Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 622-622

Abstract: Recent studies indicate that acute myeloid leukemia (AML) cells, including leukemia-initiating cells, are highly dependent on oxidative phosphorylation (OXPHOS) for survival, while normal hematopoietic stem cells predominantly utilize glycolysis for energy homeostasis. We have reported development of a series of novel, highly potent mitochondrial complex I inhibitors, which in vitro inhibit complex I with IC50 values 〈 10 nM (Marszalek et al., AACR 2014 Abstract #949). These inhibitors offer excellent therapeutic potential in the OXPHOS-dependent cancer models. IACS-1131 was selected as a preclinical tool compound from the series of more than 800 compounds across distinct structural classes. Here, we report the in vitro and in vivo efficacy of IACS-1131 in AML models. Analysis of a panel of AML cell lines showed that a subset of leukemias are markedly dependent on OXPHOS for growth and survival; in this subset, IACS-1131 treatment caused steep decreases in viable cell number via induction of apoptosis. In sensitive cell lines (HL-60, OCI-AML3, KG-1, MV4;11, Kasumi-1), IACS-1131 induced pronounced apoptosis with EC50 between 10 and 100nM, consistent with the IC50 required to inhibit OXPHOS. MOLM13 and OCI-AML2 cells were less sensitive (EC50 250nM and 120nM, and a failure to induce cell death). In primary AML samples from patients with newly diagnosed or relapsed/refractory AML (n=12), the average EC50 for IACS-1131 was 14 ± 8nM in 9 samples, and exceeded 100nM in 3 samples. Consistent with the findings in AML cell lines, 10nM IACS-1131 resulted in partial responses, and 100-250nM resulted in profound loss of viability due to apoptosis induction. In contrast, this treatment caused only a moderate decrease in CD34+ cell numbers and 〈 10% increase in apoptosis in 6 normal bone marrow samples. The effects of IACS-1131 on the two major energy-generating pathways, mitochondrial OXPHOS and glycolysis, were investigated using the Seahorse Bioscience XF96 Analyzer. Treatment for 16 hrs caused a striking dose-dependent decrease in basal oxygen consumption rates (OCR), indicating OXPHOS inhibition; reduced ATP production; and decreased maximal respiratory capacity in OCI-AML3 cells and in primary AML blasts (n=9). We confirmed inhibition of complex I in AML cells using Seahorse mitochondrial electron flow assay. These changes preceded changes in viability or apoptotic markers; as such, loss of the mitochondrial membrane potential, annexin V positivity, and induction of mitochondrial reactive oxygen species were seen only at 72 hrs of exposure. Further time-course analysis demonstrated that 2 hrs of IACS-1131 exposure caused significant inhibition of OCR in both sensitive OCI-AML3 and resistant MOLM13 cells, but in MOLM13 cells there was a greater increase in extracellular acidification rates, suggesting compensation by glycolysis. In turn, inhibition of glycolysis with 2-DG, or blockade of pyruvate dehydrogenase kinase with dicholoroacetate (which forces entry into the TCA cycle) sensitized resistant cells to IACS-1131. The intracellular metabolome (polar fraction) of OCI-AML3 cells was characterized following 2, 4, 12 and 24 hrs of treatment with 100nm IACS-1131 using high-resolution magnetic resonance spectroscopy and high mass accuracy Orbitrap mass spectrometry. IACS-1131 modulated levels of the TCA intermediates, producing increased accumulation of citrate and fumarate and decreased succinate and malate, and increased glutathione, possibly because of the oxidative stress. Furthermore, the metabolic analysis indicated a strong effect on amino acid metabolism, whereby IACS-1131 reduced (between 25% and 62% of control) multiple anaplerotic amino acids (including arginine, leucine, isoleucine, valine, phenylalanine, asparagine, histidine, and glutamine, but not aspartate). Finally, IACS-1131 at 60 mg/kg QD po demonstrated robust anti-leukemia activity in an orthotopic OCI-AML3 model. At this dose, IACS-1131 was well tolerated for 〉 50 days and increased median survival duration by more than 5 times (Fig. 1). Studies exploring the anti-AML efficacy of single-agent IACS-1131 in primary AML xenografts are ongoing. Taken together, these data strongly indicate that OXPHOS inhibition constitutes a novel therapeutic approach that targets a unique metabolic vulnerability of AML cells and indicate that further preclinical evaluation of OXPHOS inhibitors is warranted. Figure 1 Figure 1. Figure 1 Treatment with IACS-1131 prolongs survival in a OCI-AML3 xenograft model. Luciferase-expressing OCI-AML3 cells were injected in the tail vein of NSG mice. On day 16 after injection, engraftment was confirmed and mice were randomized on the basis of IVIS-based imaging of luciferase activity after luciferin injection. For the next 58 days, mice received either vehicle or 60 mg/kg/day of IACS-1131 via oral gavage. Mice were sacrificed when body weight was reduced by 〉 20% or for signs of morbidity. Right, bioluminescence imaging before (D0) and 10 days after 1 st dose; left survival. Figure 1. Treatment with IACS-1131 prolongs survival in a OCI-AML3 xenograft model. Luciferase-expressing OCI-AML3 cells were injected in the tail vein of NSG mice. On day 16 after injection, engraftment was confirmed and mice were randomized on the basis of IVIS-based imaging of luciferase activity after luciferin injection. For the next 58 days, mice received either vehicle or 60 mg/kg/day of IACS-1131 via oral gavage. Mice were sacrificed when body weight was reduced by 〉 20% or for signs of morbidity. Right, bioluminescence imaging before (D0) and 10 days after 1 st dose; left survival. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.622.622

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3745-3745

Abstract: LY2510924 is a novel selective peptidic CXCR4 antagonist that blocks SDF-1α from binding to its receptor. We have demonstrated that LY2510924 at nanomolar concentrations durably disrupts the SDF-1α/CXCR4 axis in acute myeloid leukemia (AML) cells and exerts anti-leukemia effects as a single agent (AACR 2014: #4768). We further investigated the pronounced anti-leukemia activity of LY2510924 and the mechanisms underlying the anti-leukemia effect. To test the efficacy of LY2510924 in combination with chemotherapy, we injected OCI-AML3/luc/GFP cells into NSG mice. Mice were randomized into 4 groups (10 mice per group) on day 8: control, chemotherapy (cytarabine [50 mg/kg, daily for 5 days, intravenous or intraperitoneal]/doxorubicin [1.5 mg/kg, daily for 3 days, co-delivered intravenously] ), LY2510924 (2.5 mg/kg, daily for 3 weeks, subcutaneously), or chemotherapy and LY2510924. Bioluminescence imaging demonstrated that LY2510924 exerted an anti-leukemia effect equal to that achieved with chemotherapy (P=0.249), and the combination therapy group had the lowest luciferase activity. LY2510924-treated mice had prolonged survival (Figure 1) compared to controls (52 days vs. 40 days, p=0.006), and combination therapy extended survival even further (62 days vs. 52 days, p=0.004). Next, we examined anti-leukemia efficacy of LY2510924 in primary human AML xenograft models. NSG mice were injected with primary AML cells and randomized into 2 groups on day 25, after engraftment was documented: control (n=13) and treatment with LY2510924 (n=15; 2.5 mg/kg subcutaneously, daily). First, we examined AML cell mobilization by measuring the proportion of circulating leukemic cells after daily LY2510924 administration. Mice treated with LY2519024 had a significant increase of circulating leukemic cells at 3 hours (2.1-fold, P=0.008), and further increases at 24 hours (2.7-fold, P=0.008) and 48 hours (3.0-fold, P=0.009) compared to controls. Flow cytometry showed a sustained inhibition of CXCR4 12G5 surface expression at 3 and 24 hours after the first LY2510924 injection. Thereafter, weekly examination of circulating leukemic cells in both groups revealed slower progression of leukemia in the LY2510924-treated group (54% vs. 86% circulating AML cells on day 45, P 〈 0.001). Additionally, we sacrificed 3 mice per group on days 35 and 45 and demonstrated that LY2510924-treated mice had significantly lower leukemic cell burden in the spleen (22% vs. 51%, P=0.001) on day 35, and in both spleen (20% vs. 60%, P 〈 0.001) and bone marrow (72% vs. 90%, P=0.012) on day 45 by flow cytometry. CXCR4 blockade with LY2510924 was associated with reduced AKT and/or ERK signaling in leukemic cells of spleen, bone marrow, and blood as measured by multi-parametric phospho-flow cytometry. This anti-leukemia effect translated into a significant prolongation of survival in LY2510924-treated mice (56 days vs. 44 days, p 〈 0.001, Figure 2). Our previous study (AACR 2014:#4768) demonstrated that LY2510924 did not induce AML cell death in vitro on its own but inhibited AML cell growth in co-cultures with human marrow stromal cells (hMSC). To explore how CXCR4-mediated signaling in AML cells elicits anti-leukemia effects, we performed whole gene expression profiling of FACS-sorted OCI-AML3 cells co-cultured with hMSC for 48 hours and co-treated with LY2510924, in duplicates. Among genes modified by CXCR4 antagonist, we found that CTNNB1 (human beta-catenin), JARID1C (lysine-specific demethylase 5C), RARA (retinoic acid receptor alpha), RARRES2 (chemerin), and COQ4 (coenzyme Q) were downregulated in co-cultured OCI-AML3 cells treated with LY2510925, when compared to either mono-cultured cells or co-cultured cells without LY2510924. These findings are currently being validated by using functional in vitro assays. In conclusion, our findings demonstrate that CXCR4 antagonist LY2510924 inhibits AML progression in leukemia xenograft models in vivo and has a synergistic anti-leukemia effect in combination with chemotherapy. LY2510924 efficiently inhibits CXCR4 signaling in primary AML cells in vivo and induces mobilization of leukemic cells into circulation. This results in pronounced anti-leukemia activity as a single agent. LY2510924's potency and durable occupancy of CXCR4 receptors will likely translate into greater anti-leukemia potency in future clinical applications. Disclosures Peng: Eli Lilly & Company: Employment. Thornton:Eli Lilly & Company: Employment, stocks Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3745.3745

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Бюллетень Восточно-Сибирского научного центра Сибирского отделения Российской академии медицинских наук, Infra-M Academic Publishing House, Vol. 1, No. 3 ( 2017-05-02), p. 41-45

Type of Medium: Online Resource

ISSN: 1811-0649

Uniform Title: СИСТЕМА ПЕРЕКИСНОГО ОКИСЛЕНИЯ ЛИПИДОВ И АНТИОКСИДАНТНОЙ ЗАЩИТЫ У БЕРЕМЕННЫХ, УПОТРЕБЛЯВШИХ СЛАБОАЛКОГОЛЬНЫЕ НАПИТКИ В МАЛЫХ И УМЕРЕННЫХ ДОЗАХ

URL: Issue

URL: Article

DOI: 10.12737/issue_590823a3d6f756.29958315

DOI: 10.12737/article_590823a43604c8.50478550

Language: English , Russian

Publisher: Infra-M Academic Publishing House

Publication Date: 2017

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4380-4380

Abstract: Tumor cells normally depend on both glycolysis and oxidative phosphorylation (OXPHOS) to provide the energy and macromolecule building blocks needed to enable continued tumor cell growth. Genetic or epigenetic inactivation of one of these two redundant pathways represents a metabolic vulnerability that should be susceptible to an inhibitor of the other pathway. Through an extensive medicinal chemistry campaign, IACS-10759 was identified as a potent inhibitor of complex I of oxidative phosphorylation. In isolated mitochondria or permeabilized cells, ATP production or oxygen consumption was inhibited at single digit nM concentrations in the presence of malate/glutamate, but not succinate. More directly, IACS-10759 inhibited the conversion of NADH to NAD+ in an immunoprecipitated complex I assay at low nM concentrations. Using genetic and pharmacological approaches, the specific complex I subunit inhibited by IACS-10759 has been identified and the mechanism of complex I inhibition is being investigated. Importantly, IACS-10759 is orally bioavailable with excellent physicochemical properties in preclinical species and achieved significant in vivo efficacy with daily oral dosing of 10-25 mg/kg. Specifically, there was a & gt;50 day extension of median survival in an orthotopic AML cell line xenograft and robust regression in DLBCL and GBM xenograft models. In light of these results, as well as its drug like profile IACS-10759 has entered IND enabling studies with first-in-human studies targeted for third quarter of 2015. Citation Format: Marina Protopopova, Madhavi Bandi, Jennifer Bardenhagen, Christopher Bristow, Christopher Carroll, Edward Chang, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Marina Konopleva, Polina Matre, Zhijun Kang, Gang Liu, Florian Muller, Timothy Lofton, Timothy McAfoos, Yuting Sun, Melinda Smith, Jay Theroff, Yuanqiang Wu, Lynda Chin, Giulio Draetta, Philip Jones, Carlo Toniatti, M. Emilia Di Francesco, Joseph R. Marszalek. IACS-10759: A novel OXPHOS inhibitor which selectively kill tumors with metabolic vulnerabilities. [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 4380. doi:10.1158/1538-7445.AM2015-4380

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2015-4380

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2015

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

In: Nature Medicine, Springer Science and Business Media LLC, Vol. 24, No. 7 ( 2018-07), p. 1036-1046

Type of Medium: Online Resource

ISSN: 1078-8956 , 1546-170X

URL: Article

DOI: 10.1038/s41591-018-0052-4

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2018

detail.hit.zdb_id: 1484517-9

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 1_Supplement ( 2017-01-01), p. PR01-PR01

Abstract: Tumor cells normally depend on both glycolysis and oxidative phosphorylation (OXPHOS) to provide the energy and macromolecule building blocks needed to enable continued tumor cell growth. Genetic or epigenetic inactivation of one of these two redundant pathways represents a metabolic vulnerability that should be susceptible to an inhibitor of the other pathway. We have identified multiple contexts where all or a subset of these tumors demonstrate a dependence on mitochondrial OXPHOS, which represents an exciting therapeutic opportunity. Through an extensive medicinal chemistry campaign, IACS-10759 was identified as a potent inhibitor of complex I of oxidative phosphorylation. In isolated mitochondria or permeabilized cells, ATP production or oxygen consumption is inhibited at single digit nM concentrations in the presence of malate/glutamate, but not succinate. More directly, IACS-10759 inhibits the conversion of NADH to NAD+ in an immunoprecipitated complex I assay at low nM concentrations. Importantly, IACS-10759 is orally bioavailable with excellent pharmacokinetics properties in preclinical species, and has an overall profile suitable for clinical development. Our group and others have demonstrated that a variety of tumor types including: AML, plus subsets of lymphoma, breast, melanoma and PDAC are highly dependent on OXPHOS to meet energy and biomass demands. Treatment of multiple cell lines and patient derived xenograft (PDX) models in multiple cancer types with IACS-10759 led to decreased oxygen consumption rate (OCR). IACS-10759 treatment also led to a robust decrease in cell viability and often an increase in apoptosis with EC50 values between 1 nM - 50 nM across multiple lines. In multiple PDX models of primary AML IACS-10759 treatment extends the median survival. Efficacy was paralleled by robust modulation of OCR, aspartate, and p-AMPK levels. Additionally, tumor growth inhibition or regression was also observed in cell line and PDX xenograft models of lymphoma, triple negative breast, melanoma and PDAC treated with IACS-10759, indicating that subsets of several non-AML indications are also dependent on OXPHOS. Mechanistically, extensive metabolic profiling revealed that the response to IACS-10759 was associated with induction of a metabolic imbalances that negatively impacted energy homeostasis, amino acid biosynthesis, and NTP production due to reduced conversion of NADH to NAD+ by complex I, decreased ATP production, TCA cycle flux and nucleotide biosynthesis. As a result of the robust preclinical response in multiple model systems, IACS-10759 has been advanced through IND enabling studies. GLP safety and toxicology have been completed, clinical supplies manufactured, and a Phase I clinical trial in AML will be initiated during the second quarter of 2016. This abstract is also being presented as Poster B35. Citation Format: Philip Jones, M Emilia Di Francesco, Jennifer M. Molina, Marina Protopopova, Madhavi Bandi, Jennifer Bardenhagen, Christopher A. Bristow, Christopher L. Carroll, Ningping Feng, Jason P. Gay, Mary K. Geck Do, Jennifer M. Greer, Marina Konopleva, Zhijun Kang, Gang Liu, Timothy McAfoos, Pietro Morlacchi, Melinda G. Smith, Sonal Fnu, Jay P. Theroff, Giulio Draetta, Giulio Draetta, Carlo Toniatti, Joseph R. Marszalek. IACS-010759 a novel inhibitor of oxidative phosphorylation advancing into first-in-human studies to exploit metabolic vulnerabilities. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr PR01.

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1557-3265.PMCCAVULN16-PR01

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2017

detail.hit.zdb_id: 1225457-5

detail.hit.zdb_id: 2036787-9

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4768-4768

Abstract: Disruption of the SDF-1α/CXCR4 axis by CXCR4 inhibitors has been proven to be an attractive investigational therapeutic approach for acute myeloid leukemia (AML). Moreover, the addition of CXCR4 inhibitor plerixafor to cytotoxic chemotherapy in a phase 1/2 study was associated with increased response rates in relapsed AML (Blood 2012:119;3917). However, plerixafor as a single agent induces only 2- to 4-fold mobilization of leukemic blasts, and this is thought to be due to incomplete inhibition of the SDF-1α/CXCR4 axis and short half-life. LY2510924 is a selective peptidic CXCR4 antagonist that blocks SDF-1α from binding to the receptor. Flow cytometry using OCI-AML3 cells showed that LY2510924 inhibited binding of anti-CXCR4 antibody 12G5 to surface CXCR4 in a concentration-dependent fashion. LY2510924 was 100 times more potent compared to plerixafor (normalized surface expression, LY2510924 at 1 nM, 10.7±0.27%; plerixafor at 1 nM and 100 nM, 74.6±1.23% and 11.0±0.29%, respectively). The action of LY2510924 started as early as 1 minute and continued up to 72 hours at 10 nM. SDF-1α induced migration of OCI-AML3 and primary AML cells, which was abolished by 1 nM LY2510924 but not suppressed by 1 nM plerixafor. LY2510924 inhibited SDF-1α-induced AKT and/or ERK phosphorylation in AML cell lines (OCI-AML3 and U937) and primary AML cells as shown by immunoblotting and multi-parameter phospho-flow cytometry. To test the efficacy of LY2510924 in vivo, we injected OCI-AML3/luc/mCherry cells into sub-lethally irradiated NSG mice. Twelve days after cell injection, mice were randomized into 4 groups: control, cytarabine, LY2510924, and LY2510924 plus cytarabine. On day 21 after cell injection, we observed a 3.4±1.4-fold increase of circulating leukemic cells at 3 hours and a 24.1±15.4-fold mobilization at 24 hours after LY2510924 injection. Bioluminescence imaging demonstrated that mice treated with LY2510924 had lower leukemia burden than cytarabine-treated and control mice. On day 39, the combination group showed less luciferase activity than the LY2510924 group (P=0.034). Hematoxylin-eosin and immunohistochemical staining with human CD45 antibody demonstrated that the LY2510924-treated groups had a significant decrease in leukemic infiltration of bone marrow, spleen, liver, and lung. This anti-leukemia effect translated into a significant prolongation of survival in LY2510924-treated mice (40 days vs. 26 days, P & lt;0.001). In summary, in vitro data showed that a novel peptidic CXCR4 antagonist, LY2510924, could effectively disrupt the SDF-1α/CXCR4 axis in AML cells and was more potent than plerixafor. In vivo data showed anti-leukemia effects of LY2510924 as a single agent. LY2510924's stronger potency than plerixafor, rapidity of action, and prolonged CXCR4-inhibitory effects will likely translate into a higher anti-leukemia potency than that of plerixafor in future clinical applications. Citation Format: Byung Sik Cho, Zhihong Zeng, Hong Mu, Teresa McQueen, Marina Protopopova, Jorge Cortes, Joe Marszalek, Sheng-Bin Peng, Donald E. Thornton, Michael Andreeff, Marina Konopleva. Novel peptidic CXCR4 antagonist LY2510924 disrupts the SDF-1α/CXCR4 axis resulting in anti-AML efficacy in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4768. doi:10.1158/1538-7445.AM2014-4768

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2014-4768

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2014

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. LB-A15-LB-A15

Abstract: Acute myeloid leukemia (AML) is a highly aggressive disease with a high mortality rate that encompasses several genetically and clinically diverse hematological malignancies characterized by clonal expansion of transformed stem/progenitor cells with limited ability to differentiate into mature blood cells. Standard of care for AML has progressed minimally in the past 30 years for relapse/refractory AML, with survival rates of & lt;12% for those aged & gt;65 years. Therefore, novel, highly effective therapeutics are needed for this population. Targeting bioenergetic susceptibilities is an exciting area of oncology therapeutics that is potentially applicable in AML. Our group and others have shown that AML blasts depend significantly on mitochondrial oxidative phosphorylation to meet their energy and biomass production demands. Through an extensive medicinal chemistry campaign IACS-10759 was identified as a potent, selective inhibitor of complex I of the electron transport chain with excellent PK and a suitable overall profile. In AML cell lines and primary AML blasts treated ex vivo, we observe a robust decrease in proliferation and a concomitant increase in apoptosis with EC50 values of less than 10 nM. Response to IACS-10759 in AML cells was associated with induction of a metabolic catastrophe that negatively impacted the cells' ability to sustain energy homeostasis, amino acid biosynthesis, and nucleotide production. In a primary AML patient derived xenograft model from a patient who was refractory to standard of care and salvage therapies, 42 days of IACS-10759 (QDx5/week) treatment at 10 mg/kg extended the median survival by greater than 2-fold. Inhibition of OXPHOS by IACS-10759 was confirmed in AML cell lines and PDX models by a decrease in oxygen consumption and significant changes in gene and protein expression, non-essential amino acids and nucleotides. Due to the robust response in AML cell lines, primary AML samples ex vivo, and in vivo efficacy in primary AML PDX models, IACS-10759 has been advanced through IND enabling studies with first-in-human studies targeted for the second quarter of 2016. Citation Format: Jennifer R. Molina, Marina Protopopova, Madhavi Bandi, Jennifer Bardenhagen, Christopher Bristow, Maria Alimova, Christopher Carroll, Edward Chang, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Sha Huang, Yongying Jiang, Marina Konopleva, Polina Matre, Zhijun Kang, Gang Liu, Timothy McAfoos, Pietro Morlacchi, Melinda Smith, Sonal Sonal, Jay Theroff, Quanyun Xu, Giulio Draetta, Philip Jones, Carlo Toniatti, M. Emilia Di Francesco, Joseph R. Marszalek. IACS-010759 is a novel inhibitor of oxidative phosphorylation that selectively targets AML cells by inducing a metabolic catastrophe. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A15.

Type of Medium: Online Resource

ISSN: 1535-7163 , 1538-8514

URL: Article

DOI: 10.1158/1535-7163.TARG-15-LB-A15

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2015

detail.hit.zdb_id: 2062135-8

SSG: 12

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1655-1655

Abstract: Over the past few years we and others reported that specific populations of tumor cells including AML, subsets of lymphoma, glioblastoma, triple negative breast cancer (TNBC), melanoma and pancreatic ductal adenocarcinoma (PDAC) are highly dependent upon oxidative phosphorylation (OXPHOS) to meet their energy and biomass needs. Inhibition of OXPHOS in the context of these dependent tumor populations represents therefore an exciting therapeutic opportunity. Through an extensive medicinal chemistry campaign we discovered IACS-010759, a potent, selective small molecule inhibitor of complex I of the mitochondria electron transport chain that possesses excellent pharmacokinetic (PK) and pharmacologic properties, making it suitable for clinical development. We advanced IACS-010759 through IND studies and have recently initiated Phase I studies in patients with relapsed/refractory acute myeloid leukemia (AML) and advanced solid tumors and lymphomas (NCT02882321 and NCT03291938). In this presentation we will describe the identification of a novel series of Complex I inhibitors and their optimization into the clinical candidate compound IACS-010759. Several challenges were successfully overcome, including the optimization of the pharmacokinetic profile and the identification of inhibitors with minimal activity shift across preclinical species, thus enabling a thorough evaluation of the efficacy and toxicology profile. Aspects of the extensive translational research conducted to elucidate the mechanism of action of IACS-010759 and to position it into the clinic will be discussed, including the compelling pharmacological response observed in multiple PDX models of primary AML, and PDX xenograft models of lymphoma, TNBC, glioblastoma, melanoma and PDAC. The observed response was associated with robust pharmacodynamic read-out as assessed by modulation of oxygen consumption rate (OCR), aspartate and specific transcriptional changes. The presentation will also cover the preclinical development activities which resulted in IACS-010759 advancing into on-going phase 1 evaluation in AML and solid tumors. Citation Format: Maria Emilia Di Francesco, Joseph R. Marszalek, Timothy McAfoos, Christopher L. Carroll, Zhijun Kang, Gang Liu, Jay P. Theroff, Jennifer P. Bardenhager, Madhavi L. Bandi, Jennifer R. Molina, Sonal Gera, Marina Protopopova, Yuting Sun, Mary K. Geck Do, Ningping Feng, Jason P. Gay, Florian Muller, Marina Konopleva, Funda Meric-Bernstam, Carlo Toniatti, Timothy P. Heffernan, Giulio F. Draetta, Philip Jones. Discovery and development of IACS-010759, a novel inhibitor of Complex I currently in phase I studies to exploit oxidative phosphorylation dependency in acute myeloid leukemia and solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1655.

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2018-1655

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2018

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 335-335

Abstract: Tumor cells depend on both glycolysis and oxidative phosphorylation (OXPHOS) for energy and biomass production leading to robust cell proliferation. Recent data has demonstrated a dependence of various tumor types on mitochondrial OXPHOS, which represents an exciting therapeutic opportunity. Through an extensive medicinal chemistry campaign, IACS-10759 was identified as a potent, selective inhibitor of complex I of the electron transport chain, which is orally bioavailable and has excellent PK and physicochemical properties in preclinical species. Our group and others have demonstrated that a variety of tumor types including: AML, plus subsets of lymphoma, breast, melanoma and PDAC are highly dependent on OXPHOS to meet energy and biomass demands. Treatment of multiple cell lines and patient derived xenograft (PDX) models in multiple cancer types with IACS-10759 led to decreased oxygen consumption rate (OCR). IACS-10759 treatment also led to a robust decrease in cell viability and often an increase in apoptosis with EC50 values between 1 nM - 50 nM across multiple lines. Through a series of mechanistic studies we established that IACS-10759 blocks complex I of the electron transport at the quinone binding site. In an orthotopic xenograft model of primary AML cells derived from a patient who was refractory to standard of care and salvage therapies, 42 days of IACS-10759 treatment with 3 and 10 mg/kg orally using a 5 on/2 off schedule extended the median survival by greater than 2-fold. Efficacy was paralleled by robust modulation of OCR, aspartate, and p-AMPK levels. Additionally, tumor growth inhibition or regression was also observed in cell line and PDX xenograft models of lymphoma, triple negative breast, melanoma and PDAC treated with IACS-10759, indicating that subsets of several non-AML indications are also dependent on OXPHOS. Mechanistically, extensive metabolic profiling and flux analysis revealed that the response to IACS-10759 was associated with induction of a metabolic imbalance that negatively impacted energy homeostasis, amino acid biosynthesis, and NTP production due to reduced conversion of NADH to NAD+ by complex I, decreased ATP production, TCA cycle flux and nucleotide biosynthesis. As a result of the robust response in multiple cell lines, primary patient samples, and efficacy in PDX models, IACS-10759 has been advanced through IND enabling studies. GLP safety and toxicology have been completed, and we expect to file an IND at the end of 1Q2016 and initiate a Phase I clinical trial in AML during the second quarter of 2016. Citation Format: Jennifer R. Molina, Marina Protopopova, Madhavi Bandi, Jennifer Bardenhagen, Christopher Bristow, Christopher Carroll, Edward Chang, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Sha Huang, Yongying Jiang, Marina Konopleva, Polina Matre, Jing Han, Zhijun Kang, Gang Liu, Timothy McAfoos, Pietro Morlacchi, Melinda Smith, Sonal Gera, Jay Theroff, Quanyun Xu, Juliana Velez, Carlo Toniatti, Timothy Heffernan, Giulio Draetta, M. Emilia Di Francesco, Philip Jones, Joseph R. Marszalek. Title: IACS-010759 is a novel clinical candidate that targets AML cells by inducing a metabolic catastrophe through inhibition of oxidative phosphorylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 335.

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2016-335

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2016

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detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3