as Charles Dickens wrote in Our Mutual Friend.1


yclophosphamide is one of the oldest active agents in oncology and has been experiencing a recent renaissance in the myeloma community. Its mechanism of action as an alkylating agent is decidedly “old school.”2 Pomalidomide is the newest agent approved for the treatment of relapsed and refractory myeloma and has activity when combined with dexamethasone even among patients proven to be resistant to lenalidomide.3 The availability of pomalidomide for patients with refractory myeloma has been a major step forward, yet there is clearly room to further enhance response rates and response duration. This is where the fortuitous combination comes into play. The benefit of combination therapy has been demonstrated in the induction therapy setting, in which the use of 3 agents induces a deeper response than is seen with 2 agents, and this is associated with superior posttransplant outcomes.4 Among patients with early relapse, there is a single trial testing 3 agents (bortezomib/thalidomide/ dexamethasone) vs 2 agents (thalidomide/ dexamethasone).5 In this study, the use of a 3-drug regimen improved overall response rate, depth of response, and progression-free survival with a trend toward improved overall

survival.6 To further build on this concept of 3 vs 2 drugs in the early-relapse setting, ongoing phase 3 studies will provide further evidence to address this question with other new agents such carfilzomib (carfilzomib/ lenalidomide/dexamethasone vs lenalidomide/dexamethasone), panobinostat (panobinostat/bortezomib/dexamethasone vs bortezomib/dexamethasone), elotuzumab (elotuzumab/lenalidomide/dexamethasone vs lenalidomide/dexamethasone), and pomalidomide (pomalidomide/bortezomib/ dexamethasone vs bortezomib/dexamethasone). From a tumor biology perspective, the use of combination therapy also offers the potential benefit of suppressing and eliminating more subclones, which may delay the development of refractory relapse. Given data with newly diagnosed and early-relapse patients supporting combination therapy, the pressing question now is, does the effect of combination therapy hold true even in the refractory relapse setting? There are data supporting the clinical benefit associated with minor responses in the relapsed and refractory disease, using bortezomib,7 pomalidomide,8 and carfilzomib,9 and it is also known that patients


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with refractory disease may be more debilitated and unable to tolerate aggressive combination treatments. In contrast, patients with refractory disease may stand to benefit the greatest from combination therapy. Thus, should we abandon the use of single-agent therapy in favor of combinations in all settings? The data from Larocca et al1 clearly demonstrate the benefits of triple drug combinations, combining the old with the new, and it appears that this regimen both is more active than pomalidomide/ dexamethasone in lenalidomide-refractory patients and is well-tolerated. However, the patients, although lenalidomide-resistant, were less heavily pretreated overall (1-3 prior lines vs .5 for the Richardson study8). This difference in inherent drug exposure limits the ability to extrapolate the pomalidomide/ cyclophosphamide/prednisone data from Larocca to the generalized refractory myeloma patient population. The unanswered question remaining for the clinician is, who is this regimen best suited for? It appears that the pomalidomide/ cyclophosphamide/prednisone combination is effective and can be safely administered with very encouraging results. However, it remains unclear whether the benefits of combination therapy realized in early lines of therapy can be routinely applied to a sicker, less robust, refractory population after numerous lines of prior treatment. Until these types of trials are performed in the refractory relapse population, decisions regarding combination therapy, although they may be biologically appealing, need to be based on the physical and hematological reserve of the refractory patient in question. Thus, although the combination may be fortuitous, circumstances of an individual patient will dictate the ultimate utility and success of this approach. Conflict-of-interest disclosure: S.L. is a consultant for Millennium, Celgene, Novartis, BMS, Onyx, and Sanofi. n

4. Cavo M, Tacchetti P, Patriarca F, et al; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376(9758): 2075-2085. 5. Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomidedexamethasone over the dual combination of thalidomidedexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 Randomized Phase III Trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012;30(20):2475-2482. 6. Lonial S, Kaufman JL. The era of combination therapy in myeloma. J Clin Oncol. 2012;30(20):2434-2436.

7. Niesvizky R, Richardson PG, Rajkumar SV, et al. The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma. Br J Haematol. 2008;143(1):46-53. 8. Richardson PG, Siegel DS, Vij R, et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results [abstract]. Blood. 2011;118(21):Abstract 634. 9. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):2817-2825. © 2013 by The American Society of Hematology


Comment on Shukla et al, page 2848

IRF42/2Vh11 mice: a novel mouse model of CLL ----------------------------------------------------------------------------------------------------Yiming Zhong1 and John C. Byrd1



In this issue of Blood, Shukla and colleagues identify IRF42/2Vh11 mice, which develop spontaneous chronic lymphocytic leukemia (CLL) with 100% penetrance within 10 months as a novel mouse model of CLL, providing a new tool for investigating the pathogenesis of CLL and evaluating therapeutic agents.1


enetically modified mice are essential tools for investigating the roles of genes in development and progression of diseases and for preclinical testing of new therapies. The absence of good mouse models of CLL, the most common leukemia in Western countries, has hindered research and the development of therapies to combat this incurable disease. Due to the nonproliferating nature of circulating CLL cells, xenograft models of human CLL are inaccurate models of disease. In the last decade, several mouse models representing different subtypes of CLL have been developed. For

example, Em-TCL1 transgenic mice resemble aggressive CLL,2 Dlu2/miR15a/16-1 deletion mice3 and miR29b transgenic mice4 are related to indolent CLL, and TRAF2DN/Bcl2 double transgenic mice5 may be a model of refractory CLL. However, because of the complexity and heterogeneity of CLL and the limitations of current mouse models, the development of new mouse models of CLL is attractive. In this issue, Shukla and colleagues establish IRF42/2Vh11 mice as a novel mouse model of CLL with 100% penetrance within 10 months.1

REFERENCES 1. Larocca A, Montefusco V, Bringhen S, et al. Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open label study. Blood. 2013;122(16):2799-2806. 2. Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009; 6(11):638-647. 3. Richardson PG, Siegel D, Baz R, et al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood. 2013;121(11):1961-1967.

Spontaneous CLL development in IRF42/2Vh11 mice. See Figure 1 in the article by Shukla et al that begins on page 2848.



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2013 122: 2768-2769 doi:10.1182/blood-2013-09-522409

''A fortuitous combination of circumstances'' Sagar Lonial

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