Therapeutic Potential of Cladribine in Combination with STAT3 Inhibitor Against Multiple Myeloma

2014 ◽  
pp. 251-270
Keyword(s):  
Multiple Myeloma ◽  
Therapeutic Potential

scholarly journals Ex Vivo Activity of Immunotherapeutic Approaches Targeting CD38 Against Daratumumab-Resistant Multiple Myeloma Patient Samples

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1848-1848
Author(s):  
Maria Karvouni ◽  
Heyue Zhou ◽  
Arnika Kathleen Wagner ◽  
Qiangzhong Ma ◽  
Alamdar H. Baloch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Phase 1 ◽  
Employment Equity ◽  
Multiple Myeloma Patient ◽  
Myeloma Cells ◽  
Car T ◽  
Equity Ownership

Background: Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. The identification of CD38, a transmembrane glycoprotein overexpressed on MM cells, led to the development of target-specific therapeutics such as the FDA approved monoclonal antibody (mAb) Daratumumab (DARA). Although a valuable treatment option for refractory/relapsed (R/R) MM patients, DARA has a limited response rate of below 50%, which highlights the clinical need for novel therapeutics. Aims: Aiming to further exploit the therapeutic potential of CD38 in the MM setting, immunotherapies based on the novel anti-CD38 mAb CD38A2 were tested. Methods: For the first approach, the CD38A2 mAb -that binds to a unique, distinct from DARA's, CD38 epitope- was conjugated with either the alkylating agent Duomycin (ADC-136) or the microtubulin binder Duostatin (ADC-129). The ADCs were compared to DARA, in cultures of primary MM cells from patients refractory to DARA treatment. In a second approach, a chimeric antigen receptor (CAR) consisting of the CD38A2 scFv and the intracellular domains of CD28 and CD3ζ was used to transduce primary T and NK cells from R/R MM patients. The functionality of the CAR-T and CAR-NK cells was assessed in cytotoxicity assays against autologous myeloma cells. Results: ADC-136 demonstrated the most potent cytotoxicity against the MM cells with an IC50 of 6pM at day 6 following a single dose treatment. ADC-129 showed cell killing with an IC50 of 30pM, while DARA did not exhibit appreciable cytotoxicity. Regarding the cell therapy approach, patients' T and NK cells were effectively transduced, showing a CD38A2-CAR expression ranging between 11-68%. In functional assays, CAR-T and CAR-NK cells were assayed against autologous myeloma cells, where they exhibited an increase in target cell cytotoxicity, compared to the untransduced cells. Summary/Conclusion: Altogether, our preliminary findings demonstrate that CD38 targeting using CD38A2-based immunotherapies could be a viable therapeutic approach in R/R MM patients previously exposed to DARA. Currently, an anti-CD38 CAR-T therapy based on CD38A2 is being evaluated in Phase 1 studies in R/R MM patients by Sorrento Therapeutics, Inc. Disclosures Zhou: Sorrento Therapeutics Inc: Employment, Equity Ownership. Ma:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhu:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhang:Sorrento Therapeutics Inc: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

scholarly journals Chemometric and Transcriptomic Profiling, Microtubule Disruption and Cell Death Induction by Secalonic Acid in Tumor Cells

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3224
Author(s):  
Nadire Özenver ◽  
Mona Dawood ◽  
Edmond Fleischer ◽  
Anette Klinger ◽  
Thomas Efferth
Keyword(s):  
Multiple Myeloma ◽  
Therapeutic Potential ◽  
Expression Profiles ◽  
Tumor Cell Line ◽  
Hierarchical Cluster ◽  
Myeloma Cell ◽  
New Drugs ◽  
Myeloma Cells ◽  
Multiple Myeloma Cell ◽  
Microtubule Disruption

Nature is an indispensable source of new drugs, providing unique bioactive lead structures for drug discovery. In the present study, secalonic acid F (SAF), a naturally occurring ergochrome pigment, was studied for its cytotoxicity against various leukemia and multiple myeloma cells by the resazurin assay. SAF exhibited cytotoxic activity on both leukemia and multiple myeloma cells. Generally, multiple myeloma cells were more sensitive to SAF than leukemia cells. NCI-H929 cells were the most affected cells among the tested panel of multiple myeloma cell lines and were taken for further studies to assess the mode of action of SAF on those cells. Cell cycle analysis revealed that SAF induced S and G2/M arrest in NCI-H929 cells. SAF-associated apoptosis and necrosis resulted in cytotoxicity. SAF further inclined the disassembly of the tubulin network, which may also account for its cytotoxicity. COMPARE and hierarchical cluster analyses of transcriptome-wide expression profiles of the NCI tumor cell line panel identified genes involved in numerous cellular processes (e.g., cell differentiation, cell migration, and other numerous signaling pathways) notably correlated with log10IC50 values for secalonic acid. In conclusion, the present study supports the therapeutic potential of SAF to treat multiple myeloma.

Abstract 1077: Targeting oncogenic miR-17-92 primary transcripts by LNA gapmeRs in multiple myeloma: Molecular findings and therapeutic potential

2016 ◽  
Author(s):  
Eugenio Morelli ◽  
Lavinia Biamonte ◽  
Cinzia Federico ◽  
Maria Teresa Di Martino ◽  
Nicola Amodio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Therapeutic Potential

A Mini-Review on Thalidomide: Chemistry, Mechanisms of Action, Therapeutic Potential and Anti-Angiogenic Properties in Multiple Myeloma

2017 ◽  
Vol 24 (25) ◽  
Author(s):  
Annalisa Mercurio ◽  
Giulia Adriani ◽  
Alessia Catalano ◽  
Alessia Carocci ◽  
Luigia Rao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Therapeutic Potential ◽  
Mechanisms Of Action

A Novel Orally Bioavailable Heat Shock Protein 90 Inhibitor Induces Apoptosis and Synergises with Bortezomib in Human Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1838-1838
Author(s):  
Tiffany T. Khong ◽  
Sung Lin Yeh ◽  
Andrew Spencer
Keyword(s):  
Multiple Myeloma ◽  
Heat Shock ◽  
Cell Lines ◽  
Research Funding ◽  
Drug Exposure ◽  
Therapeutic Potential ◽  
Primary Tumour ◽  
Parp Cleavage ◽  
Oncology Research ◽  
Orally Bioavailable

Abstract Abstract 1838 Poster Board I-864 Heat shock proteins (HSP) are ubiquitously expressed in human cells. The expression of HSP proteins is transcriptionally regulated and escalates in response to stress, furthermore, HSPs assist in the folding and establishment of new proteins as well as removing unwanted protein aggregation by transportation to the proteasome. In cancer, HSPs stabilise and protect oncoproteins such as AKT and p53, increase angiogenesis by VEGF induction and support metastasis by assisting MMP2. We evaluated the therapeutic potential of a novel orally bioavailable HSP90 inhibitor (HSP90i) against a panel of human myeloma cell lines (HMCL) and primary tumour samples from multiple myeloma (MM) patients. 8 genetically heterogenous HMCL were screened by MTS assay and found to be sensitive to HSP90i with an IC50 of 50–100nM at 72 hours. This was associated with accumulation of cells in the G0-G1 phase and decreasing number of cells in the S and G2/M phases indicative of cell cycle arrest. Apoptosis was confirmed by the presence of increasing numbers of propidium iodide stained cells as measured by flow cytometry and PARP cleavage on immunoblot analysis within 24 hours of HSP90i treatment. Three HMCLs, NCI H929, an IL6 independent cell line and OCI-MY1 and U266, two IL6-dependent cell lines were used for mechanistic studies. HSP90i was found to down regulate the client proteins IL-6R, STAT3, MEK, AKT, BID, MCL-1, NFkB and IkB conversely the chaperone proteins HSP70 and HSP27 were up regulated in all 3 HMCL. Importantly HSP90i treatment was associated with a rapid reduction in the phosphorylated forms of STAT3, MEK and NFkB. Furthermore, the down-regulation of P-STAT3 and IL6-R protein was not reversed by exposure to exogenous IL-6. Combination studies with bortezomib, a proteasome inhibitor, were undertaken to define the extent of possible synergy and schedule dependency. The combination of bortezomib with HSP90i displayed strong synergism in both IL-6 dependent and IL-6 independent HMCL with maximal killing seen with simultaneous drug exposure (CI = 0.089 — 0.338). Finally, HSP90i was also tested against primary MM tumour cells from patients with relapsed/refractory MM with killing of CD38+veCD45−ve cells, as evidenced by Apo2.7 staining, seen with concentrations of HSP90i from 100nM to 1000nM at 24 and 48 hours following treatment. These in vitro findings justify the further evaluation of HSP90i as a potential therapeutic agent for MM. Disclosures: Khong: Novartis Oncology: Research Funding. Yeh:Novartis Oncology: Research Funding. Spencer:Novartis Oncology: Research Funding.

scholarly journals Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress

Oncogene ◽  
2015 ◽  
Vol 35 (8) ◽  
pp. 1015-1024 ◽  
Author(s):  
Y Shi ◽  
Y Yang ◽  
B Hoang ◽  
C Bardeleben ◽  
B Holmes ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Er Stress ◽  
Therapeutic Potential ◽  
Myeloma Cells

Therapeutic potential of CCR1 antagonists for multiple myeloma

2011 ◽  
Vol 3 (15) ◽  
pp. 1889-1908 ◽  
Author(s):  
Angela R Karash ◽  
Annette Gilchrist
Keyword(s):  
Multiple Myeloma ◽  
Therapeutic Potential

In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 4181-4187 ◽  
Author(s):  
Patrick Frost ◽  
Farhad Moatamed ◽  
Bao Hoang ◽  
Yijiang Shi ◽  
Joseph Gera ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Therapeutic Potential ◽  
Xenograft Model ◽  
Mtor Inhibitors ◽  
Antitumor Effects ◽  
Mtor Inhibition ◽  
Inhibition Of Proliferation ◽  
Induction Of Apoptosis

Abstract In vitro studies indicate the therapeutic potential of mTOR inhibitors in treating multiple myeloma. To provide further support for this potential, we used the rapamycin analog CCI-779 in a myeloma xenograft model. CCI-779, given as 10 intraperitoneal injections, induced significant dose-dependent, antitumor responses against subcutaneous growth of 8226, OPM-2, and U266 cell lines. Effective doses of CCI-779 were associated with modest toxicity, inducing only transient thrombocytopenia and leukopenia. Immunohistochemical studies demonstrated the antitumor responses were associated with inhibited proliferation and angiogenesis, induction of apoptosis, and reduction in tumor cell size. Although CCI-779-mediated inhibition of the p70 mTOR substrate was equal in 8226 and OPM-2 tumor nodules, OPM-2 tumor growth was considerably more sensitive to inhibition of proliferation, angiogenesis, and induction of apoptosis. Furthermore, the OPM-2 tumors from treated mice were more likely to show down-regulated expression of cyclin D1 and c-myc and up-regulated p27 expression. Because earlier work suggested heightened AKT activity in OPM-2 tumors might induce hypersensitivity to mTOR inhibition, we directly tested this by stably transfecting a constitutively active AKT allele into U266 cells. The in vivo growth of the latter cells was remarkably more sensitive to CCI-779 than the growth of control U266 cells.

scholarly journals Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy

Blood ◽  
2012 ◽  
Vol 119 (20) ◽  
pp. 4686-4697 ◽  
Author(s):  
Samuel K. McBrayer ◽  
Javelin C. Cheng ◽  
Seema Singhal ◽  
Nancy L. Krett ◽  
Steven T. Rosen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Glucose Transporter ◽  
Therapeutic Potential ◽  
Family Members ◽  
Glucose Consumption ◽  
Myeloma Cell ◽  
Hiv Protease ◽  
Primary Cells ◽  
Cancer Knowledge

Abstract Multiple myeloma is one of numerous malignancies characterized by increased glucose consumption, a phenomenon with significant prognostic implications in this disease. Few studies have focused on elucidating the molecular underpinnings of glucose transporter (GLUT) activation in cancer, knowledge that could facilitate identification of promising therapeutic targets. To address this issue, we performed gene expression profiling studies involving myeloma cell lines and primary cells as well as normal lymphocytes to uncover deregulated GLUT family members in myeloma. Our data demonstrate that myeloma cells exhibit reliance on constitutively cell surface-localized GLUT4 for basal glucose consumption, maintenance of Mcl-1 expression, growth, and survival. We also establish that the activities of the enigmatic transporters GLUT8 and GLUT11 are required for proliferation and viability in myeloma, albeit because of functionalities probably distinct from whole-cell glucose supply. As proof of principle regarding the therapeutic potential of GLUT-targeted compounds, we include evidence of the antimyeloma effects elicited against both cell lines and primary cells by the FDA-approved HIV protease inhibitor ritonavir, which exerts a selective off-target inhibitory effect on GLUT4. Our work reveals critical roles for novel GLUT family members and highlights a therapeutic strategy entailing selective GLUT inhibition to specifically target aberrant glucose metabolism in cancer.

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