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  • 1
    Online Resource
    Online Resource
    Abstract 1742: Inhibition of BET signaling leads to reversible GATA1-associated repression of hematopoietic progenitors: translation from preclinical assessment to clinical development
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1742-1742
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1742-1742
    Abstract: Bromodomain and extraterminal (BET) proteins recognize acetylated lysine residues for the purpose of transcriptional regulation of genes, including those involved in stem cell renewal and oncogenes such as MYC. Inhibition of BET proteins BRD2, BRD3, BRD4, and BRDT represents a promising treatment option for patients with cancer. However, little is known about the consequence of BET inhibition on normal stem cell renewal processes, such as hematopoiesis. This study explored the mechanistic effects of BET inhibition on bone marrow (BM) hematopoiesis. Rats treated with BET inhibitors JQ1, BMS-X, or BMS-986158 for 4 days in vivo showed dose-dependent pan-cellular BM atrophy and reduction of hematopoietic progenitors of myeloid and erythroid lineage (combination of anti-rat CD45, CD11b, anti-granulocyte, CD71, anti-erythroid, and CD90 via flow cytometry) and consequential reductions in circulating platelet and reticulocyte counts, with complete reversibility within 10 days of stopping treatment with BET inhibitors. Primary rat BM stem and progenitor cells treated with BET inhibitors in vitro were evaluated with the colony-forming unit assay and resulted in dose-dependent reduction of multiple lineage progenitor colonies, especially the erythroid and megakaryocyte lineages. To further elucidate pathways involved in BET-related BM atrophy, erythropoiesis and thrombopoiesis genes regulated by GATA1, a BRD-associated transcription factor, from rat BM, as well as rat and human whole-blood samples exposed to BET inhibitor(s) were evaluated via RNAseq and RT-PCR. Dose-dependent responses in genes involved in erythropoiesis (Alas2, ABCme, PBG-D, HMBS) and thrombopoiesis (NFE2, PF4, GP1Bb, MPL) were observed after 4 days of treatment with BMS-986158. In a clinical trial (NCT02419417), patients with solid tumors treated with BMS-986158 demonstrated reversible thrombocytopenia and downregulation of NFE2, PF4, and HMBS expression, similar to that observed in rats. GATA1 was also downregulated in rat BM, with target engagement in rat and human demonstrated by the induction of HEXIM1 transcription, a pharmacodynamic (PD) biomarker of growth inhibition and apoptosis induced by BRD4 inhibition. Overall, our results suggest inhibition of BET signaling causes target-related, dose-dependent repression of hematopoietic progenitors through alterations of GATA1-associated erythropoiesis and thrombopoiesis regulation in rat BM and human blood samples, and these effects are reversible on cessation of BET inhibitor treatment. This is the first in vivo study demonstrating the mechanism of BET inhibition resulting in GATA1-associated repression of hematopoietic progenitors that is correlated to clinical pharmacokinetics and PD (Chen X, et al. AACR 2020) and is translatable from preclinical evaluation to clinical experience. Citation Format: Cindy Zhang, Ke Xu, Julie Panzica-Kelly, Jennifer Price, Denise Bounous, Shodeinde Coker, Kezi Unsal-Kacmaz, Danielle Greenawalt, Ashvinikumar Gavai, Ronald Fleming, Karen Augustine-Rauch, Richard Westhouse. Inhibition of BET signaling leads to reversible GATA1-associated repression of hematopoietic progenitors: translation from preclinical assessment to clinical development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1742.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-1742
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Abstract B025: Purine biosynthesis regulates mTORC1 by modulating Rheb GTPase activity
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. B025-B025
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. B025-B025
    Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) regulates protein synthesis through effects on mRNA translation and ribosome biogenesis. Emerging evidence suggests that active mTORC1 also stimulates the de novo biosynthesis of purine and pyrimidine nucleotides. Here, using pharmacologic and genetic tools, we demonstrate that mTORC1 signaling is modulated by cellular purine nucleotide pools arising from the metabolic processes that generate ATP and GTP. Inhibition of GARFT, the enzyme that catalyzes the first folate-dependent step in purine synthesis, by the specific inhibitor AG2037, dramatically inhibits mTORC1 signaling via an AMPK-independent mechanism. GARFT inhibition suppresses the level of the activated form of the Rheb GTPase, a requisite upstream activator of mTORC1, through a global reduction in intracellular guanine-based nucleotides, and subsequently reduces Rheb protein farnesylation. Moreover, we demonstrate that mTORC1 blockade resulting from AG2037-mediated inhibition of GARFT impacts both translation initiation and pyrimidine biosynthesis and results in robust tumor growth inhibition of non-small cell lung cancer (NSCLC) xenografts. Our findings indicate that the regulatory relationship between mTORC1 activity and purine nucleotide pool is bidirectional, and suggest that mTORC1 inhibition contributes to the clinically established antiproliferative effects of purine biosynthesis inhibitors in cancer and inflammatory diseases. Citation Format: Kezi Unsal-Kacmaz, Natasha Emmanuel, Shoba Ragunathan, Qin Shan, Fang Wang, Andreas Giannakou, Nanni Huser, Guixian Jin, Jeremy Myers, Robert T. Abraham. Purine biosynthesis regulates mTORC1 by modulating Rheb GTPase activity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B025.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-B025
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Abstract 3021: Integrated pharmacokinetic (PK)/pharmacodynamic (PD) modeling leveraging PK, biomarker, and safety data to support dose and schedule selection for the BET inhibitor BMS-986158
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3021-3021
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3021-3021
    Abstract: Background: BMS-986158 is a potent, selective, and orally bioavailable small-molecule inhibitor of the bromodomain and extraterminal (BET) family of transcription modulators being evaluated in patients with various tumors in a phase 1 clinical study (NCT02419417). An integrated PK/PD analysis leveraging PK, biomarker, and safety data from the phase 1 study was performed to support dose and schedule (Sch) selection further clinical studies with BMS-986158. Methods: Five doses (0.75-4.5 mg) and 3 dosing regimens (Sch A: 5 days on, 2 days off over 21 days; Sch B: 14 days on, 7 days off; Sch C: 7 days on, 14 days off) were evaluated. Reversible thrombocytopenia (TTP) was the primary safety signal observed, and peripheral gene expression modulation was a PD biomarker indicative of drug target engagement. BMS-986158 serum PK was characterized with a 2-compartment population PK (PPK) model. A semimechanistic PK/PD model describing the platelet-reducing effect with BMS-986158 was developed to characterize platelet profiles for individual patients and to simulate and project the incidence of TTP at different doses and dosing regimens. The association of BMS-986158 exposure with expression modulation of select peripheral BET target genes, including HEXM1 and CCR2, was also examined. Results: BMS-986158 exhibited linear PK with rapid oral absorption (Tmax ≈ 2-4 h) and a terminal half-life of ≈ 60 h over the dose range of 0.75-4.5 mg. PPK modeling and simulation suggested that at the same dose level, Sch A led to comparable Cmax, with a higher Ctrough and Cavg at steady state compared with Sch B and C across the dosing interval. The semimechanistic PK/PD model predicted a higher incidence rate of TTP with Sch A than Sch C at the same dose level, and the predictions agreed with observed primary safety data from the phase 1 study. The model predicted grade 4 TTP incidence rates of 24% (95% CI, 21%-26%) and 43% (95% CI, 38%-45%) at 4.5 and 6 mg, respectively, with Sch A. This suggests that 4.5 mg would be the maximum tolerated dose, given that a 6 mg dose was predicted to exceed the target dose-limiting toxicity (DLT) rate of grade 4 TTP at 27%. The exploratory analysis of BMS-986158 exposure and expression of selected peripheral genes associated with the BET pathway suggested a direct association between BMS-986158 exposure and the magnitude of peripheral gene expression modulation. Conclusions: An integrated PK/PD analysis of BMS-986158 incorporating incidence of reversible TTP and modulation of peripheral BET target genes identified a maximum dose of 4.5 mg at Sch A for further clinical development. With the assumption that sustained gene expression modulation is desirable for BMS-986158 efficacy, Sch A, which provides sustained drug exposure, is recommended to enable continuous BET target gene expression modulation. Citation Format: Xi (Cindy) Chen, Lora Hamuro, Shodeinde Coker, John Hilton, Jennifer R. Diamond, Capucine Baldini, Mark Voskoboynik, Mihaela Cristea, William Edenfield, Kezi Unsal-Kacmaz, Donald Jackson, Abraham Apfel, Ke Xu, Li Zhu, Amit Roy, Akintunde Bello, Ronald Fleming, Paul Statkevich. Integrated pharmacokinetic (PK)/pharmacodynamic (PD) modeling leveraging PK, biomarker, and safety data to support dose and schedule selection for the BET inhibitor BMS-986158 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3021.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-3021
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    MCT4 is an important determinant for the growth of highly glycolytic and aggressive malignancies
    Springer Science and Business Media LLC ; 2012
    In:  BMC Proceedings Vol. 6, No. S3 ( 2012-6)
    Details
    In: BMC Proceedings, Springer Science and Business Media LLC, Vol. 6, No. S3 ( 2012-6)
    Type of Medium: Online Resource
    ISSN: 1753-6561
    URL: Article
    DOI: 10.1186/1753-6561-6-S3-O26
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2012
    detail.hit.zdb_id: 2411867-9
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