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Journal articles on the topic 'Molecular pharming'

Author: Grafiati

Published: 4 June 2021

Last updated: 13 February 2022

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1

Paul, Mathew, Craig van Dolleweerd, Pascal M. W. Drake, Rajko Reljic, Harry Thangaraj, Tommaso Barbi, Elena Stylianou, et al. "Molecular pharming." Human Vaccines 7, no. 3 (March 2011): 375–82. http://dx.doi.org/10.4161/hv.7.3.14456.

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2

Boscaiu, Monica, and Oscar Vicente. "Plant ‘molecular pharming’." Journal of Biotechnology 231 (August 2016): S6—S7. http://dx.doi.org/10.1016/j.jbiotec.2016.05.048.

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3

Humphreys, John M., and Clint Chapple. "Molecular ‘pharming’ with plant P450s." Trends in Plant Science 5, no. 7 (July 2000): 271–72. http://dx.doi.org/10.1016/s1360-1385(00)01680-0.

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4

Ramessar, Koreen, Teresa Capell, and Paul Christou. "Molecular pharming in cereal crops." Phytochemistry Reviews 7, no. 3 (February 23, 2008): 579–92. http://dx.doi.org/10.1007/s11101-008-9087-3.

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5

Marsian, Johanna, and George P. Lomonossoff. "Molecular pharming — VLPs made in plants." Current Opinion in Biotechnology 37 (February 2016): 201–6. http://dx.doi.org/10.1016/j.copbio.2015.12.007.

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6

Horn, Michael E. "Plant molecular pharming 2012 and beyond." Plant Cell Reports 31, no. 3 (February 4, 2012): 437–38. http://dx.doi.org/10.1007/s00299-012-1227-y.

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7

Spalding, B. J. "Transgenic Pharming Advances." Nature Biotechnology 10, no. 5 (May 1992): 498–99. http://dx.doi.org/10.1038/nbt0592-498.

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8

Abdullah, M. A., Anisa ur Rahmah, A. J. Sinskey, and C. K. Rha. "Cell Engineering and Molecular Pharming for Biopharmaceuticals." Open Medicinal Chemistry Journal 2, no. 1 (May 14, 2008): 49–61. http://dx.doi.org/10.2174/1874104500802010049.

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9

Ma, J. K. C. "Molecular pharming—innovation, product development and manufacture." New Biotechnology 25 (September 2009): S282. http://dx.doi.org/10.1016/j.nbt.2009.06.636.

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10

Lössl, Andreas G., and Jihong L. Clarke. "Conference Scene: Molecular pharming: manufacturing medicines in plants." Immunotherapy 5, no. 1 (January 2013): 9–12. http://dx.doi.org/10.2217/imt.12.146.

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11

Murad, Sheeba, Sebastian Fuller, Jonathan Menary, Cathy Moore, Elizabeth Pinneh, Tim Szeto, Inga Hitzeroth, et al. "Molecular Pharming for low and middle income countries." Current Opinion in Biotechnology 61 (February 2020): 53–59. http://dx.doi.org/10.1016/j.copbio.2019.10.005.

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12

Nasto, Barbara. "Pharming seeks public support." Nature Biotechnology 16, no. 9 (September 1998): 807–8. http://dx.doi.org/10.1038/nbt0998-807b.

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13

Stewart, C. Neal. "Pharming in crop commodities." Nature Biotechnology 26, no. 11 (November 2008): 1222–23. http://dx.doi.org/10.1038/nbt1108-1222.

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14

Chappell, J. "Production platforms for the molecular pharming of alkaloid diversity." Proceedings of the National Academy of Sciences 105, no. 23 (June 9, 2008): 7897–98. http://dx.doi.org/10.1073/pnas.0803930105.

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15

Ou, Jiquan, Zhibin Guo, Jingni Shi, Xianghong Wang, Jingru Liu, Bo Shi, Fengli Guo, Chufu Zhang, and Daichnag Yang. "Transgenic rice endosperm as a bioreactor for molecular pharming." Plant Cell Reports 33, no. 4 (January 12, 2014): 585–94. http://dx.doi.org/10.1007/s00299-013-1559-2.

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16

Bialy, Harvey. "Transgenic Pharming Comes of Age." Nature Biotechnology 9, no. 9 (September 1991): 786–88. http://dx.doi.org/10.1038/nbt0991-786.

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17

Peerenboom, Ellen. "Pharming cloning ban could spread." Nature Biotechnology 16, no. 4 (April 1998): 321–22. http://dx.doi.org/10.1038/nbt0498-321b.

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18

Paul, Mathew, Audrey Teh, Richard Twyman, and Julian Ma. "Target Product Selection - Where Can Molecular Pharming Make the Difference?" Current Pharmaceutical Design 19, no. 31 (August 1, 2013): 5478–85. http://dx.doi.org/10.2174/1381612811319310003.

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19

Mir‐Artigues, Pere, Richard M. Twyman, Derry Alvarez, Pedro Cerda Bennasser, Merce Balcells, Paul Christou, and Teresa Capell. "A simplified techno‐economic model for the molecular pharming of antibodies." Biotechnology and Bioengineering 116, no. 10 (July 24, 2019): 2526–39. http://dx.doi.org/10.1002/bit.27093.

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20

Stoger, Eva, Rainer Fischer, Maurice Moloney, and Julian K. C. Ma. "Plant Molecular Pharming for the Treatment of Chronic and Infectious Diseases." Annual Review of Plant Biology 65, no. 1 (April 29, 2014): 743–68. http://dx.doi.org/10.1146/annurev-arplant-050213-035850.

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21

Sabalza, Maite, Evagelia Vamvaka, Paul Christou, and Teresa Capell. "Seeds as a Production System for Molecular Pharming Applications: Status and Prospects." Current Pharmaceutical Design 19, no. 31 (August 1, 2013): 5543–52. http://dx.doi.org/10.2174/1381612811319310009.

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22

Ramessar, Koreen, Maite Sabalza, Teresa Capell, and Paul Christou. "Maize plants: An ideal production platform for effective and safe molecular pharming." Plant Science 174, no. 4 (April 2008): 409–19. http://dx.doi.org/10.1016/j.plantsci.2008.02.002.

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23

Ritala, Anneli, Suvi T. Häkkinen, and Stefan Schillberg. "Molecular pharming in plants and plant cell cultures: a great future ahead?" Pharmaceutical Bioprocessing 2, no. 3 (June 2014): 223–26. http://dx.doi.org/10.4155/pbp.14.21.

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24

McNulty, Matthew J., Yongao (Mary) Xiong, Kevin Yates, Kalimuthu Karuppanan, Jacob M. Hilzinger, Aaron J. Berliner, Jesse Delzio, et al. "Molecular pharming to support human life on the moon, mars, and beyond." Critical Reviews in Biotechnology 41, no. 6 (March 9, 2021): 849–64. http://dx.doi.org/10.1080/07388551.2021.1888070.

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25

Qiang, Weidong, Tingting Gao, Xinxin Lan, Jinnan Guo, Muhammad Noman, Yaying Li, Yongxin Guo, et al. "Molecular Pharming of the Recombinant Protein hEGF-hEGF Concatenated with Oleosin Using Transgenic Arabidopsis." Genes 11, no. 9 (August 19, 2020): 959. http://dx.doi.org/10.3390/genes11090959.

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We set out to assess the NIH/3T3 cell proliferation activity of Arabidopsis oil body-expressed recombinant oleosin–hEGF–hEGF protein. Normally, human epidermal growth factor (hEGF) is purified through complex process, however, oleosin fusion technology provides an inexpensive and scalable platform for its purification. Under a phaseolin promoter, we concatenated oleosin gene to double hEGF (hEGF–hEGF) with plant-preferred codons in the expression vectors and the construct was transformed into Arabidopsis thaliana (Arabidopsis). The transgenic Arabidopsis was validated by RT–PCR and the content of recombinant protein oleosin–hEGF–hEGF was quantified by western blot. Subsequently, the proliferation assay and transdermal absorption were determined by MTT method and immunohistochemical staining, respectively. First, the expression level of hEGF was recorded to be 14.83-ng/μL oil body and due to smaller size transgenic oil bodies expressing the recombinant oleosin–hEGF–hEGF, they were more skin permeable than those of control. Second, via the staining intensity of transgenic oil bodies was greater than EGF at all time points via immunohistochemical staining in transdermal absorption process. Lastly, activity assays of oil bodies expressed oleosin–hEGF–hEGF indicated that they stimulated the NIH/3T3 cell proliferation activity. Our results revealed oil-body-expressed oleosin–hEGF–hEGF was potential new material having implications in the field of medicine.

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26

Venkataraman, Srividhya, Kathleen Hefferon, Abdullah Makhzoum, and Mounir Abouhaidar. "Combating Human Viral Diseases: Will Plant-Based Vaccines Be the Answer?" Vaccines 9, no. 7 (July 8, 2021): 761. http://dx.doi.org/10.3390/vaccines9070761.

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Molecular pharming or the technology of application of plants and plant cell culture to manufacture high-value recombinant proteins has progressed a long way over the last three decades. Whether generated in transgenic plants by stable expression or in plant virus-based transient expression systems, biopharmaceuticals have been produced to combat several human viral diseases that have impacted the world in pandemic proportions. Plants have been variously employed in expressing a host of viral antigens as well as monoclonal antibodies. Many of these biopharmaceuticals have shown great promise in animal models and several of them have performed successfully in clinical trials. The current review elaborates the strategies and successes achieved in generating plant-derived vaccines to target several virus-induced health concerns including highly communicable infectious viral diseases. Importantly, plant-made biopharmaceuticals against hepatitis B virus (HBV), hepatitis C virus (HCV), the cancer-causing virus human papillomavirus (HPV), human immunodeficiency virus (HIV), influenza virus, zika virus, and the emerging respiratory virus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been discussed. The use of plant virus-derived nanoparticles (VNPs) and virus-like particles (VLPs) in generating plant-based vaccines are extensively addressed. The review closes with a critical look at the caveats of plant-based molecular pharming and future prospects towards further advancements in this technology. The use of biopharmed viral vaccines in human medicine and as part of emergency response vaccines and therapeutics in humans looks promising for the near future.

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27

Faye, Loïc, Aurelia Boulaflous, Meriem Benchabane, Véronique Gomord, and Dominique Michaud. "Protein modifications in the plant secretory pathway: current status and practical implications in molecular pharming." Vaccine 23, no. 15 (March 2005): 1770–78. http://dx.doi.org/10.1016/j.vaccine.2004.11.003.

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28

Makhzoum, Abdullah, Shifa Tahir, Marjorie Elizabeth Osborn Locke, Jocelyne Trémouillaux-Guiller, and Kathleen Hefferon. "An in silico overview on the usefulness of tags and linkers in plant molecular pharming." Plant Science Today 1, no. 4 (October 1, 2014): 201–12. http://dx.doi.org/10.14719/pst.2014.1.4.72.

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29

Webster, Gina R., Audrey Y. H. Teh, and Julian K. C. Ma. "Synthetic gene design-The rationale for codon optimization and implications for molecular pharming in plants." Biotechnology and Bioengineering 114, no. 3 (December 15, 2016): 492–502. http://dx.doi.org/10.1002/bit.26183.

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30

Makhzoum, Abdullah, Roukia Benyammi, Khaled Moustafa, and Jocelyne Trémouillaux-Guiller. "Recent advances on host plants and expression cassettes' structure and function in plant molecular pharming." BioDrugs 28, no. 2 (August 20, 2013): 145–59. http://dx.doi.org/10.1007/s40259-013-0062-1.

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31

Ma, Julian K.-C., Paul Christou, Rachel Chikwamba, Hugh Haydon, Mathew Paul, Merardo Pujol Ferrer, Sathishkumar Ramalingam, et al. "Realising the value of plant molecular pharming to benefit the poor in developing countries and emerging economies." Plant Biotechnology Journal 11, no. 9 (October 14, 2013): 1029–33. http://dx.doi.org/10.1111/pbi.12127.

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32

Prudhomme, N., R. Pastora, B. Muselius, M. D. McLean, D. Cossar, and J. Geddes-McAlister. "Exposure of Agrobacterium tumefaciens to agroinfiltration medium demonstrates cellular remodelling and may promote enhanced adaptability for molecular pharming." Canadian Journal of Microbiology 67, no. 1 (January 2021): 85–97. http://dx.doi.org/10.1139/cjm-2020-0239.

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Agroinfiltration is used to treat plants with modified strains of Agrobacterium tumefaciens for the purpose of transient in planta expression of genes transferred from the bacterium. These genes encode valuable recombinant proteins for therapeutic or industrial applications. Treatment of large quantities of plants for industrial-scale protein production exposes bacteria (harboring genes of interest) to agroinfiltration medium that is devoid of nutrients and carbon sources for prolonged periods of time (possibly upwards of 24 h). Such conditions may negatively influence bacterial viability, infectivity of plant cells, and target protein production. Here, we explored the role of timing in bacterial culture preparation for agroinfiltration using mass spectrometry-based proteomics to define changes in cellular processes. We observed distinct profiles associated with bacterial treatment conditions and exposure timing, including significant changes in proteins involved in pathogenesis, motility, and nutrient acquisition systems as the bacteria adapt to the new environment. These data suggest a progression towards increased cellular remodelling over time. In addition, we described changes in growth- and environment-specific processes over time, underscoring the interconnectivity of pathogenesis and chemotaxis-associated proteins with transport and metabolism. Overall, our results have important implications for the production of transiently expressed target protein products, as prolonged exposure to agroinfiltration medium suggests remodelling of the bacterial proteins towards enhanced infection of plant cells.

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33

Prudhomme, N., C. Gianetto-Hill, R. Pastora, W. F. Cheung, E. Allen-Vercoe, M. D. McLean, D. Cossar, and J. Geddes-McAlister. "Quantitative proteomic profiling of shake flask versus bioreactor growth reveals distinct responses of Agrobacterium tumefaciens for preparation in molecular pharming." Canadian Journal of Microbiology 67, no. 1 (January 2021): 75–84. http://dx.doi.org/10.1139/cjm-2020-0238.

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The preparation of Agrobacterium tumefaciens cultures with strains encoding proteins intended for therapeutic or industrial purposes is an important activity prior to treatment of plants for transient expression of valuable protein products. The rising demand for biologic products such as these underscores the expansion of molecular pharming and warrants the need to produce transformed plants at an industrial scale. This requires large quantities of A. tumefaciens culture, which is challenging using traditional growth methods (e.g., shake flask). To overcome this limitation, we investigate the use of bioreactors as an alternative to shake flasks to meet production demands. Here, we observe differences in bacterial growth among the tested parameters and define conditions for consistent bacterial culturing between shake flask and bioreactor. Quantitative proteomic profiling of cultures from each growth condition defines unique growth-specific responses in bacterial protein abundance and highlights the functional roles of these proteins, which may influence bacterial processes important for effective agroinfiltration and transformation. Overall, our study establishes and optimizes comparable growth conditions for shake flask versus bioreactors and provides novel insights into fundamental biological processes of A. tumefaciens influenced by such growth conditions.

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34

Singh, Davinder Pal, Angelica M. Jermakow, and Stephen M. Swain. "Preliminary development of a genetic strategy to prevent transgene escape by blocking effective pollen flow from transgenic plants." Functional Plant Biology 34, no. 12 (2007): 1055. http://dx.doi.org/10.1071/fp06323.

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Genetic modification (GM) of plants has great potential in the production of food and industrial compounds, and in molecular pharming. One of the greatest public concerns regarding this technology is effective pollen flow, in which wind- or insect-borne transgenic pollen is able to fertilise either non-GM crops of the same species, or closely related weed species, and lead to viable seed formation. In this paper we describe a novel concept, based on epigenetic inheritance (imprinting) and post-transcriptional gene silencing (PTGS)/RNA interference (RNAi), designed to prevent transgene escape via pollen flow from transgenic plants. A key advantage of this strategy is that it would allow all seeds from self-pollinated transgenic plants to be harvested and re-sown, without the need for specific treatments, while retaining all of the transgenes present in the parent. Thus, this strategy is not a Genetic Use Restriction Technology (GURT) and if implemented would not prevent seed saving by end-users.

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35

Abiri, Rambod, Hazandy Abdul-Hamid, Oksana Sytar, Ramin Abiri, Eduardo Bezerra de Almeida, Surender K. Sharma, Victor P. Bulgakov, Randolph R. J. Arroo, and Sonia Malik. "A Brief Overview of Potential Treatments for Viral Diseases Using Natural Plant Compounds: The Case of SARS-Cov." Molecules 26, no. 13 (June 24, 2021): 3868. http://dx.doi.org/10.3390/molecules26133868.

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The COVID-19 pandemic, as well as the more general global increase in viral diseases, has led researchers to look to the plant kingdom as a potential source for antiviral compounds. Since ancient times, herbal medicines have been extensively applied in the treatment and prevention of various infectious diseases in different traditional systems. The purpose of this review is to highlight the potential antiviral activity of plant compounds as effective and reliable agents against viral infections, especially by viruses from the coronavirus group. Various antiviral mechanisms shown by crude plant extracts and plant-derived bioactive compounds are discussed. The understanding of the action mechanisms of complex plant extract and isolated plant-derived compounds will help pave the way towards the combat of this life-threatening disease. Further, molecular docking studies, in silico analyses of extracted compounds, and future prospects are included. The in vitro production of antiviral chemical compounds from plants using molecular pharming is also considered. Notably, hairy root cultures represent a promising and sustainable way to obtain a range of biologically active compounds that may be applied in the development of novel antiviral agents.

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36

Ahmad, Norazlina, Rajnesh Sant, Milovan Bokan, Kathryn J. Steadman, and Ian D. Godwin. "Expression Pattern of the Alpha-Kafirin Promoter Coupled with a Signal Peptide fromSorghum bicolorL. Moench." Journal of Biomedicine and Biotechnology 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/752391.

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Regulatory sequences with endosperm specificity are essential for foreign gene expression in the desired tissue for both grain quality improvement and molecular pharming. In this study, promoters of seed storage α-kafirin genes coupled with signal sequence (ss) were isolated fromSorghum bicolorL. Moench genomic DNA by PCR. The α-kafirin promoter (α-kaf) contains endosperm specificity-determining motifs, prolamin-box, the O2-box 1, CATC, and TATA boxes required for α-kafirin gene expression in sorghum seeds. The constructs pMB-Ubi-gfpand pMB-kaf-gfpwere microprojectile bombarded into various sorghum and sweet corn explants. GFP expression was detected on all explants using the Ubi promoter but only in seeds for the α-kaf promoter. This shows that the α-kaf promoter isolated was functional and demonstrated seed-specific GFP expression. The constructs pMB-Ubi-ss-gfpand pMB-kaf-ss-gfpwere also bombarded into the same explants. Detection of GFP expression showed that the signal peptide (SP)::GFP fusion can assemble and fold properly, preserving the fluorescent properties of GFP.

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37

Řepková, J. "Potential of chloroplast genome in plant breeding." Czech Journal of Genetics and Plant Breeding 46, No. 3 (October 14, 2010): 103–13. http://dx.doi.org/10.17221/79/2010-cjgpb.

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Chloroplast engineering (or chloroplast transformation technology, CTT) is a strategy consisting of inserting a transgene into the chloroplast genome of a plant instead of its nuclear genome. CTT brings advantages such as control of the site of gene insertion, high rates of transgene expression and protein accumulation, lack of transmission of the transgene via pollen due to the fact that plastid genes are maternally inherited and an absence of epigenetic effects. Tobacco remains the species most amenable to CTT to date, although chloroplast genetic engineering has also been achieved successfully in crops such as maize, tomato, cotton, potato, rice and sugar beets. Improving agricultural traits such as herbicide and pathogen resistance, resistance to drought, salt tolerance and phytoremediation potential are all promising applications. Molecular pharming is another area of chloroplast engineering with high potential; the production of a wide range of products such as vaccine antigens, pharmaceutical proteins (human somatotropin, human serum albumin, human interferon, monoclonal antibodies) and industrial proteins (avidin, beta casein, liquid crystal polymers, xylanase, anthranilate synthase) is economically beneficial in comparison with bacterial cultivation or animal cell cultures. This review summarises the current status of CCT and its potential economic impact from the viewpoint of high levels of transgene expression and high accumulation of foreign proteins.  

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38

Andrianov, A. M., Yu V. Kornoushenko, A. D. Karpenko, and A. V. Tuzikov. "Identification of potential inhibitors of coronavirus SARS-CoV-2 using the methods of virtual screening and molecular modeling." Doklady of the National Academy of Sciences of Belarus 64, no. 3 (July 9, 2020): 308–16. http://dx.doi.org/10.29235/1561-8323-2020-64-3-308-316.

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To find small-molecule compounds that can simulate the structural and functional properties of the high affinity X77 ligand of the main protease of SARS-CoV-2 - etiologic agent of COVID-19, the virtual screening of 9 molecular libraries of the Pharmit web server containing over 213.5 million chemical structures was performed. Using molecular modeling, the neutralizing activity of the identified molecules was evaluated, resulting in 5 leader compounds promising for synthesis and testing for antiviral activity. The data obtained indicate that these compounds may be used as basic structures for the development of effective drugs to treat the novel coronavirus infection.

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39

Mor, Tsafrir S. "Molecular pharming’s foot in the FDA’s door: Protalix’s trailblazing story." Biotechnology Letters 37, no. 11 (July 7, 2015): 2147–50. http://dx.doi.org/10.1007/s10529-015-1908-z.

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40

Eckstein, Olive S., Nitya Gulati, Lisa Forbes, Erin Peckham-Gregory, Nmazuo Wudo Ozuah, M. Cecilia Poli, Tiphanie Vogel, et al. "Genomic Characterization of a Pediatric Cohort with Non-Malignant Lymphoproliferative Disorders." Blood 134, Supplement_1 (November 13, 2019): 83. http://dx.doi.org/10.1182/blood-2019-131884.

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Introduction: Pediatric non-malignant lymphoproliferative disorders (LPDs) are a clinically and genetically heterogeneous. While transient lymphadenopathy is extremely common and rarely dangerous, long-standing immune dysregulation and lymphoproliferation in children may be life-threatening. Data to guide evaluation and treatment of children with benign LPD are lacking. The primary objective of this study was to define the genomic spectrum and clinical characteristics of a cohort of children with nonmalignant LPD. Identification of the underlying pathogenic mechanisms may facilitate timely interventions and potentially guide optimal therapeutic strategies. Method s: Patients at Texas Children's Hospital and collaborating referral centers who met criteria for non-malignant LPD were offered participation in this study, approved by the Baylor College of Medicine Institutional Review Board. LPD was defined as persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant EBV infection. Chronic or significant EBV infection was defined as recurrent or persistent EBV viremia more than 3 months, invasive EBV disease, or EBV PCR copies >100,000. All subjects and/or family members provided written informed consent to have their clinical and genetic information published. Genetic testing was performed clinically or through research-based whole-exome sequencing (WES). Results : Fifty-one subjects from 47 different families with non-malignant LPD were identified. Median age at disease presentation was 3.3 years (range 3.9 weeks - 21 years) with nearly equal proportions of males (n = 26) and females (n = 25). Almost half of subjects were Hispanic (49%), and 29% were non-Hispanic white. Fifteen subjects (29%) met HLH-2004 diagnostic criteria for HLH. Twenty-one patients had EBV-associated lymphoproliferative disorders (EBV-LPD) and 6 of the 51 ultimately developed malignancy. Clinical genetic testing was performed in 29 patients, and research-based WES was performed in 44 patients. Potential disease-causing genetic defects were identified in 62% of families. Of these pathogenic variants, targeted therapies may be effective for treatment in at least 10 of the conditions (17 subjects, 33%). Furthermore, genetic results supported potential for curative HSCT in 35% of the patients. Mechanistically, all of the LPD-associated genes could be placed into 1 of 3 categories: 1) defective control of lymphocyte activity; 2) impaired lymphocyte activation, cytoskeletal organization, and apoptosis; and 3) dysregulated inflammation. Ten-year survival for the entire cohort was 72.4% with a median 5.6 years of follow-up (range 0.10 - 26.6). Patients without evidence of a genetic explanation had a lower ten-year survival compared to those patients for whom a genetic explanation was identified (48% versus 82%, respectively, p=0.03). When both EBV-LPD and genetic explanation were considered, the ten-year survival estimate for those with EBV-associated disease and no genetic explanation was significantly worse than those with EBV-associated disease and a genetic explanation (17% vs. 90%; p =0.002). Patients without EBV-associated disease were at lower risk of death than those with EBV-LPD. Evaluating outcomes associated with maximum treatment received, ten-year survival was lowest (25% survival) among those who underwent HSCT. Conclusion s: Pediatric non-malignant LPD represents a group of conditions with high risk of death. WES identified actionable mutations in the majority of LPD cases in this cohort. Early identification of these mutations can guide therapy by confirming diagnosis, revealing molecular targets and/or supporting definitive therapy with stem cell transplant. Disclosures Forbes: Takeda: Consultancy. Jolles:CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; LFB: Consultancy, Honoraria, Research Funding, Speakers Bureau; UCB Pharma: Consultancy, Other: Drug Safety Committee; Shire/Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharming: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Heslop:Marker Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allovir: Equity Ownership; Gilead Biosciences: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cell Medica: Research Funding. Rouce:Novartis: Consultancy, Honoraria; Tessa Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria.

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41

Fautrel, B., R. Caporali, E. Holdsworth, B. Donaghy, M. Khalid, M. Moore, K. Van Beneden, et al. "POS0305 PHYSICIAN AND PATIENT ATTITUDES TOWARDS TREAT-TO-TARGET, ITS IMPLEMENTATION AND STATED TREATMENT GOALS IN PATIENTS WITH RHEUMATOID ARTHRITIS IN A REAL-WORLD SETTING ACROSS EUROPE." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 378–79. http://dx.doi.org/10.1136/annrheumdis-2021-eular.893.

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Background:The principles of treat to target (T2T) include defining an appropriate treatment target, assessed at pre-defined intervals, with a commitment to changing therapeutic approach if the target is not met (1). T2T is recommended as a key strategy for the treatment of rheumatoid arthritis (RA).Objectives:To explore attitudes towards T2T, its implementation and stated treatment goals among physicians and their patients with RA.Methods:The Adelphi RA Disease Specific Programme™ was a large, quantitative, point-in-time survey conducted amongst rheumatologists (n=296) and their consulting patients with RA (n=3042) in Europe (France, Germany, Italy, Spain, UK) between Q4 2019–Q3 2020. Physicians were recruited via publicly available lists, completing an online survey and medical record extraction for their next 10–12 consecutive patients. The same patients were invited to voluntarily complete a self-report questionnaire (n=1098, 36% response), collecting data on attitudes towards T2T and treatment goals.Results:Physicians reported that 76% of patients were in remission (DAS28: <2.6) or had low disease activity (DAS28: 2.6 – 3.2), and 24% had moderate-high disease activity (DAS28: >3.2). Patient mean age was 53.0 years (SD 14.0), mean time since diagnosis was 7.2 years (SD 7.2). The proportion of patients currently receiving an advanced therapy (AT; defined as biologic or targeted synthetic DMARD) was 68%, of whom 70% were on a first line AT. No difference was observed between disease activity groups.In the physician survey, 86% of physicians stated they followed T2T principals in at least some of their RA patients, and would utilize a T2T approach in RA patients with moderate-high disease activity (61%), the most uncontrolled patients (37%) and those who do not respond well to initial therapy (34%). In this sample of real-world RA patients, 66% were reported by physicians to be on a T2T plan at the time of data collection. The most common physician-reported targets were remission (DAS28: <2.6) (75%), improvement of quality of life (QoL) (41%) and reduction of pain (31%), with 85% of physicians perceiving these treatment goals were fully or partially met. The most stated reasons for not implementing T2T was physician preference not to adjust current treatment (34%), patient preference not to adjust current treatment (23%), and there are no achievable goals for this patient (16%).Overall, 29% of patients reported they were involved in setting their T2T goals, while 34% stated their T2T goals were set by their physicians only, and 29% perceived no T2T goal had been set (n=620). The most common overall T2T goals from the patient perspective were remission (61%), controlling symptoms (41%), and reducing impact on QoL (34%). Of those patients who acknowledged a T2T goal had been set (n=407), 77% reported their T2T goal was fully or partially achieved.Of 719 patients who had moderate-high disease activity, 57% were on a T2T plan, with 46% of physicians perceiving these treatment goals were fully or partially met. The most common physician-stated reason for not implementing T2T was a lack of achievable targets (29%).Conclusion:Rheumatologists in this study reported a strong belief in T2T. The most common physician-set T2T goals were remission, improvement of QoL and reduction of pain, corresponding with T2T goals as reported by patients. However, a third of patients in this cohort were not aware of a defined T2T objective in their management, which may be a result of a perceived lack of achievable goals by physicians. It may be desirable to promote more patient involvement in defining achievable targets amongst those with moderate-high disease activity who despite best efforts may not reach a clinical state of remission. Further research is needed to identify and understand goals important to RA patients.References:[1]van Vollenhoven R. Treat-to-target in rheumatoid arthritis - are we there yet? Nat Rev Rheumatol. 2019;15(3):180-6.Acknowledgements:This study was funded by Galapagos NV, Belgium.Medical writing support was provided by Gary Sidgwick, PhD (Adelphi Real World, Bollington, UK) and editorial support was provided by Debbie Sherwood, BSc, CMPP (Aspire Scientific, Bollington, UK), both funded by Galapagos NV.Disclosure of Interests:Bruno Fautrel Consultant of: AbbVie, Amgen, Biogen, BMS, Celgene, Celltrion, Fresenius Kabi, Gilead, Janssen, Lilly, Medac, MSD, Mylan, NORDIC Pharma, Novartis, Pfizer, Roche, Sandoz, Sanofi-Genzyme, SOBI, UCB, Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Roberto Caporali Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Galapagos, Gilead, Lilly, Pfizer, Roche, UCB, Sanofi, Fresenius Kabi, Samsung Bioepis, MSD, Consultant of: Galapagos, Gilead, Lilly, Janssen, MSD, Elizabeth Holdsworth Employee of: Adelphi Real World, Bethany Donaghy Employee of: Adelphi Real World, Mona Khalid Shareholder of: Galapagos, Employee of: Galapagos, Mark Moore Shareholder of: Gilead Sciences, Speakers bureau: Gilead Sciences (only as employee), Paid instructor for: Gilead Sciences (only as employee), Consultant of: Gilead Sciences (only as employee), Grant/research support from: Gilead Sciences (only as employee), Employee of: Gilead Sciences, and previously Sanofi and AstraZeneca, Katrien Van Beneden Shareholder of: Galapagos, Employee of: Galapagos, Yves Piette Consultant of: AbbVie, Amgen, Galapagos, Grünenthal and Sandoz, Grant/research support from: Amgen, Mylan and UCB, Susana Romero-Yuste Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Grunenthal, Kern Pharma, Lilly, Roche, Sandoz, Sanofi, UCB, Janssen, Consultant of: AbbVie, Biogen, Fresenius, Galapagos, Gebro, Janssen, Lilly, Grant/research support from: Bristol Myers Squibb, MSD, Novartis, Pfizer, Jasper Broen Shareholder of: Pharming Group, Consultant of: Galapagos, Gilead, Novartis, Peter C. Taylor Consultant of: AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Pfizer, Roche, Sanofi, Nordic Pharma, Fresenius, UCB, Grant/research support from: Celgene, Galapagos, Gilead, Lilly

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Fayyazi, Neda, Somayeh Esmaeili, Salman Taheri, Frederico F. Ribeiro, Marcus T. Scotti, Luciana Scotti, Jahan B. Ghasemi, Lotfollah Saghaei, and Afshin Fassihi. "Pharmacophore Modeling, Synthesis, Scaffold Hopping and Biological β- Hematin Inhibition Interaction Studies for Anti-malaria Compounds." Current Topics in Medicinal Chemistry 19, no. 30 (January 3, 2020): 2743–65. http://dx.doi.org/10.2174/1568026619666191116160326.

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Backgound: Exploring potent compounds is critical to generating multi-target drug discovery. Hematin crystallization is an important mechanism of malaria. Methods: A series of chloroquine analogues were designed using a repositioning approach to develop new anticancer compounds. Protein-ligand interaction fingerprints and ADMET descriptors were used to assess docking performance in virtual screenings to design chloroquine hybrid β-hematin inhibitors. A PLS algorithm was applied to correlate the molecular descriptors to IC50 values. The modeling presented excellent predictive power with correlation coefficients for calibration and cross-validation of r2 = 0.93 and q2 = 0.72. Using the model, a series of 4-aminoquinlin hybrids were synthesized and evaluated for their biological activity as an external test series. These compounds were evaluated for cytotoxic cell lines and β-hematin inhibition. Results: The target compounds exhibited high β-hematin inhibition activity and were 3-9 times more active than the positive control. Furthermore, all the compounds exhibited moderate to high cytotoxic activity. The most potent compound in the dataset was docked with hemoglobin and its pharmacophore features were generated. These features were used as input to the Pharmit server for screening of six databases. Conclusion: The compound with the best score from ChEMBL was 2016904, previously reported as a VEGFR-2 inhibitor. The 11 compounds selected presented the best Gold scores with drug-like properties and can be used for drug development.

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Marqui, F. N., A. Martins, T. E. Cruz, T. I. U. Berton, C. P. Freitas-Dell'Aqua, D. G. Souza, and S. H. V. Perri. "10 Evaluation of Frozen Sperm Quality After Single Layer Centrifugation with Percoll Plus® of Fresh Bull Semen." Reproduction, Fertility and Development 30, no. 1 (2018): 144. http://dx.doi.org/10.1071/rdv30n1ab10.

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The single layer centrifugation (SLC) with Percoll Plus® (PP; GE Healthcare, Uppsala, Sweden) before freezing is not a common technique used for selection of spermatozoa in bovine. Thus, this study aimed to verify the effect of SLC with PP before freezing on integrity of plasma and acrosome membranes (IPAM), phospholipid translocation (PT), and mitochondrial membrane potential (MMP) of frozen–thawed bull sperm. Three Nellore bulls housed at the Tairana Artificial Insemination Station were used. The ejaculates (6/bull) were collected by artificial vagina and assessed for sperm motility, concentration, and morphology. Then, the sperm were pooled and ~1 billion spermatozoa, either diluted [D; 1:2 (v/v)] in freezing extender (FE; tris, fructose, citric acid, egg yolk and antibiotics, without glycerol) or undiluted (UN), were placed on top of a 9-mL column of PP (in 15-mL centrifuge tubes) at concentrations of 70% or 90%, to form the 70D, 70UD, 90D, and 90UD treatment groups. After centrifugation at 839 × g for 13 min, except for the control (C), the supernatant was discarded and the pellet diluted in FE (plus glycerol) to a final concentration of 50 × 106 spermatozoa mL−1. Afterward, 0.5-mL straws were filled, cooled for 5 h at 4°C, and frozen in a programmable freezer (Digitcool, IMV, L’Aigle, France) following the temperature/time curve: from 4°C to –10°C (5°C min−1), –10°C to –100°C (40°C min−1) and from –100°C to –140°C (20°C min−1), in a total of 8 min, when the straws were plunged into and stored in liquid nitrogen until evaluation. Thawed sperm (at 37°C/30 s) was diluted at 5 × 106 spermatozoa mL−1 in TALP-polyvinyl alcohol (PVA) plus Hoechst 342 (100 μg mL−1; Sigma Co., St. Louis, MO, USA). After that, samples were stained for membrane integrity with the association of fluorescent probes propidium iodide (PI, 50 μg mL−1; Sigma Co.), fluorescein thiocyanate (FITC)-Pisum sativum agglutinin (PSA, 1 mg mL−1; Sigma Co.) and Annexin V-APC (BD Pharmingen, Franklin Lakes, NJ, USA), and with MitoStatus Red (20 nM; BD Pharmingen) and YO-PRO-1 (7.5 μM; Molecular Probes Inc., Eugene, OR, USA) for MMP. Sperm samples were analysed by flow cytometer (BD LSR; Fortessa, Becton Dickinson, Mountain View, CA, USA) and the results expressed as percentage of intact cells or qualitative fluorescence expressed in arbitrary units (AU). Analysis of variance and Tukey’s test were used for statistical analysis with P < 0.05 taken as significant. There were no differences between groups for IPAM (values ranging from 45.9 ± 7.0% to 55.6 ± 8.5%). Similarly, results of PT translocation did not differ among the groups (range from 34.7 ± 7.0% to 47.6 ± 7.0%). However, there was a tendency of increasing MMP (P = 0.10) in 70UD (1789 ± 258 UA), 70D (1776 ± 162.1 UA), and 90UD (1757 ± 133.8 UA) compared with C (1368 ± 267.4 UA) and 90D (1356 ± 145 UA). In conclusion, SLC did not compromise sperm membrane functionality and it seemed to select spermatozoa with higher mitochondrial functional activity when centrifuged at the concentration of 70% and 90D. This research was funded by FAPESP # 2015/20986-3, Tairana Artificial Insemination Station, MasterFertility Ltda, Brazil.

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Shah, Bijal D., Alejandro Villagra, Oscar Merino, Jennifer Rock-Klotz, Karrune Woan, Edward Seto, Peter Martin, et al. "HDAC Profiling In Mantle Cell Lymphoma Unveils HDAC11 and HDAC10 as Potential Molecular Targets." Blood 116, no. 21 (November 19, 2010): 2506. http://dx.doi.org/10.1182/blood.v116.21.2506.2506.

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Abstract Abstract 2506 Background: Epigenetic changes in chromatin structure involving histone modifications have been recently implicated in the deregulated expression of critical genes in MCL, including cyclin D1 and some tumor suppressor genes. Special emphasis has been given therefore to the assessment of the therapeutic role of epigenetic modifiers in MCL. Among these, a family of compounds known as histone deacetylase inhibitors (HDI) display antitumor activity both in experimental models as well as in recently completed clinical trials in MCL patients. Given that aberrant expression of histone deacetylases (HDACs) has been shown to influence disease aggressiveness and response to treatment in several malignancies1,2,3, we seek to determine the expression of specific HDACs in human MCL. Methods: Expression of HDAC class I (HDAC1, 2, 3, 8), class II (HDAC4, 5, 6, 9, 10) and Class IV (HDAC11) was determined by quantitative real-time RT-PCR using specific HDAC primers in four human MCL cell lines (JEKO, Z138, MINO, SP53), primary malignant cells from lymph nodes of patients with MCL and in B-lymphocytes isolated from normal donors (Control). Protein expression of selected HDACs was evaluated by western blot. Knocking down of specific HDACs was performed using shRNAs lentiviruses targeting specific human HDAC sequences. Cell proliferation and cell cycle analysis of MCL cells lacking a specific HDAC were performed using standard techniques. Results: No significant differences in class I HDAC expression was found among normal B-lymphocytes, MCL cell lines and malignant B-cells from MCL patients. In contrast, the expression all class II HDACs, but HDAC9, was reduced in MCL cell lines and primary human MCL cells relative to normal B-cells. Of note, HDAC10 expression was consistently absent or significantly decreased in all MCL cell lines and primary MCL cells. Analysis of HDAC11 revealed interesting findings: increased expression of HDAC11 mRNA was observed in human MCL cell lines and primary human MCL cells, with the highest expression among two patients with the blastoid variant of MCL and the lowest expression in cells from two patients with a clinically indolent MCL. Next, we knocked-down HDAC11 in Z138 MCL cells and generated two stable clones (HDAC11KD) that displayed a slower cell proliferation relative to non-target shRNA control cells. Cell cycle analysis revealed that HDAC11KD clones are cycling at a significantly lower rate than control cells. Conclusion: HDAC11 over-expression in MCL seems to confer a proliferation/survival advantage to malignant cells. This finding provides a rationale to selectively disrupt this HDAC in MCL. Given that decreased HDAC10 expression is associated with a more aggressive behavior in other malignancies1, our findings of diminished HDAC10 expression in MCL warrant further investigation. Disclosures: Leonard: Hospira: Consultancy, Honoraria; Cell Therapeutics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Biogen IDEC: Consultancy, Honoraria; Calistoga: Consultancy, Honoraria; Johnson and Johnson: Consultancy, Honoraria; EMD Serono: Consultancy, Honoraria; Sanofi Aventis: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Biotest: Consultancy, Honoraria; Cephalon: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Eisai: Consultancy, Honoraria; Cougar Biotechnology: Consultancy, Honoraria; Immunomedics: Honoraria; Genentech: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

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Hayes, *Catriona A., *Paul Dowling, Joseph Negri, Michael Henry, Leutz Buon, Jana Jakubikova, Jake E. Delmore, et al. "Proteomic Characterization of An Isogenic Multiple Myeloma Cell Line Model of Bortezomib Resistance." Blood 118, no. 21 (November 18, 2011): 1820. http://dx.doi.org/10.1182/blood.v118.21.1820.1820.

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Abstract Abstract 1820 Proteasome inhibitors such as Bortezomib (Bort) represent a key drug class for the therapeutic management of multiple myeloma (MM). However, MM patients, even those who initially achieve complete clinical and biochemical remission with bortezomib-based regimens eventually relapse, and bortezomib-refractory disease is associated with short overall survival. Identifying the molecular basis of resistance to bortezomib is therefore crucial for the rational development of novel therapies to hopefully improve clinical outcome for advanced MM. To address this question, we generated an isogenic cell line model of bortezomib resistance by successive rounds of in vitro exposure of bortezomib-sensitive MM.1R cells to progressively increasing bortezomib concentrations. Serial dose-response analyses confirmed the generation of several clones with variable reduction in bortezomib-sensitivity (IC50 range 40–80nM vs. <10nM for parental MM.1R). The proteomic profile of one of these clones, provisionally termed MM.1VDR, was compared to its isogenic bortezomib-sensitive lines MM.1S and MM.1R, using Liquid Chromatography-Mass Spectrometry (Orbitrap XL). Fold change, Mascot scores (as a measure of confidence for the identity of a given protein) and ANOVA scores for differentially expressed proteins were determined using the Progenesis LC-MS software. 386 proteins were determined to be differentially expressed, of which 154 demonstrated a 2–32 fold change, with p values <0.05. We reasoned that proteins or transcripts differentially expressed in multiple isogenic bortezomib-resistance models may be implicated in molecular mechanism(s) of this resistance. We therefore cross-referenced the list of proteins differentially expressed in MM.1VDR cells with a reanalysis of publically available gene expression profiling datasets of other isogenic models of bortezomib-sensitivity vs. resistance. These included the HT-29 colon cancer cell line (GSE29713) and the mantle cell lymphoma (MCL) lines HBL2-BR and JEKO-BR (GSE20915). In this integrative molecular profiling analysis, we identified no protein/transcript that was concordantly up- or down-regulated in all 4 isogenic models studied. However, we identified that eleven proteins differentially expressed in MM.1VDR cells had concordant differential expression of their transcripts in Bort-resistant HT-29, and either HBL2-BR or JEKO-BR MCL cells. Upregulated markers included FH, DDX46, PSMB4, AKR1A1, EIF3B, BLVRA, PSMB2, RPA3, HPRT1 and PSME3; while PPFIBP2 was down-regulated. These differentially expressed molecules are known to be involved in proteasome structure and function (PSMB4, PSMB2, PSME3, DDX46), mRNA binding and translation initiation (EIF3B/EIF3S9), DNA repair (RPA3), as well as drug metabolism and chemo-resistance (AKR1A1), while several are differentially expressed in diverse neoplasias vs. normal cells (e.g. PPFIB2P is differentially expressed in endometrial cancer, Colas et al, Int J Cancer 2011). Importantly, in gene expression profiling studies in CD138+ tumor cells from selected bortezomib-treated MM patients (treated as part of the APEX and/or SUMMIT clinical trials), high transcript levels for FH, EIF3B, PSMB4 or AKR1A1 or low transcript levels for PPFIBP2 correlate with shorter overall survival (p<0.05, log-rank tests), suggesting that these molecules may have a functional link with the mechanisms responsible for emergence of clinical resistance to bortezomib. Our data, taken together, therefore indicate that the mechanisms of bortezomib resistance are likely multifactorial and potentially tumor-type/specificity-dependent. However, through integrative proteogenomic analyses, we identified functionally and potentially clinically relevant candidate markers of bortezomib resistance. These markers may represent novel targets in efforts to overcome bortezomib-resistance and further improve outcome of MM patients. *Authors contributed equally. Disclosures: Hayes: Pfizer: Research Funding; Amgen: Research Funding. van de Donk:Celgene: Research Funding. Richardson:Johnson & Johnson: Advisory Board; Millennium: Advisory Board; Celgene: Advisory Board; Bristol-Myers Squibb: Advisory Board; Novartis: Advisory Board. Anderson:Millennium: Consultancy, Research Funding. Mitsiades:Millennium Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck &Co.: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centocor: Consultancy, Honoraria; Amnis Therapeutics: Consultancy, Honoraria; PharmaMar.: Licensinig royalties; OSI Pharmaceuticals: Research Funding; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding; Johnson & Johnson: Research Funding.

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Ghobrial, Irene M., Joanna M. Ghobrial, Patricia Bramati, Terry Kimlinger, Michael M. Timm, Ashock Kumar, Karen E. Hedin, and Thomas E. Witzig. "Molecular Mechanisms Involved in Homing and Migration of Plasma Cells in Response to CXCR4 Stimulation and Downstream Activation of the PI3K Pathway." Blood 104, no. 11 (November 16, 2004): 2188. http://dx.doi.org/10.1182/blood.v104.11.2188.2188.

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Abstract Malignant plasma cells characteristically home to the bone marrow (BM). However, the mechanisms by which cells are recruited into and mobilized from the bone marrow into the peripheral blood (PB) are not well understood. In this study, we explore the molecular mechanisms involved in homing and migration of plasma cells in response to CXCR4 and investigated the role of the PI3K pathway in migration of MM cells in response to SDF-1. CXCR4 surface expression was determined by FACS analysis (PE CXCR4, Pharmingen) using samples from bone marrow and peripheral blood of patients diagnosed with multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS) and primary systemic amyloidosis (AL). All results were expressed as percent expression in gated CD38+ and CD45+ cells. Boyden chamber in vitro migration assays were performed using Kas6/1MM cells. In addition, live confocal microscopy was used to visualize changes in the subcellular location of YFP-fluorescent CXCR4 before and after SDF-1 stimulation. Cells were pretreated with 10mM LY294002 or 200nM rapamycin to assess the effect of inhibition of PI3K or mTOR on CXCR4 subcellular localization. Immunoblotting was performed to confirm inhibition of the PI3K pathway. Comparisons between groups was performed using Mann-Whitney testing. The median CXCR4 expression is described in table 1. There was a significant difference between expression of BM CXCR4 in MM and MGUS (p=0.02). SDF-1 induced dose dependent migration of Kas 6/1 cells indicating a functional CXCR4 receptor. MM cells transfected with YFP-CXCR4 demonstrated surface localization on the cells. 3-Dimensional and continuous live imaging after SDF-1 stimulation for 30 minutes demonstrated alterations in the CXCR4-YFP leading to its capping, internalization subcellularly, and production of pseudopodia in response to SDF-1. This process was abrogated with pretreatment with LY294002 and rapamycin. These data demonstrate for the first time that the surface expression of CXCR4 is markedly elevated in the peripheral blood as compared to the bone marrow. Once in the bone marrow, and with the presence of excess SDF-1, the receptor becomes internalized and downregulated. In contrast to MM, CXCR4 expression on plasma cells in the bone marrow of normal and MGUS patients was higher. In addition, we demonstrate that the process of CXCR4 subcellular localization is abrogated by the administration of PI3K inhibitors LY294002 and rapamycin. These data suggest that CXCR4 expression is required for MM cells to circulate, and that downregulation occurs in the BM leading to immobilization of the cells. Future clinical trials using CXCR4 inhibitors, or inhibitors of PI3K and mTOR to prevent the homing and migration of MM cells into the bone marrow may be explored. This was supported in part by CAP50 CA97274. CXCR4 expression N=45 Median CXCR4% expression of total plasma cells Range MM BM (n=23) 27 4.3–90.1 MM PB (n=5) 91 60–95.5 MGUS BM (n=6) 65 41–78.6 AL BM (n=7) 46 17.5–71.6 Normal BM (n=4) 59 6.3–69.5 Kas6/1 cell line 100 -

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Ngo, Hai T., Xavier Leleu, Anne-Sophie Moreau, Evdoxia Hatjiharissi, Xiaoying Jia, Garrett O’Sullivan, Judith Runnels, et al. "Analysis of Chemokine and Adhesion Markers in Waldenstrom Macroglobulinemia." Blood 108, no. 11 (November 16, 2006): 4653. http://dx.doi.org/10.1182/blood.v108.11.4653.4653.

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Abstract Background: Waldenstrom Macroglobulinemia (WM) is characterized by widespread involvement of the bone marrow (BM), indicating continuous entry and egression of malignant cells in and out of the BM. The process of homing and trafficking involves chemokines, cytokines, and adhesion molecules. In this study, we sought to determine the level of chemokines, cytokines and adhesion molecules in the BM and peripheral blood (PB) of patients with WM. Method: We compared BM supernatant to serum samples from 10 patients with WM, including 5 matched samples from the same patients, and PB serum and BM supernatant from 2 normal healthy controls. The Luminex® xMAP® Multiplex (Upstate, VA) allows detection of human cytokines, chemokines, and growth factors using the Beadlite® products (Upstate, VA). We focused on chemokines that regulate migration: Eotaxin, GRO, IP10, MIP1a, MIP1b, MCP1, MCP3, MDC/CCL22, and RANTES; cytokines that regulate proliferation: Interleukin (IL)-2, -4, -6, -8, -10, and -15; and adhesion molecules: ICAM, VCAM. The means fluorescence intensity (MFI) was measured for all molecules. Chemokine and adhesion receptor expression on primary WM cells and WM cell line BCWM.1 was assessed using flow cytometry. Adhesion was measured using the in vitro adhesion assay (EMD Biosciences, CA), and the anti-VLA-4 antibody (10–100ug/ml, BD Pharmingen, CA). Results: We first compared the BM supernatant of patients with WM to healthy donors. Adhesion molecules ICAM (mean MFI 5624 in WM vs 720 in control) and VCAM (mean MFI 9096 in WM vs 2135 in control) were significantly higher in the WM supernatant, p=0.03 and p=0.05 respectively. In addition, the chemokines IP-10 (Mean MFI 8186 in WM vs 1647 in control), MDC/CCL22 (mean MFI 13015 in WM vs 4221 in control), and GRO (mean MFI 7463 in WM vs 1337 in control), that regulate migration, were significantly upregulated in WM BM supernatant. We found higher expression of MIP1a in the PB of WM patients compared to patient BM supernatant (mean MFI 5715 in PB vs 1484 in BM), p=0.02. Similarly, RANTES and IL-10 were significantly higher in patients’ PB sera. There was no statistically significant difference between the PB sera of patients and healthy controls. The expression of CXCR3 (receptor of IP-10) and CCR4 (receptor of MDC/CCL22) were highly expressed on BCWM.1 (mean 90% expression). We then determined the expression of adhesion receptors on BM CD19+ cells from patient samples and BCWM.1. The WM cells and cell line expressed very high levels of surface adhesion receptors VLA4 and LFA1 (mean expression 95%). Anti-VLA-4 antibody 10ug/ml completely abrogated adhesion to fibronectin, 6% compared to control. Conclusion: Adhesion molecules VCAM and ICAM and their receptors VLA-4 and LFA-1 were significantly elevated in the bone marrow of WM patients, indicating activation of adhesion receptors and localizing WM cells in the BM. The anti-VLA-4 antibody completely abrogated adhesion in vitro. In addition, the chemokines IP-10, MDC/CCL22 and GRO were upregulated in the BM of patients, which induce homing of cells into the BM. This study, therefore, systematically defines chemokines, cytokines and adhesion markers in WM, providing the preclinical framework for inhibition of adhesion molecules in clinical protocols to improve patient outcome in WM. * HN and XL are co-first authors.

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Kiziltepe, Tanyel, Laurence Catley, Teru Hideshima, Noopur Raje, Hiroshi Yasui, Sonia Vallet, Hiroshi Ikeda, Yutaka Okawa, and Kenneth C. Anderson. "Epigenetic Modulation by Vidaza™ induces Apoptosis and Overcomes In Vitro Drug Resistance in Human Multiple Myeloma Cells." Blood 108, no. 11 (November 16, 2006): 5001. http://dx.doi.org/10.1182/blood.v108.11.5001.5001.

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Abstract Methylation of DNA is an epigenetic modification that plays an important role in the regulation of gene expression in mammalian cells. Although DNA methylation is required for normal cell development and function, aberrant methylation and the resulting aberrant expression of genes, such as tumor suppressor genes and oncogenes, contribute to the development of malignancies. Interestingly, aberrant DNA methylation has recently emerged as one of the most frequent molecular alterations in hematologic malignancies, providing a powerful rationale to use inhibitors of DNA methylation as a novel means of targeting hematologic malignancies. Vidaza™ [Pharmion Corporation] (5-azacytidine), an FDA approved drug for the treatment of myelodysplastic syndromes, is an inhibitor of DNA methylation. Multiple myeloma (MM) is currently an incurable hematological malignancy despite all the conventional and novel therapies, and we here examined the biological effects using Vidaza™ on human MM cells. We demonstrate here that Vidaza™ has significant cytotoxicity in both conventional therapy sensitive (MM1S, RPMI-8226) and resistant (MM1R, RPMI-Dox40, RPMI-LR5) MM cell lines, as well as freshly isolated patient MM tumor cells, with an IC50 of 1.25–4 mM at 72 hours in vitro. Importantly, no cytotoxic effects of Vidaza™ were detected in peripheral blood mononuclear cells (PBMNC) obtained from healthy volunteers at ≤20 mM, suggesting a therapeutic index. Moreover, Vidaza™ overcame the survival and growth advantages conferred by interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1), or by adherence of MM cells to bone marrow stromal cells (BMSC). Vidaza™ induced apoptosis in MM cells, as determined by flow cytometric analysis using PI and Annexin V staining. Vidaza™-induced apoptosis was associated with PARP, caspase 8 and caspase 9 cleavage. Importantly, pan-caspase inhibitor zVAD-fmk, significantly, but only partially, inhibited apoptosis induced by Vidaza™, suggesting the involvement of both caspase dependent and independent pathways. Taken together, our studies therefore demonstrate that Vidaza™ induces apoptosis and overcomes in vitro drug resistance in MM cells. Ongoing studies are delineating the mechanism of action of Vidaza™ against MM cells to further provide the preclinical rationale for clinical evaluation of Vidaza™, alone or in combination with other agents, to improve patient outcome in MM.

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Sinicrope, F. A., R. L. Rego, K. C. Halling, N. R. Foster, D. J. Sargent, B. Laplant, A. J. French, et al. "Microsatellite instability but not thymidylate synthase is a prognostic variable in primary colon cancers from patients treated in 5-FU-based adjuvant studies." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10019. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10019.

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10019 Background: Colon cancers with microsatellite instability (MSI) display resistance to 5-fluorouracil (5-FU), and in vitro resistance can be reversed by restoring DNA mismatch repair proficiency. 5-FU inhibits the thymidylate synthase (TS) enzyme and TS may predict clinical outcome after 5-FU-based chemotherapy. To define molecular predictors of prognosis, we analyzed TS, p53, chromosome 17p allelic imbalance (AI), and patient survival stratified by MSI status. Methods: Primary colon carcinomas from patients enrolled in five 5-FU-based adjuvant therapy trials were analyzed for MSI and 17p AI using 11 microsatellite markers (MSI-H: ≥ 30% of the loci demonstrating instability). For 17p AI, markers included D17S261 and TP53 at or near the p53 locus. Expression of DNA mismatch repair (hMLH1, PharMingen; hMSH2; Oncogene), TS (TS106, Zymed), and p53 (D07, Novacastra) proteins were analyzed by immunohistochemistry. Correlations between markers and associations with overall survival (OS) were determined. Patients were censored at 5 years for DFS and at 8 years post study randomization for overall survival (OS) data. Results: Of 320 Dukes’ stage B2 and C cancers studied, 60 of 320 (19%) were MSI-H. TS expression variables (intensity, extent, weighted score) were similar in MSI-H and MSI stable/low frequency (MSS/MSI-L) cancers; similar results were found using DNA mismatch repair (dMMR) proteins. MSI-H tumors had lower stage (p= 0.0007), fewer metastatic lymph nodes (p= 0.004), and improved OS (vs. MSS/MSI-L tumors; p= 0.01). Loss of dMMR proteins was also associated with better OS (p= 0.006). None of the TS variables were prognostic for OS. Histologic grade (p= 0.0008) and nodal status (p= 0.0002) were associated with OS in contrast to 17p LOH or p53. Only MSI status or dMMR, histologic grade, and tumor stage were independent markers for OS. Conclusions: MSI-H tumors show earlier stage at presentation and better stage-adjusted survival rates. MSI status and TS expression were unrelated and TS was not prognostic, suggesting that TS levels cannot explain therapeutic resistance to 5-FU reported in MSI-H colon cancers. [Table: see text]

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Ladetto, Marco, Gloria Pagliano, Simone Ferrero, Federica Cavallo, Daniela Drandi, Michela Boi, Loredana Santo, et al. "Correlation Between Clinical Outcome and Disease Kinetics by Quantitative PCR in Myeloma Patients Following Post-Transplant Consolidation with Bortezomib, Thalidomide and Dexamethasone." Blood 114, no. 22 (November 20, 2009): 960. http://dx.doi.org/10.1182/blood.v114.22.960.960.

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Abstract Abstract 960 Background and aims: We have recently shown that multiple myeloma (MM) patients undergoing autologous transplantation (ASCT) followed by a consolidation with Bortezomib/Thalidomide/Dexamethasone (VTD) achieve molecular remission in 17% and major tumor shrinking assessed by real time-quantitative (RQ) PCR in the majority of cases (Ladetto et al, ASH Meeting 2008). However little is known on the minimal residual disease (MRD) kinetics occurring after such an extensive cytoreduction. In this study we have investigated the disease kinetics in the post-consolidation phase with the aim of identifying the RQ-PCR patterns associated with persistent remission or increased risk of relapse. Patients and methods: Inclusion criteria and consolidation treatment for this study have been already reported and included: 1) a documented complete or very good partial remission following ASCT delivered as first line treatment; 2) no previous treatment with thalidomide and bortezomib; 3) presence of a molecular marker based on the immunoglobulin heavy chain rearrangement (IgH-R). Consolidation consisted of four courses of: a) Bortezomib 1.6 mg/m2 on days 1, 8, 15, 22; b) Thalidomide at the initial dose of 50 mg/day with increments up to 200 mg; c) Dexamethasone 20 mg/day on days 1 to 4, 8 to 11 and 15 to 18. MRD was assessed on bone marrow samples at diagnosis, study entry, after two VTD courses, at the end of treatment and then at six months intervals. Qualitative and RQ-PCR analysis were carried out using IgH-R derived patient specific primers as already described (Voena et al, Leukemia 1997; Ladetto et al, Biol Bone Marrow Transpl 2000). MRD kinetics of relapsing vs non relapsing patients has been measured using observed marginal medians of ln RQ-PCR values. For the predictive value of MRD kinetics patients were defined as having low tumor burden (TB) if they reached after VTD a MRD level <100 IgH-R/106 diploid genomes and as having active disease whenever a 10-fold tumor burden increase was recorded. Results: Feasibility, toxicity and clinical outcome of the trial have been already reported (Ladetto et al, ASH Meeting 2008). Thirty-nine patients were enrolled. Median follow-up from study entry is currently 32 months (50 from start of first line treatment). Following VTD, six patients achieved molecular remission (MR). Of these none has so far experienced a clinical relapse. MR was persistent in all patients, with an occasional PCR positive result in a patient who later reverted to PCR negativity. Among PCR positive patients 12 clinical relapses have been so far reported (50 months PFS: MR 100% vs no MR 62% - Figure 1A, p<0.001). Figure 2 shows the kinetics of MRD overtime in relapsing vs not relapsing patients (p<0.001), assessed on 230 RQ-PCR determinations at different timepoints. When RQ-PCR results of PCR positive patients were correlated with outcome we observed the following: 1) 14 patients achieved low TB and never had signs of active disease: none of them has so far relapsed except one who refused to undergo MRD monitoring and relapsed three year after the last PCR evaluation; 2) 13 patients never achieved a low TB and 8 of them relapsed; 3) 5 patients achieved a low TB but subsequently showed evidence of active disease: 3 of them relapsed. Patients in the first subgroup showed a 50 months PFS of 100% as opposed to those in group 2-3 who had a PFS of 37% (Figure 1B, p=0.001). Conclusions: Our results indicate that: 1) MRs following VTD are stable over time with no evidence of clinical and molecular relapse; 2) The vast majority of relapses occur in patients failing to achieve a low and stable TB; 3) Molecular monitoring of MRD allows to identify a large subset of patients (51% of cases) with an extremely low-risk of short-term relapse. Disclosures: Ladetto: CELGENE: Honoraria; JANSSEN-CILAG: Research Funding. Cavallo:CELGENE: Honoraria. Caravita:CELGENE: CONSULTANCY. Musto:JANSSEN-CILAG: Honoraria; CELGENE: Honoraria. Boccadoro:CELGENE: CONSULTANCY, ADIVISORY COMMITTEES, Research Funding; JANSSEN-CILAG: CONSULTANCY, ADIVISORY COMMITTEES, Research Funding; PHARMION: CONSULTANCY, ADIVISORY COMMITTEES, Research Funding. Palumbo:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria.

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