Updates from Inside Blood 9/28/08

Blood, 15 September 2008, Vol. 112, No. 6, pp. 2177-2178.

NEOPLASIA

Comment on Oerlemans, page 2489
Many facets of bortezomib resistance/susceptibility
Shaji Kumar, and S. Vincent Rajkumar
MAYO CLINIC
In this issue of Blood, Oerlemans and colleagues present a fascinating report, detailing a mechanism by which cells acquire resistance to therapy with the proteasome inhibitor, bortezomib.
Proteasome inhibition represents one of the most successful anticancer strategies of this decade, improving the outcomes of many patients. The ubiquitin proteasome pathway is critical to normal cellular functioning and is involved in signal transduction, transcriptional regulation, and response to stress, among other pathways. The 26S proteasome consists of a core 20S catalytic complex and a 19S regulatory complex, forming 2 outer and 2 inner rings that are stacked to form a cylindrical structure.1 The 19S complex is responsible for selecting the ubiquitinated proteins for catalytic degradation by the 20S complex, which possesses chymotryptic, tryptic, and peptidylglutamyl-like activities. This critical cellular function has been successfully targeted for cancer therapy, as highlighted by the efficacy of proteasome inhibitor bortezomib in a wide spectrum of hematological and solid tumors.2 In fact, the introduction of bortezomib resulted in a paradigm shift in the treatment of multiple myeloma, and has undoubtedly contributed to the improved survival seen among patients with this incurable malignancy.3 The mechanism of antimyeloma activity of bortezomib is the subject of intense study. Bortezomib is currently believed to exert its effects through multiple pathways that target both the tumor cell and its microenvironment. For example, inhibition of the NFkB pathway leading to decreased cell proliferation and induction of apoptosis is one of the major effects of bortezomib therapy. Treatment with bor-tezomib prolongs survival in relapsed myeloma as well as newly diagnosed disease, leading to its regulatory approval for clinical use in both situations.4 However, resistance to therapy develops inevitably. Furthermore, nearly a third of the patients with multiple myeloma never respond to treatment with bortezomib, depending on the clinical situation. While some resistance mechanisms may be reversible in a small proportion of patients following withdrawal of the drug, as demonstrated by the efficacy of retreatment, the majority need to switch therapy. Understanding the mechanisms of resistance to proteasome inhibition will not only allow better use of proteasome inhibitors such as bortezomib, but should also allow the rational design of synergistic drug combinations.

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Mechanisms of resistance and susceptibility to proteasome inhibition. Signaling through canonical or noncanonical pathways leads to phosphorylation, ubiquitination, and subsequent degradation of the IkB kinases through the proteasome pathway, resulting in NFkB translocation to the nucleus and transcription of target genes. Constitutive NFkB signaling can result from mutations in regulatory genes, such as Traf3, leading to increased sensitivity of the cell to proteasome inhibition. Mechanisms of resistance include: (1) the 26S proteasome acquiring resistance due to mutations or overexpression of the PSMB5 subunit; (2) proteasome inhibitors being antagonized by upregulation of heat shock proteins, such as Hsp27; and (3) increased activity of the aggresome pathway. These resistance mechanisms can be targeted to increase the efficacy of proteasome inhibition.

Malignant cells may develop several mechanisms to escape the effects of proteasome inhibition, including alterations in the proteasome complex itself leading to decreased function, increasing the efficiency of alternate mechanisms of protein degradation (the aggresome pathway), or modulation of cell signaling pathways that are affected by proteasome inhibition. Oerlemans et al, in this issue of Blood, report on a mutation involving the β5 unit of the proteasome catalytic unit (PSMB5) that leads to impaired binding of bortezomib and thus decreased proteosome inhibition. These investigators also noted a significant upregulation of the PSMB5 subunit following exposure to bortezomib and other proteasome inhibitors, an effect that wanes with time off-therapy, but reappears rapidly after re-exposure to the inhibitors. These studies were carried out using human monocytic/macrophage THP1 cells, and whether these findings are applicable to malignant cells in diseases like myeloma is unclear. However, these findings do highlight the susceptibility of proteasome units to genetic modifications under constant selection pressure, as can occur with continued treatment in patients. Mutation and overexpression of PSMB5 can lead to bortezomib resistance in lymphoma cells lines. While mutations such as this may explain development of resistance, baseline differences in susceptibility may be due to polymorphisms involving the PSMB5 locus.5
An alternate mechanism used by the cell for ubiquitinated protein degradation and disposal is the aggresome pathway, which can potentially compensate for proteasome pathway inhibition and contribute to drug resistance. This physiological compensatory mechanism has been targeted for enhancing the efficacy of proteasome inhibitors. Use of HDAC6 specific inhibitors, such as tubacin, can shut down the aggresome pathway and can synergize with and enhance the effect of proteasome inhibition on the tumor cell.6 Upregulation of the heat shock protein Hsp27 is yet another mechanism of proteasome inhibitor resistance and has been targeted as an avenue for enhancing proteasome inhibition as well as reversing resistance to this class of drugs.7
Finally, identification of mechanisms that confer sensitivity to proteasome inhibition is as important as understanding mechanisms of resistance. Recent studies have identified mutations involving genes associated with regulation of NFkB pathways that result in constitutive activation of the NFkB pathway.8 Cells that carry these mutations appear to be particularly sensitive to the effects of proteasome inhibition, a finding that could allow us to tailor the use of this class of drugs in the future.
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests.
REFERENCES
Adams J. The proteasome: structure function, and role in the cell. Cancer Treat Rev. 2003;29(suppl 1):3–9.[Medline] [Order article via Infotrieve]
Rajkumar SV, Richardson PG, Hideshima T, et al. Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol. 2004;23:630–639.[CrossRef]
Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516–2520.[CrossRef][Medline] [Order article via Infotrieve]
Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487–2498.[Abstract/Free Full Text]
Wang L, Kumar S, Fridley BL, et al. Proteasome {beta} subunit pharmacogenomics: gene resequencing and functional genomics. Clin. Cancer Res. 2008;14:3503–3513.[Abstract/Free Full Text]
Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A. 2005;102:8567–8572.[Abstract/Free Full Text]
Chauhan D, Li G, Shringarpure R, et al. Blockade of Hsp27 overcomes bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res. 2003;63:6174–6177.[Abstract/Free Full Text]
Keats JJ, Fonseca R, Chesi M, et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 2007;12:131–144.[CrossRef][Medline] [Order article via Infotrieve]
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Blood First Edition Paper, prepublished online September 17, 2008; DOI 10.1182/blood-2008-02-141614.
Submitted February 26, 2008
Accepted July 25, 2008
Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure
Michael Wang*, Meletios A. Dimopoulos, Christine Chen, M. Teresa Cibeira, Michel Attal, Andrew Spencer, S. Vincent Rajkumar, Zhinuan Yu, Marta Olesnyckyj, Jerome B Zeldis, Robert D Knight, and Donna M Weber
Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston, TX, United States
Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece
Department of Medicine, Princess Margaret Hospital, Toronto, ON, Canada
Hematology Department, Institute of Hematology and Oncology, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain
Division of Hematology, Centre Hospitalier Universite de Purpan, Toulouse, France
Department of Malignant Hematology and Stem Cell Transplantation Service, The Alfred Hospital, Melbourne, Australia
Mayo Clinic Cancer Center, Rochester, MN, United States
Celgene Corporation, Summit, NJ, United States
* Corresponding author; email: miwang@mdanderson.org .
This analysis assessed the efficacy and safety of lenalidomide+dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide-exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide+dexamethasone led to higher overall response rate (ORR), longer time-to-progression (TTP) and progression-free survival (PFS) versus placebo+dexamethasone despite prior thalidomide exposure. Among lenalidomide+dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (p=.04), with longer median TTP (p=.04) and PFS (p =.02). Likewise for dexamethasone alone-treated patients (p =.03 for ORR, p =.03 for TTP, p=.06 for PFS). Prior thalidomide did not affect survival in lenalidomide+dexamethasone-treated patients (36.1 vs. 33.3 months, p > .05). Thalidomide-naive and thalidomide-exposed patients had similar toxicities. Lenalidomide+dexamethasone resulted in higher rates of venous thromboembolism, myelosuppression and infections versus placebo+dexamethasone, independent of prior thalidomide exposure. In conclusion, lenalidomide+dexamethasone was superior to placebo+dexamethasone in relapsed or refractory MM, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to inferior TTP and PFS compared with thalidomide-naive patients, these parameters remained superior compared with placebo+dexamethasone; similar benefits compared with placebo+ dexamethasone were not evident for thalidomide-exposed patients in terms of overall survival. Studies were registered at www.clinicaltrials.gov under: NCT00056160 and NCT00424047.
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Blood First Edition Paper, prepublished online September 19, 2008; DOI 10.1182/blood-2008-02-140434.
Submitted February 22, 2008
Accepted August 24, 2008
Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping
David C Johnson, Sophie Corthals, Christine Ramos, Antje Hoering, Kim Cocks, Nicholas J Dickens, Jeff Haessler, Harmut Goldschmidt, J. Anthony Child, Sue E Bell, Graham Jackson, Dalsu Baris, S. Vincent Rajkumar, Faith E Davies, Brian G.M. Durie, John Crowley, Pieter Sonneveld, Brian Van Ness, and Gareth J Morgan*
Institute of Cancer Research, London, United Kingdom
Erasmus Medical Center, Rotterdam, Netherlands
University of Minnesota, Minneapolis, MN, United States
Cancer Research and Biostatistics (CRAB), Seattle, WA, United States
University of Leeds, Leeds, United Kingdom
University of Heidelberg, Heidelberg, Germany
University of Newcastle, Newcastle, United Kingdom
National Cancer Institute, Bethesda, MD, United States
Mayo Clinic, Rochester, MN, United States
Cedars-Sinai Medical Center, Los Angeles, CA, United States
* Corresponding author; email: gareth.morgan@icr.ac.uk .
A venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism is a major concern in the treatment of multiple myeloma patients with thalidomide. The susceptibility to developing a VTE in response to thalidomide therapy is likely to be influenced by both genetic and environmental factors. To test genetic variation associated with treatment related VTE in patient peripheral blood DNA, we used a custom-built molecular inversion probe (MIP) based single nucleotide polymorphism (SNP) chip containing 3404 SNPs. SNPs on the chip were selected in “functional regions” within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response and side effects associated with myeloma therapy. Cases and controls were taken from three large clinical trials: MRC Myeloma IX, Hovon-50 and ECOG EA100, which compared conventional treatments with thalidomide in myeloma patients. Our analysis showed that the set of SNPs associated with thalidomide-related VTE were enriched in genes and pathways important in drug transport/metabolism, DNA repair and cytokine balance. The effects of the SNPs associated with thalidomide related VTE may be functional at the level of the tumor cell, the tumor-related microenvironment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111, HOVON50: www.clinicaltrials.gov under identifier NCT00028886, and ECOG EA100: www.clinicaltrials.gov under identifier NCT00033332.
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Blood First Edition Paper, prepublished online September 24, 2008; DOI 10.1182/blood-2008-05-155952.

Submitted May 7, 2008
Accepted August 15, 2008
Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator
Yan Jiao, John Wilkinson IV, Xiumin Di, Wei Wang, Heather Hatcher, Nancy D. Kock, Ralph D’Agostino Jr., Mary Ann Knovich, Frank M. Torti, and Suzy V. Torti*
Department of Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, NC, United States
Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC, United States
Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, United States
Section of Hematology/Oncology, Wake Forest University Health Sciences, Winston-Salem, NC, United States
Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC, United States
Department of Biochemistry, Wake Forest University Health Sciences, Winston-Salem, NC, United States
* Corresponding author; email: storti@wfubmc.edu .
Curcumin is a natural product currently in human clinical trials for a variety of neoplastic, preneoplastic and inflammatory conditions. We previously observed that in cultured cells, curcumin exhibits properties of an iron chelator. To test whether the chelator activity of curcumin is sufficient to induce iron deficiency in vivo, mice were placed on diets containing graded concentrations of both iron and curcumin for 26 weeks. Mice receiving the lowest level of dietary iron exhibited borderline iron deficiency, with reductions in spleen and liver iron, but little effect on hemoglobin, hematocrit, transferrin saturation or plasma iron. Against this backdrop of subclinical iron deficiency, curcumin exerted profound effects on systemic iron, inducing a dose-dependent decline in hematocrit, hemoglobin, serum iron and transferrin saturation, the appearance of microcytic anisocytotic red blood cells, and decreases in spleen and liver iron content. Curcumin repressed synthesis of hepcidin, a peptide that plays a central role in regulation of systemic iron balance. These results demonstrate that curcumin has the potential to affect systemic iron metabolism, particularly in a settling of subclinical iron deficiency. This may affect the use of curcumin in patients with marginal iron stores or those exhibiting the anemia of cancer and chronic disease.