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  • 1
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    Pre-Clincial Evaluation of a Novel Purine Analogue 8-NH2-Adenosine in Mantle Cell Lymphoma Indicates Efficacy Via Alterations in RNA/DNA Synthesis and Cellular Bioenergetics
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 4987-4987
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 4987-4987
    Abstract: Background: Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma (NHL) with a prevalence of approximately 15,000 cases in the United States. Although current therapeutics extend longevity, the median survival is 3 to 5 years warranting continued investigation for newer therapeutics. MCL is characterized by cells with enhanced proliferation combined with impaired apoptosis characteristic of indolent lymphomas. Therefore, therapeutic approaches targeting transcription, translation, or cellular bioenergetics may prove to be more effective than therapies targeting DNA replication. In addition, therapeutic strategies that exploit the altered cellular metabolism of tumor cells may be beneficial. Nucleoside analogues have been used extensively in the treatment of hematologic malignancies and are selective for tumor cells. Our laboratories have developed two purine nucleoside analogues i.e. 8-chloro-adenosine (currently in clinical trials) and a congener, 8-amino-adenosine (8-NH2-Ado), showing high efficacy for multiple myeloma, a slow growing plasma B-cell malignancy. Characterization of the mechanism of toxicity of 8-NH2-Ado in myeloma shows decreased RNA synthesis preceding decreased DNA synthesis, inactivation of Ser/Thr kinases, and reductions in intracellular ATP and glucose consumption. Based on this pleiotropic profile of cellular pathways involved in the execution of cell death by 8-NH2-Ado, we sought to determine its efficacy in MCL. Results: We determined toxicity of 8-NH2-Ado in a panel of MCL cell lines, including, JeKo-1, Mino and Granta 519. Viability was assessed by Annexin V/Dapi double staining after 24 hours of incubation with increasing concentrations of 8-NH2-Ado. All three cell lines demonstrated sensitivity to 8-NH2-Ado with JeKo-1 being the most sensitive (IC50 at 2 uM) followed by Mino and Granta 519. The induction of apoptosis correlated with cleavage of PARP and caspase activation and with decreases in cyclin D1 and Mcl-1 expression. JeKo-1 cells rapidly metabolized 8-NH2-Ado to 8-NH2-ATP. After 6 hrs of incubation, the 8-NH2-ATP intracellular concentration was more than 5 mM, and the ATP concentration was reduced by more than 50%. Additionally after 6 hrs of incubation, the rates of RNA and DNA synthesis were reduced by at least 60% based on [3H]uridine and [3H] thymidine incorporation assays. In an assessment of downstream signaling kinases, p38 and AKT were rapidly de-phosphorylated after 5 hrs of treatment. Because AKT controls cellular glucose consumption, we assessed effects on glucose consumption. In both the JeKo-1 and Granta 519 cells, we observed a similar reduction in glucose consumption; however, baseline glucose consumption in the less sensitive Granta 519 cells was higher. Conclusions: 8-NH2-Ado is highly toxic for the MCL cell lines tested. 8-NH2-Ado decreases Mcl-1 and cyclin D1 expression and decreases phosphorylation of AKT and p38 in both the JeKo-1 and Granta 519 cells. In the JeKo-1 cells, 8-NH2-Ado is metabolized to 8-NH2-ATP and decreases RNA/DNA synthesis and intracellular ATP. The early changes in cellular glucose consumption may facilitate 8-NH2-Ado induction of apoptosis. These pleiotropic features of 8-NH2-Ado in regulating cellular bioenergetics and induction of apoptosis may be particularly advantageous and warrant further investigation of 8-NH2- Ado for the treatment of MCL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.4987.4987
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 2
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    The Role of Proteasome Activator PA28α in Multiple Myeloma
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5499-5499
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5499-5499
    Abstract: Multiple myeloma (MM) is a commonly occurring hematologic malignancy in the United States with poor prognosis. Among all treatments, proteasome inhibitor (PI) based regimens have been a major breakthrough for patients' outcomes. Available PIs all target 20S proteasome core complex, and the duration of response is limited by toxicity and resistance development. Until now, the underlying mechanism of drug resistance remains unclear. The proteasome is the major proteolytic machinery in protein homeostasis which is pivotal for myeloma cell survival. A functional proteasome consists of 20S proteasome core particle with regulatory particle on one or both ends. There are 3 types of proteasome regulators that could activate a 20S proteasome, PA700 (19S), 11S REG (PA28) and PA200. The 11S REG (PA28) protein family consists of three members, α, β, and γ. PA28 α/β are IFN-γ inducible and with higher expression in antigen presenting cells. Currently, the function of 11S subunit remains largely unknown. Our analysis of plasma cells from MM patients and healthy donors has demonstrated that expression of 11S proteasome is higher in myeloma cells than normal plasma cells and progressively upregulated with disease progression. To further identify the function of 11S proteasome especially PA28α in MM, we generate PA28α knockdown stable MM cell lines. We have found that knockdown of PA28α inhibits MM cell growth and proliferation, also induces myeloma cell resistance to PIs. The mechanism of PI resistance is different from knocking down of 19S or 20S proteasome subunits. Silencing of PA28α inhibits proteasome activity and decreases proteasome work load concurrently, resulting in a favorable proteasome load vs capacity ratio. Altogether, in this report, we describe the function of PA28α in MM cells, also provide novel insights into regulating PIs sensitivity through modulation of the 11S proteasome subunit PA28α. Disclosures Hofmeister: Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Kaufman:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; AbbVie: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy. Nooka:Amgen: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation. Boise:Genentech Inc.: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Research Funding. Lonial:Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-128216
    RVK:
    XA 33000
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 3
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    Targeting Glycolysis and Compensatory Mitochondrial Metabolism in Multiple Myeloma with FDA Approved Ritonavir and Metformin Via Synthetic Lethality
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 4016-4016
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4016-4016
    Abstract: Abstract 4016 Multiple Myeloma (MM) is an incurable plasma cell malignancy accounting for 11,000 deaths annually in the US and 20% of deaths from all hematological malignancies. MM is one of myriad malignancies exhibiting enhanced glucose consumption associated with an aerobic glycolytic phenotype (i.e. the Warburg effect). We have recently published a study defining key glucose transporters responsible for facilitating glucose entry in myeloma and observed that MM cells exhibit reliance on constitutively cell surface-localized GLUT4 for basal glucose consumption. MM cells cultured in the absence of glucose or upon GLUT4 suppression exhibit either overt apoptosis (sensitive phenotype) or growth arrest (resistant phenotype). To further demonstrate the clinical utility of targeting GLUT4 for MM therapy we tested a HIV protease inhibitor ritonavir that has an off-target inhibitory effect on GLUT4. Treatment of MM cells with physiologically achievable concentrations of ritonavir blocks glucose entry resulting in MM cell death or growth suppression. The objective of this study was to define those metabolic pathways in resistant MM cell lines which compensate for the decrease in cellular glucose and protect the cells from toxicity caused by glucose-deprivation or GLUT4 suppression. We hypothesized that resistant cells (i.e. JJN3) cultured in the absence of glucose revert to mitochondrial metabolism or autophagy to prevent cell death. The autophagy inhibitor chloroquine did not sensitize resistant cells cultured in the absence of glucose, ruling out autophagy as a source of compensatory metabolites. We next established that the mitochondrial substrates 2-methyl pyruvate or galactose rescue sensitive cells from toxicity caused by culture in the lack of glucose (Fig. 1A). These results suggest the potential for mitochondrial metabolism to rescue cell death ensuing upon inhibition of glycolysis. We therefore treated the resistant JJN3 cells with mitochondrial inhibitors metformin or rotenone to determine if we could elicit toxicity upon glucose-withdrawal. Indeed, resistant cells were sensitized to glucose-withdrawal upon treatment with complex 1 inhibitors metformin (Figure 1B) or rotenone. Metformin treatment alone had a minimal impact on the viability of resistant cells cultured in the presence of glucose (Fig. 1B). To simulate glucose-withdrawal we tested the ability of ritonavir (HIV protease inhibitor that has an off target inhibitory effect on GLUT4) to elicit toxicity in combination with metformin in the resistant cells. Our studies revealed that addition of ritonavir with metformin synergizes to elicit toxicity in resistant cells (Fig. 1C). This synergy was also observed in additional MM cell lines (KMS11 and U266). The biguanide metformin is the most commonly prescribed anti-hyperglycemic drug for the treatment of Type II diabetes. Epidemiologic studies have correlated metformin with a reduced risk of cancer in diabetics earning the drug recognition as a possible anti-neoplastic agent for various types of malignancies. This combinatorial regimen of ritonavir and metformin was not toxic in normal PBMC. The selective tumor specific synthetic lethality induced in ritonavir treated resistant cells upon metformin treatment is detected at doses that are clinically achievable with both compounds. We have initiated studies to evaluate this combination in mouse models of myeloma and patient samples. HIV patients chronically treated with ritonavir who exhibit diabetic symptoms have been treated with metformin indicating this combination treatment is well tolerated in humans. Our studies reveal a potent combinatorial regimen involving repurposed, FDA approved, ritonavir and metformin for the treatment of MM and potentially other glucose-driven malignancies. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.4016.4016
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 4
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    Targeting Glucose Metabolism and Compensatory Metabolic Resistance in Chronic Lymphocytic Leukemia
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1801-1801
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1801-1801
    Abstract: Abstract 1801 Chronic lymphocytic leukemia (CLL) is the most common leukemia seen in Western countries, primarily in the elderly, with a median age of diagnosis of 72 years. CLL is characterized by the aggressive accumulation of monoclonal peripheral (mature) CD5+ B cells in primary and secondary lymphoid tissues. Several classes of drugs currently exist to treat CLL and these include - nitrogen mustard alkylating agents, purine analogs, monoclonal antibodies, cyclin dependent kinase inhibitors, BTK and PI3K inhibitors. CLL can become resistant to existing therapies necessitating the need for identification of new targets and therapeutic strategies. Unique metabolic dependencies of cancer cells have been identified, further investigation of which could provide tumor cell specific targeting modalities. A myriad of tumor cells exhibit increased glucose uptake and metabolism of glucose via the in-efficient glycolytic pathway, a phenomenon first described by Warburg in the 1900's. Restriction of glucose utilization and metabolism has been shown to chemosensitize and/or elicit toxicity in a wide range of cancers. CLL metabolism is a relatively unexplored area. We sought to determine the dependency of CLL on glucose metabolism. As there are currently no CLL cell lines we used primary patient samples for these studies. CLL cells harvested from PBMCs were cultured in both glucose free and glucose containing media. Our results show that when CLL cells are cultured in these media, there is variation in sensitivity to glucose deprivation ranging from very sensitive to highly resistant (Figure 1). We have investigated possible resistance mechanisms and alternate sources of energy in CLL that could be responsible for maintaining viability even during glucose-withdrawal. We first investigated a role for glutamine. CLL cells sensitive to glucose withdrawal and cultured in the absence of glutamine, did not exhibit enhanced toxicity. These results suggest that cells resistant to glucose withdrawal were not maintaining viability via glutamine metabolism. The role of the mitochondrial metabolism was also investigated. We observed that when the CLL cells are cultured in the absence of glucose and are substituted with galactose, there is a rescue effect, with cell viability being restored. This rescue effect is also observed (although not to the same extent as with galactose) when the CLL cells in the absence of glucose are treated with 2-methylpyruvate (2MP). 2MP feeds directly into the mitochondria and can bypass the glycolytic pathway. CLL cells were also treated with metformin, which is complex-1 inhibitor, and we observed enhanced cell death. The results with galactose, 2MP and metformin all suggest that mitochondrial metabolism is an integral part of CLL metabolism, potentially playing a compensatory role upon glucose-withdrawal. The role of autophagy was also investigated and, using chloroquine we observed that autophagy was pro-survival in CLL patient samples. In summary we have observed varying sensitivity of CLL patient samples to glucose deprivation, and identified resistance mechanisms and alternative sources of energy in CLL cells. The reduction of extracellular glucose has been shown to induce resistance of normal cells to DNA damaging therapeutics, and enhancement of sensitivity in cancer cells, suggesting that glycolysis inhibition may expand the therapeutic window of currently used therapeutics. Targeting these unique metabolic dependencies in CLL could provide strategies to chemo-sensitize and target CLL more effectively with less toxicity. Figure 1: Variable sensitivity of CLL patient samples to 48-hour glucose free culture Figure 1:. Variable sensitivity of CLL patient samples to 48-hour glucose free culture Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1801.1801
    RVK:
    XA 33000
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 5
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    Targeting cancer metabolism through synthetic lethality-based combinatorial treatment strategies
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Current Opinion in Oncology Vol. 30, No. 5 ( 2018-09), p. 338-344
    Details
    In: Current Opinion in Oncology, Ovid Technologies (Wolters Kluwer Health), Vol. 30, No. 5 ( 2018-09), p. 338-344
    Abstract: Targeting cancer metabolism for therapy has received much attention over the last decade with various small molecule inhibitors entering clinical trials. The present review highlights the latest strategies to target glucose and glutamine metabolism for cancer therapy with a particular emphasis on novel combinatorial treatment approaches. Recent findings Inhibitors of glucose, lactate, and glutamine transport and the ensuing metabolism are in preclinical to clinical trial stages of investigation. Recent advances in our understanding of cell-intrinsic and cell-extrinsic factors that dictate dependence on these targets have informed the development of rational, synthetic lethality-based strategies to exploit these metabolic vulnerabilities. Summary Cancer cells exhibit a number of metabolic alterations with functional consequences beyond that of sustaining cellular energetics and biosynthesis. Elucidating context-specific metabolic dependencies and their connections to oncogenic signaling and epigenetic programs in tumor cells represents a promising approach to identify new metabolic drug targets for cancer therapy.
    Type of Medium: Online Resource
    ISSN: 1040-8746 , 1531-703X
    URL: Article
    DOI: 10.1097/CCO.0000000000000467
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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  • 6
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    Co-inhibition of BET and proteasome enhances ER stress and Bim-dependent apoptosis with augmented cancer therapeutic efficacy
    Elsevier BV ; 2018
    In:  Cancer Letters Vol. 435 ( 2018-10), p. 44-54
    Details
    In: Cancer Letters, Elsevier BV, Vol. 435 ( 2018-10), p. 44-54
    Type of Medium: Online Resource
    ISSN: 0304-3835
    URL: Article
    DOI: 10.1016/j.canlet.2018.07.033
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
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  • 7
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    P-165 Incidence, risk factors and impact of supraventricular tachycardia (SVT) with high dose therapy melphalan among myeloma patients undergoing autologous stem cell transplant (HDT/ASCT)
    Elsevier BV ; 2023
    In:  Clinical Lymphoma Myeloma and Leukemia Vol. 23 ( 2023-09), p. S126-S127
    Details
    In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 23 ( 2023-09), p. S126-S127
    Type of Medium: Online Resource
    ISSN: 2152-2650
    URL: Article
    DOI: 10.1016/S2152-2650(23)01783-4
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 8
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    Downregulation of PA28α induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma
    Springer Science and Business Media LLC ; 2020
    In:  Blood Cancer Journal Vol. 10, No. 12 ( 2020-12-14)
    Details
    In: Blood Cancer Journal, Springer Science and Business Media LLC, Vol. 10, No. 12 ( 2020-12-14)
    Abstract: Protein homeostasis is critical for maintaining eukaryotic cell function as well as responses to intrinsic and extrinsic stress. The proteasome is a major portion of the proteolytic machinery in mammalian cells and plays an important role in protein homeostasis. Multiple myeloma (MM) is a plasma cell malignancy with high production of immunoglobulins and is especially sensitive to treatments that impact protein catabolism. Therapeutic agents such as proteasome inhibitors have demonstrated significant benefit for myeloma patients in all treatment phases. Here, we demonstrate that the 11S proteasome activator PA28α is upregulated in MM cells and is key for myeloma cell growth and proliferation. PA28α also regulates MM cell sensitivity to proteasome inhibitors. Downregulation of PA28α inhibits both proteasomal load and activity, resulting in a change in protein homeostasis less dependent on the proteasome and leads to cell resistance to proteasome inhibitors. Thus, our findings suggest an important role of PA28α in MM biology, and also provides a new approach for targeting the ubiquitin-proteasome system and ultimately sensitivity to proteasome inhibitors.
    Type of Medium: Online Resource
    ISSN: 2044-5385
    URL: Article
    DOI: 10.1038/s41408-020-00393-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 9
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    Abstract 2715: Deciphering a metabolic basis for single-agent venetoclax efficacy in t(11;14) multiple myeloma
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2715-2715
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2715-2715
    Abstract: Multiple myeloma (MM) is the second most common hematologic malignancy. In 2017, MM accounted for approximately 30,770 new diagnoses and 12770 deaths in the US. Although, advancements in treatment options have increased survival rates and life expectancy, MM remains incurable due to development of resistance. Venetoclax is a highly selective, potent BCL-2 antagonist, currently in phase I/II trials for MM and FDA approved for the treatment of CLL patients exhibiting 17p deletion. Venetoclax is effective in eliciting cell death as a single agent in a subset of MM with the (11;14) translocation (which we henceforth designate “sensitive”) in contrast to the majority of MM that is resistant (which we henceforth designate “resistant”). We previously reported that glutamine deprivation increases BIM binding to BCL-2 thereby sensitizing MM to venetoclax, while alpha-ketoglutarate supplementation reversed this sensitivity. We were therefore interested to explore if there was a metabolic basis for t(11;14)-myeloma sensitivity to single agent venetoclax to aid in 1) identifying venetoclax sensitive MM and; 2) inform us of metabolic targets that could be inhibited to sensitize resistant MM to venetoclax. We first queried the CoMMpass MM patient RNAseq trial data and cell lines for electron transport chain (ETC) and TCA cycle gene expression differences in t(11;14) vs non-t(11;14) patients and cell lines. All sensitive cells exhibited varied suppression of TCA/ETC genes, and reduced TCA cycle metabolites and oxygen consumption rates (OCR) compared to resistant cells. Examination of TCA cycle activities connected to the ETC and OCR showed significant decrease in Complex II Succinate ubiquinone reductase (SQR) activity in sensitive cell lines and purified CD38+ve MM patient cells and elevated SQR activity in resistant cells. Furthermore, inhibition of SQR with thenoyltrifluoroacetone (TTFA) sensitized resistant cells to venetoclax. Consistent with SQR inhibition leading to ABT-199 sensitivity, overexpression of an SQR mutant (SDHCR72C) in SDHC-knockout resistant MM, increased venetoclax sensitivity, identifying a unique role for SQR in regulating BCL-2 dependence. In interrogating the mechanistic underpinnings of SQR inhibition-induced sensitivity to venetoclax, we identified increased expression of ATF4 and BIM upon SQR inhibition. ATF4KD or BIMKO restored viability in TTFA and venetoclax co-treated MM further confirming the role of SQR inhibition-induced ATF4 and BIM in venetoclax sensitivity. In testing translationally relevant compounds, we determined that the histone deacetylase inhibitor, panobinostat reduced SQR activity in a dose dependent manner and sensitized MM cells to venetoclax. Our study thus identifies SQR as a novel target and predictive marker to aid in identifying ABT-199-responsive MM patients in a functional biomarker informed manner. Citation Format: Richa Bajpai, Abhinav Achreja, Changyong Wei, Arusha Siddiqa, Shannon M. Matulis, Vikas Gupta, Samuel K. McBrayer, Anjali Mittal, Manali Rupji, Hsiao-Rong Chen, Jeanne Kowalski, Sagar Lonial, Ajay K. Nooka, Lawrence H. Boise, Deepak Nagrath, Mala Shanmugam. Deciphering a metabolic basis for single-agent venetoclax efficacy in t(11;14) multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2715.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2715
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
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    Abstract 972: Targeting glucose and glutamine regulated BCL2 family members for multiple myeloma therapy
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 972-972
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 972-972
    Abstract: Multiple myeloma (MM) is a plasma cell malignancy accounting for approximately 11000 deaths annually in the US. Despite use of immunomodulatory drugs and proteasome inhibitors, MM is largely incurable with a median survival of 5 years due to the development of intrinsic and acquired resistance to these drugs. Targeting metabolic dependencies in a cancer cell may provide an effective strategy to target the molecular heterogeneity and chemo resistance characteristic of MM. Resistance is in part mediated by ineffective regulation of Bcl-2 family members. Myeloid cell leukemia factor 1 (MCL-1) is a key resistance promoting anti-apoptotic protein expressed in MM cells. We and others have previously established that glucose regulates expression of MCL-1. MM cells are heavily reliant upon glucose and glutamine and withdrawal of either nutrient is associated with varying levels of apoptosis. While glucose withdrawal was found to suppress MCL-1 expression uniformly, this did not always correlate with the extent of apoptosis induced. One potential mechanism for continued survival despite suppression of MCL-1 could be due to a shift in binding of pro-apoptotic BCL2 proteins to alternate pro-survival BCL2 members. Our investigation through co-immunoprecipitation experiments revealed that glucose or glutamine withdrawal enhances a shift in binding of pro-apoptotic BIM from MCL-1 to BCL2/ BCLxL. This shift in the association of BIM to BCL2 and BCLxL increased sensitivity to BH3 mimetics ABT-199/737. Induction of NOXA, that has a greater affinity for MCL-1 than BIM, is known to promote the redistribution of BIM to BCL2 and BCLxL. Indeed, glucose and glutamine withdrawal were found to increase NOXA expression associated with activation of the upstream GCN2/PERK/eIF2α/ATF4 axis in a cell type specific manner. Knock down of NOXA in MM cells successfully increased cell survival and reduced sensitivity towards ABT-199 in glucose or glutamine deprived cells. We have extended these observations to a panel of 7 myeloma cell lines and primary myeloma patient samples. Our study broadly divides MM cells into two subtypes on the basis of glucose or glutamine dependency and provides effective ways to their survival by targeting their specific metabolic dependencies in combination with the BH3 mimetic ABT-199. We also demonstrate that glucose transport and metabolism in MM can be targeted with the FDA approved GLUT4 inhibitor ritonavir and glutamine utilization can be inhibited by glutamine antagonist DON (6-Diazo-5-oxo-L-norleucine). Both ritonavir and DON treatments sensitized MM cell lines and primary patient samples to ABT-199, bolstering the utility of repurposing FDA-approved ritonavir and ABT-199 (in clinical trial) for MM therapy. Citation Format: Richa Bajpai, Shannon M. Matulis, Changyong Wei, Ajay K. Nooka, Lawrence H. Boise, Mala Shanmugam. Targeting glucose and glutamine regulated BCL2 family members for multiple myeloma therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 972. doi:10.1158/1538-7445.AM2015-972
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-972
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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