scholarly journals CDK9 Inhibition Reverses Resistance to ABT-199 (GDC-0199) By Down-Regulating MCL-1

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2161-2161 ◽  
Author(s):  
Jun Chen ◽  
Sha Jin ◽  
Paul Tapang ◽  
Stephen K Tahir ◽  
Morey Smith ◽  
...  
Keyword(s):  
Clin Oncol ◽  
Cell Lines ◽  
Small Molecule ◽  
Hodgkin’S Lymphoma ◽  
Acquired Resistance ◽  
Hematologic Malignancies ◽  
Hodgkin's Lymphoma ◽  
Employment Equity ◽  
Non Hodgkin's Lymphoma ◽  
Equity Ownership

Abstract All authors are employees of AbbVie and participated in the design, conduct, and interpretation of these studies. AbbVie and Genentech provided financial support for these studies and participated in the review and approval of this publication. The BCL-2-selective inhibitor ABT-199 has demonstrated efficacy in numerous preclinical models of hematologic malignancies without causing thrombocytopenia, a dose-limiting toxicity associated with the BCL-2/BCL-XL inhibitor navitoclax (Souers et al. 2013. Nat. Med. 19, 202-208). ABT-199 has also demonstrated clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL) (Seymour et al. 2014. J. Clin. Oncol. 32, 448s; Davids et al. 2014. J. Clin. Oncol. 32, 544s). Despite these encouraging early clinical data, some subjects do not respond to ABT-199 or progress while on treatment. Pre-clinical models indicate that both intrinsic and acquired resistance may be a consequence of MCL-1 expression. Consequently, we have explored potent and selective small molecule inhibitors of CDK9, a kinase known to maintain the expression of MCL-1 through its role in p-TEFb-mediated transcription. Inhibition of CDK9 resulted in the rapid loss in RNA polymerase II phosphorylation (Serine 5) and MCL-1 expression that was closely followed by the induction of apoptosis in MCL-1-dependent cell lines, a cellular response that could be rescued by overexpression of BCL-2. Substantial synergy was observed between CDK9 inhibitors and ABT-199 in a number of hematologic cell lines with intrinsic or acquired resistance to ABT-199. Direct inhibition of MCL-1 with the small molecule BH3 mimetic A-1210477 was also highly synergistic with ABT-199, further validating the utility of co-inhibiting MCL-1 and BCL-2 function simultaneously in ABT-199 resistant tumors. Importantly, the CDK9 inhibitor-ABT-199 combination was well tolerated in vivo and demonstrated efficacy superior to either agent alone in xenograft models of non-Hodgkin’s lymphoma (NHL) and acute myelogenous leukemia (AML). These data indicate that CDK9 inhibitors may be highly efficacious when used in combination with ABT-199 for the treatment of hematologic malignancies. Disclosures Chen: Abbvie: Employment, Equity Ownership. Jin:Abbvie: Employment, Equity Ownership. Tapang:abbvie: Employment, Equity Ownership. Tahir:abbvie: Employment, Equity Ownership. Smith:abbvie: Employment, Equity Ownership. Xue:abbvie: Employment, Equity Ownership. Zhang:abbvie: Employment, Equity Ownership. Gao:abbvie: Employment, Equity Ownership. Tong:abbvie: Employment, Equity Ownership. Clark:abbvie: Employment, Equity Ownership. Ricker:abbvie: Employment, Equity Ownership. Penning:abbvie: Employment, Equity Ownership. Albert:abbvie: Employment, Equity Ownership. Phillips:abbvie: Employment, Equity Ownership. Souers:abbvie: Employment, Equity Ownership. Leverson:abbvie: Employment, Equity Ownership.

Development of a Novel Small Molecule CRM-1 Inhibitor for Non Hodgkin's Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 598-598 ◽  
Author(s):  
Asfar Sohail Azmi ◽  
Ayad Al-Katib ◽  
Amro Aboukameel ◽  
Michael Kauffman ◽  
Dilara McCauley ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Small Molecule ◽  
Nuclear Localization ◽  
Therapeutic Target ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Equity Ownership

Abstract Abstract 598 Recent evidence demonstrates that Non Hodgkin's Lymphoma (NHL) tumors have elevated expression of the XPO1 gene that codes for the nuclear exporter protein CRM-1 controlling the localization of critical tumor suppressors including p53 family members. For effective apoptosis and cell cycle regulation, p53/p73 nuclear localization and DNA binding are highly critical making CRM-1 an attractive therapeutic target for NHL that carries >90% wild type/functional p53 and only rare mutations in p73. We have identified novel small molecule inhibitors of CRM-1 (KPTs) that bind irreversibly and lock target proteins (including p53 and p73) in the nucleus leading to apoptosis of tumor cells. We demonstrate for the first time that KPTs can induce apoptosis in resistant NHL cell lines and corresponding xenograft models. The most potent CRM-1 inhibitor (KPT-185) induced growth inhibition and apoptosis in a panel of NHL cell lines with a median IC50 ∼25 nM. Western blot and confocal microscopy analyses demonstrated that KPT-185 treatment resulted in nuclear localization of p53 in wt-p53 and p73 in mut-p53 cell lines. Additionally, we observed KPT-185 mediated activation of p21 and Bax, known downstream executioners of p53/p73 cell cycle control and apoptosis, respectively. Most significantly, siRNA knockdown of p53 in WSU-FSCCL and p73 in WSU-DLCL2 abrogated the apoptotic potential of KPT-185, confirming that these were indeed p53/p73 dependent apoptotic events. KPT-185 showed a substantial enhancement in apoptosis when combined with genotoxic p53/p73 re-activating regimen CHOP. The KPTs selectively kill cancer cells with minimal toxicity to normal tissues, and possess clinically acceptable pharmacokinetic parameters. Using WSU-DLCL2 SCID models, we further show that oral administration of related CRM-1 inhibitor KPT-276 (75 and 150 mg/Kg p.o) resulted in 65 and 70% tumor reduction, respectively and subcutaneous injections of KPT-251 (25 and 75 mg/Kg) resulted in 70 and 74% suppression of tumor growth with no observed toxicity to the host. Remnant tumor tissue analysis (histology and protein markers) fell in line with our in vitro results with clear activation of p73 pathway. Our study verifies CRM-1 as a potential therapeutic target in NHL irrespective of the functional status of p53. These results build a strong case for the clinical use of our novel CRM-1 inhibitors either as single agents or in combination with CHOP. Disclosures: Kauffman: Karyopharm: Equity Ownership. McCauley:Karyopharm: Employment. Shacham:Karyopharm: Equity Ownership.

Risk of Infection Among Patients with Non-Metastatic Solid Tumors or Non-Hodgkin’s Lymphoma Receiving Myelosuppressive Chemotherapy and Antimicrobial Prophylaxis in US Clinical Practice

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1730-1730
Author(s):  
Derek Weycker ◽  
David Chandler ◽  
Rich Barron ◽  
Hairong Xu ◽  
Hongsheng Wu ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Solid Tumors ◽  
Research Funding ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Employment Equity ◽  
Myelosuppressive Chemotherapy ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Equity Ownership

Abstract Background Clinical practice guidelines recommend oral antimicrobials (AMB)—principally, the fluoroquinolones—for prophylaxis against chemotherapy-related infections (CRI) in intermediate- and high-risk patients undergoing myelosuppressive chemotherapy. Available evidence on the risk of CRI among patients with non-metastatic solid tumors or non-Hodgkin's lymphoma (NHL) receiving myelosuppressive chemotherapy and AMB prophylaxis in US clinical practice is currently limited. Methods A retrospective cohort design and data from two US private healthcare claims repositories (2008-2011) were employed. The study population included adult patients who received myelosuppressive chemotherapy for non-metastatic cancer of the breast, colon/rectum, or lung, or for NHL. For each study subject, the first qualifying chemotherapy course, and each chemotherapy cycle and episode of CRI within the course, were identified. Use of prophylaxis with oral AMB agents—including antibacterial, antifungal, and antiviral drugs—as well as colony-stimulating factors (CSF) in each cycle also was identified. CRI was ascertained based on admission to an acute-care inpatient facility with a corresponding diagnosis (1⁰ or 2⁰) or an ambulatory encounter with a corresponding diagnosis and evidence of AMB therapy. Risk of CRI was evaluated during chemotherapy cycles in which patients received AMB prophylaxis; only results for the most frequently observed regimen for each tumor type are reported herein. Results The most common regimens—by tumor—were: breast cancer, docetaxel + cyclophosphamide (“TC”, 29% of 34,876); colorectal cancer, folinic acid (leucovorin) + fluorouracil + oxaliplatin (“FOLFOX”, 34% of 14,334); lung cancer, paclitaxel + carboplatin (“PC”, 25% of 17,334); and NHL, cyclophosphamide + doxorubicin + vincristine + prednisone with Rituxan (“CHOP-R”, 45% of 9,612). Across these four regimens, use of AMB prophylaxis in cycle 1 ranged from 3.5-8.6%; fluoroquinolones were the most common agents administered (range, 27.1-43.5%) (Table 1). Use of CSF prophylaxis in cycle 1 ranged from 10.4-61.2%. Among subjects who received first-cycle AMB prophylaxis, risk of CRI in that cycle ranged from 1.2-7.5%; among these subjects, 45-68% had CRI in the inpatient setting (Table 2). CRI risks in subsequent cycles with AMB prophylaxis were generally comparable. Conclusion Among patients with non-metastatic solid tumors or NHL receiving common myelosuppressive chemotherapy and AMB prophylaxis in US clinical practice, risk of CRI ranged from 1.2-8.6% in cycles in which AMB prophylaxis was administered. Disclosures: Weycker: Amgen Inc.: Research Funding. Chandler:Amgen Inc.: Employment, Equity Ownership. Barron:Amgen Inc.: Employment, Equity Ownership. Xu:Amgen Inc.: Employment, Equity Ownership. Wu:Amgen Inc.: Research Funding. Girardi:Amgen Inc.: Employment, Equity Ownership. Edelsberg:Amgen Inc.: Research Funding. Lyman:Amgen Inc.: PI on a research grant to Duke University Other.

scholarly journals SL-501, a Next-Generation Targeted Therapy Directed to the IL-3 Receptor (IL-3R), Possesses Preclinical Anti-Tumor Activity Against Hodgkin’s and Non-Hodgkin’s Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4500-4500 ◽  
Author(s):  
Janice Chen ◽  
Vince Macri ◽  
Pedro Herrera ◽  
Christopher Brooks ◽  
Eric Rowinsky
Keyword(s):  
Targeted Therapy ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Next Generation ◽  
Employment Equity ◽  
Equity Ownership ◽  
Anti Tumor Activity

Abstract While Hodgkin’s lymphoma (HL) is among the most curable lymphomas, a significant percentage of patients relapse after frontline therapy or have primary refractory disease. Patients that remain resistant after second or third line chemotherapy or autologous stem cell transplantation (ASCT) have very limited treatment options. Non-Hodgkin’s lymphoma (NHL) comprises a wide array of clinical subtypes, which have indolent to aggressive clinical courses. Multiple lines of chemotherapy and ASCT are part of the NHL treatment strategy, but indolent forms frequently recur, and patients can develop resistance to therapies that were previously effective. The prognosis for patients with HL and NHL who fail to achieve durable remission with approved therapeutics or transplantation is poor. Therefore, new treatment strategies for such patients are desperately needed. The interleukin-3 receptor (IL-3R) alpha chain (CD123) is overexpressed on the tumor bulk and cancer stem cells (CSCs) of multiple hematologic malignancies. In particular, CD123 has been shown to be upregulated on a variety of leukemias and lymphomas, including HL and certain NHLs. We previously showed that SL-401, a novel IL-3R-targeted therapy comprised of IL-3 fused to a truncated diphtheria toxin payload, possesses cytotoxic activity against IL-3R-expressing HL and NHL cells. SL-501 is a next-generation IL-3R targeted therapy with increased binding affinity for the IL-3R and enhanced potency against both tumor bulk and CSCs of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Here, the anti-tumor activity of SL-501 against HL and NHL cells was investigated. Our flow cytometry assessment of CD123 showed that the receptor was expressed on two nodular sclerosing HL cell lines (L-428 and HDLM2), one mixed cellularity HL line (L-1236), and two mantle cell lymphoma lines (Mino and JeKo-1). CD123 was expressed to varying extents, ranging from high expression in HDLM-2 (99.5%) and L-428 (89.1%), to moderate-to-low expression in Mino (25.4%), L-1236 (19.5%) and JeKo-1 (2.9%). In this study, the activity of SL-501 was tested against this panel of cell lines. Cell were treated with SL-501 (range: 6.3 pM – 1.5 mM) for 48 hours and then assessed for viability using the CellTiter Glo® in vitro cytotoxicity assay. We found that SL-501 reduced the viability of all cell lines tested in a dose-dependent fashion. In particular, SL-501 showed very high potency against the HDLM2 and L-1236 lines, with IC50 values in the sub-nanomolar range (0.139 nM and 0.191 nM, respectively). SL-501 was also cytotoxic against L-428, JeKo-1, and Mino cell lines, with IC50s of 91 nM, 97 nM, and 116 nM, respectively. Taken together, these findings demonstrate that SL-501, a novel next-generation IL-3R-targeted therapeutic, possesses potent in vitro anti-cancer activity against a variety of HL and NHL cell lines. Additional functional studies are ongoing. These promising results provide a rationale for further development of SL-501 in HL and NHL. Disclosures Chen: Stemline Therapeutics: Employment, Equity Ownership. Macri:Stemline Therapeutics: Employment, Equity Ownership. Herrera:Stemline Therapeutics: Employment. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Rowinsky:Stemline Therapeutics: Consultancy, Employment, Equity Ownership.

scholarly journals Translational Study of Cell Surface Proteins in Non-Hodgkin Lymphoma Patients Treated with the First-in-Class Anti-CD47 Antibody Magrolimab (5F9) in Combination with Rituximab

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5229-5229 ◽  
Author(s):  
Roy Louis Maute ◽  
James Y Chen ◽  
Kristopher David Marjon ◽  
Jiaqi Duan ◽  
Timothy Choi ◽  
...  
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Therapeutic Response ◽  
Hodgkin's Lymphoma ◽  
Phase 2 ◽  
Indolent Lymphoma ◽  
Employment Equity ◽  
Phase 2 Trial ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Equity Ownership

Introduction Magrolimab (Hu5F9-G4, 5F9) is a first-in-class IgG4 antibody targeting CD47, a macrophage immune checkpoint and "don't eat me" signal expressed on cancer cells. Blockade of CD47 leads to phagocytosis of tumor cells. Magrolimab synergizes with rituximab to eliminate CD20-positive lymphoma by enhancing antibody-dependent cellular phagocytosis. Magrolimab +rituximab demonstrated encouraging safety and efficacy in a Phase (Ph)1b dose escalation cohort in patients with relapsed/refractory (r/r) DLBCL and FL that were rituximab-refractory (Advani et al., NEJM 2018). CD24 is an additional "don't eat me" signal, and has been proposed as a potential target for immunotherapy (Barkal et al. Nature 2019). Here we describe immunohistochemical analysis of CD47 and CD24 in primary patient biopsies from an ongoing follow-up Phase 2 trial of Non-Hodgkin's lymphoma (including DLBCL and indolent lymphoma) patients treated with magrolimab+rituximab. Results By immunohistochemistry, 54 out of 54 patients assessed were positive for expression of CD47 at screening. High levels of CD47 expression were maintained during treatment with clinically-efficacious doses of magrolimab. Therapeutic response did not correlate with CD47 H-score expression levels. At screening, patients presented with highly variable levels of CD24 expression, with 40 of 54 samples showing positive staining in >30% of cells. We observed no significant correlation between CD24 expression by H-score and response to therapy (complete response + partial response) in either DLBCL or indolent lymphoma. Conclusions CD47 shows consistently high expression in primary biopsies from Non-Hodgkin's lymphoma patients and remains persistently high during treatment. In our Phase 2 trial, therapeutic response did not correlate with CD47 expression levels, suggesting that the degree of target expression is not a primary driver of magrolimab efficacy in Non-Hodgkin's lymphoma. Although we observe wide variation in CD24 expression within this cohort, its levels are not predictive of outcome for this disease indication. We are evaluating the expression of additional biomarkers to identify those Non-Hodgkin's lymphoma patients most likely to benefit from magrolimab+rituximab combination therapy. Disclosures Maute: Forty Seven Inc.: Employment, Equity Ownership, Patents & Royalties. Chen:Forty Seven Inc.: Consultancy, Equity Ownership. Marjon:Forty Seven Inc.: Employment, Equity Ownership. Duan:Forty Seven Inc.: Employment, Equity Ownership. Choi:Forty Seven Inc.: Employment, Equity Ownership. Chao:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties. Takimoto:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties. Agoram:Forty Seven Inc.: Employment, Equity Ownership. Volkmer:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties.

Phase I Trial Evaluating the Safety and Biological Activity of Iboctadekin (rhIL-18) in Combination with Rituximab in Patients with CD20+ B Cell Non-Hodgkin's Lymphoma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3697-3697
Author(s):  
Michael J. Robertson ◽  
John Bauman ◽  
Olivia Gardner ◽  
Zdenka Jonak ◽  
Herbert Struemper ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Biological Activity ◽  
Phase I ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Employment Equity ◽  
Non Hodgkin's Lymphoma ◽  
Equity Ownership ◽  
Anti Tumor Activity

Abstract Abstract 3697 Background: Iboctadekin (recombinant human interleukin-18; rhIL-18) is an immunostimulatory cytokine with anti-tumor activity in preclinical animal models. Phase I clinical trials have demonstrated that rhIL-18 is well-tolerated as monotherapy for patients with advanced solid tumors. Preclinical and clinical data indicate that rhIL-18 acts a costimulatory cytokine that may be optimally used in combination with other agents such as monoclonal antibodies. Methods: Patients with CD20+ B-cell non-Hodgkin's lymphoma (NHL) were given rituximab 375 mg/m2 IV weekly for 4 consecutive weeks in combination with rhIL-18 (in six dose cohorts of 1, 3, 10, 20, 30, and 100 mcg/kg) IV weekly for 12 weeks. Eligible patients had disease which progressed after standard therapy or for which there was no effective standard treatment. Assessments included safety/tolerability, pharmacokinetics, pharmacodynamics (serum cytokines, peripheral blood phenotypic markers and tumor biomarkers), immunogenicity, and anti-tumor activity. Results: Nineteen patients were enrolled on study (10 follicular NHL, 5 mantle cell lymphoma, 2 diffuse large B-NHL, 2 other subtypes). The combination was well-tolerated with a safety profile similar to that observed with rituximab or rhIL-18 given as monotherapy. The pharmacodynamic response is as expected based on results of prior clinical trials of rhIL-18 as monotherapy for cancer. Using the IWC response criteria, two (11%) of 18 evaluable patients had complete responses (CR) and 3 (16%) had partial responses (PR). Six (33%) patients had stable disease. Overall response rate for follicular lymphoma was 33% (1 CR, 2 PR). Conclusions: The combination of rhIL-18 and rituximab is safe, well-tolerated, and induces potent biological activity. A maximum tolerated dose of rhIL-18 was not identified. Further study of rhIL-18 plus rituximab in patients with CD20+ B cell malignancies is warranted. Disclosures: Bauman: GlaxoSmithKline: Employment, Equity Ownership. Gardner:GlaxoSmithKline: Employment, Equity Ownership. Jonak:GlaxoSmithKline: Employment, Equity Ownership. Struemper:GlaxoSmithKline: Employment, Equity Ownership. Germaschewski:GlaxoSmithKline: Employment, Equity Ownership. Koch:GlaxoSmithKline: Employment, Equity Ownership. Murray:GlaxoSmithKline: Employment, Equity Ownership. Toso:GlaxoSmithKline: Employment, Equity Ownership.

Use Of Pegfilgrastim Primary Prophylaxis By Chemotherapy Cycle Among Patients With Non-Hodgkin’s Lymphoma Or Breast Cancer

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5598-5598
Author(s):  
Wendy J Langeberg ◽  
Conchitina C Siozon ◽  
PK Morrow ◽  
John H Page ◽  
Victoria M Chia
Keyword(s):  
Breast Cancer ◽  
Clinical Guidelines ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Chemotherapy Cycle ◽  
Study Cohort ◽  
Employment Equity ◽  
Non Hodgkin's Lymphoma ◽  
Equity Ownership ◽  
Dose Dense

Abstract Introduction A recent open-label, randomized, phase III study in patients with breast cancer (BC) treated with myelosuppressive chemotherapy found a 3-fold higher incidence of febrile neutropenia (FN) among patients who received pegfilgrastim (peg) prophylaxis during the first two chemotherapy cycles only compared with those who received peg prophylaxis during all chemotherapy cycles (36% vs 10%, respectively; Aarts et al. Journal of Clinical Oncology, April 29, 2013). We examined the use of peg prophylaxis in a real-world setting to assess if practice conforms to clinical guidelines, which recommend granulocyte colony-stimulating factor (G-CSF) every chemotherapy cycle where the risk of FN is ≥20%. Methods The study cohort was selected from the MarketScan Research Database of administrative claims maintained by Truven Health Analytics. The selection criteria included adults diagnosed with non-Hodgkin's lymphoma (NHL) or female BC who began chemotherapy between January 1, 2005 and December 31, 2010. Patients were excluded if they received filgrastim, radiotherapy, or a bone marrow or stem cell transplant during their first chemotherapy course. The proportion of patients in the study cohort who received peg prophylaxis was calculated during cycle 1. For each subsequent cycle, the proportion of patients who received peg prophylaxis was calculated among the patients who had received peg in cycle 1 and continued on the same regimen. Results Table 1 shows the use of peg prophylaxis among patients with NHL who received CHOP (cyclophosphomide, doxorubicin, vincristine, prednisone), with or without rituxumab (R) in cycle 1, for 2-week (Q2W) or 3-week (Q3W) cycles, and did not receive filgrastim during their course. Of the 81 patients who received CHOP or CHOP-R Q2W, 61% received peg in cycle 1; of those who remained on the regimen, 74% to 95% received peg in subsequent cycles. Of the 892 patients who received CHOP or CHOP-R Q3W, 54% received peg in cycle 1; of those who remained on the regimen, 90%-95% received peg in subsequent cycles. Table 2 shows the use of peg among patients with BC who received TAC (docetaxel, doxorubicin, cyclophosphamide), ddAC-T (dose-dense doxorubicin, cyclophosphamide followed by dose-dense paclitaxel), or TC (docetaxel, cyclophosphamide) in cycle 1 and did not receive filgrastim during their course. Of the 1,730 patients who received TAC, 78% received peg in cycle 1; of those who remained on the regimen, 88% to 94% received peg in subsequent cycles. Of the 3,170 patients who received ddAC-T, 76% received peg in cycle 1; of those who remained on the regimen, 86% to 93% received peg cycles 2 to 4. Of the 3,639 patients who received TC, 51% received peg in cycle 1; of those who remained on the regimen, about 90% received peg in subsequent cycles. Conclusions Despite clinical guidelines recommending G-CSF prophylaxis with chemotherapy regimens with a high risk of FN, many NHL and BC patients do not receive appropriate FN prophylaxis. However, among NHL and BC patients who receive peg in cycle 1 and remain on the regimen, the majority appear to continue prophylaxis as indicated. The dataset has some limitations: we could not determine dose, complete risk factors for FN, or reasons patients did not receive or discontinued peg. Disclosures: Langeberg: Amgen: Employment, Equity Ownership. Siozon:Amgen: Employment. Morrow:Amgen: Employment, Equity Ownership. Page:Amgen Inc. : Employment, Equity Ownership. Chia:Amgen: Employment, Equity Ownership.

scholarly journals Blocking Protein Secretion with Novel Small Molecule Inhibitors of Sec61 Represents a Potential Treatment Strategy Against Hematologic Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 408-408
Author(s):  
Eric Lowe ◽  
Andrea R Fan ◽  
Jing Jiang ◽  
Henry W. B. Johnson ◽  
Christopher J. Kirk ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Er Stress ◽  
Cell Lines ◽  
Protein Secretion ◽  
Small Molecule ◽  
Life Sciences ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Equity Ownership

Secreted and membrane proteins play key roles in cancer development, including as autocrine growth factors, receptors in oncogenic signaling cascades, and checkpoints in immune system evasion. The biogenesis of most secreted and transmembrane proteins involves cotranslational translocation of nascent polypeptides ("clients") into the endoplasmic reticulum (ER) through the Sec61 translocon. Multiple inhibitors of protein secretion have been described that target Sec61 and have antitumor activity but lack adequate pharmaceutical properties or tolerability to be studied clinically. Here we describe novel small molecule inhibitors of Sec61 which exhibit activity against hematologic tumor cells in vitro and in vivo. KZR-8834 (8834) was identified through a screening campaign for novel inhibitors of Sec61-dependent protein secretion, where it exhibited nanomolar potency against multiple Sec61 client proteins of therapeutic value, including several immune checkpoint proteins. The broad Sec61 client inhibition profile of 8834 led to its in vitro assessment of anti-cancer activity against a panel of 346 human cancer cell lines. 8834 displayed broad cytotoxic activity against both solid and hematologic tumor types with high potency for hematologic malignancies including acute lymphoid leukemia (mean IC50=317nM, n=8 cell lines), acute myeloid leukemia (IC50=359nM, n=14), lymphoma (IC50=250nM, n=15) and multiple myeloma (IC50=352nM, n=11). In mouse xenograft models of multiple myeloma (H929) and mantle cell lymphoma (Mino), once weekly administration of 8834 or KZR-9261 (8834 analog) resulted in >90% tumor growth inhibition without significant clinical toxicity. Two multiple myeloma cell lines, H929 and U266, were chosen to assess cellular response due to their sensitivity and resistance to 8834, respectively. In H929 cells, 250nM 8834 induced activation of caspase 3/7 (>15 fold) within 8 hours of exposure which corresponded with a cell viability IC50 of 98nM at 24 hours. In contrast, no caspase 3/7 activation was noted in U266 cells through 24 hours of exposure, which corresponded with minimal effects on cell viability. Gene expression profiling by RNAseq and quantitative proteomic profiling by mass spectrometry was performed on these cell lines to elucidate mechanisms of sensitivity and resistance to Sec61 inhibition. Both methods revealed rapid upregulation of ER stress response genes/proteins and activation of the unfolded protein response, which was greater in H929 cells and confirmed by immunoblot and QPCR. Gene set enrichment analysis revealed significantly higher basal levels of ER stress-related genes in H929 vs U266 cells, suggesting ER stress response capacity as a possible predictive biomarker. In summary, blockade of Sec61-dependent translocation of secreted and membrane proteins with novel small molecule inhibitors exhibits a broad antitumor profile in vitro, potentially in part through activation of proteotoxic stress. These effects translate into therapeutic activity in multiple mouse xenograft models, demonstrating a potential novel treatment for hematologic malignancies. Disclosures Lowe: Kezar Life Sciences: Employment, Equity Ownership. Fan:Kezar Life Sciences: Employment, Equity Ownership. Jiang:Kezar Life Sciences: Employment, Equity Ownership. Johnson:Kezar Life Sciences: Employment, Equity Ownership. Kirk:Kezar Life Sciences: Employment, Equity Ownership. McMinn:Kezar Life Sciences: Employment, Equity Ownership. Muchamuel:Kezar Life Sciences: Employment, Equity Ownership. Qian:Kezar Life Sciences: Employment, Equity Ownership. Tuch:Kezar Life Sciences: Consultancy.

scholarly journals CC-92480 Is a Novel Cereblon E3 Ligase Modulator with Enhanced Tumoricidal and Immunomodulatory Activity Against Sensitive and Resistant Multiple Myeloma Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1812-1812 ◽  
Author(s):  
Antonia Lopez-Girona ◽  
Courtney G. Havens ◽  
Gang Lu ◽  
Emily Rychak ◽  
Derek Mendy ◽  
...  
Keyword(s):  
Cell Lines ◽  
Acquired Resistance ◽  
E3 Ligase ◽  
Immunomodulatory Activity ◽  
Employment Equity ◽  
Ic50 Value ◽  
Ic50 Values ◽  
Equity Ownership ◽  
Induction Of Apoptosis ◽  
Low Levels

Lenalidomide- and pomalidomide-based therapies are effective drugs in the treatment of patients with multiple myeloma (MM), however most patients with MM eventually relapse or become resistant. CC-92480, a novel cereblon (CRBN) E3 ligase modulator (CELMoD) with multiple activities including potent immunomodulation and single-agent antiproliferative effects, is being investigated in a phase 1 clinical trial (CC-92480-MM-001; NCT03374085) for patients with relapsed/refractory MM (RRMM). The present study investigates the preclinical data and mechanism of action of CC-92480 in MM models. CELMoD agents bound to CRBN confer differentiated substrate-degradation specificity on the CRL4CRBN E3 ubiquitin ligase. CRBN-modulator agents mediate destruction of Ikaros and Aiolos, transcription factors that contribute to myeloma cell survival. CC-92480 was found to produce rapid, deep, and sustained degradation of Ikaros and Aiolos, with superior antimyeloma activity. Accordingly, in a CRBN protein competitive binding assay, CC-92480 displaced a Cy-5-labeled CELMoD analog from CRBN with a 50% inhibitory concentration (IC50) value of 0.03 μM, whereas lenalidomide competed with an IC50 value of 1.27 μM in the same assay, demonstrating a higher binding affinity of CC-92480 for CRBN. Additionally, CC-92480 promoted the recruitment of Ikaros to the CRBN E3 ligase complex more effectively than pomalidomide in 2 orthogonal CRBN/Ikaros binding assays; it also triggered a more extensive cellular ubiquitination of Ikaros, and a faster, more efficient depletion of cellular Ikaros and Aiolos than pomalidomide. In various MM cell lines, including those with acquired resistance to lenalidomide or pomalidomide and low levels of CRBN, CC-92480 produced robust degradation of Ikaros and Aiolos followed by strong reduction of 2 additional and highly critical transcription factors, c-Myc and interferon regulatory factor 4, which are linked to the induction of apoptosis as measured by cleaved caspase-3. The tumoricidal activity of CC-92480 was shown to be CRBN dependent, since the effect was prevented by complete loss of CRBN or by the stabilization of Ikaros and Aiolos. CC-92480 displayed broad and potent antiproliferative activity across a panel of 20 MM cell lines that are either sensitive, have acquired resistance, or are refractory to lenalidomide or pomalidomide; the cell lines also contained diverse chromosomal translocations and oncogenic drivers typically found in MM patients. Approximately half of the MM cell lines evaluated were highly sensitive to CC-92480, with IC50 values for antiproliferative activity ranging from 0.04 to 5 nM; only 2 cell lines had IC50 values > 100 nM. CC-92480 inhibits cell proliferation and induces apoptosis in MM cell lines that are not sensitive to lenalidomide or pomalidomide. This panel of cell lines includes both refractory cell lines and resistant cell lines generated through continuous exposure to lenalidomide and pomalidomide that acquired low levels of CRBN protein or mutations in the CRBN gene. CC-92480 also induced deep destruction of Ikaros and Aiolos in cultures of peripheral blood mononuclear cells (PBMCs), which led to the activation of T cells and increased production of the cytokines interleukin-2 and interferon gamma. These responses occurred at the range of CC-92480 concentrations that show potent tumoricidal effect against MM cells. The T cell activation and enhanced cytokine production by CC-92480 led to the potent and effective immune-mediated killing of MM cells in co-cultures with PBMCs. CC-92480 is a potent antiproliferative and proapoptotic novel CELMoD with enhanced autonomous cell-killing activity in MM cells that are either sensitive, resistant, or have acquired resistance to lenalidomide and pomalidomide. CC-92480 has a unique and rapid degradation profile stemming from the enhanced efficiency to drive the formation of a protein-protein interaction between Ikaros and Aiolos and CRBN, inducing cytotoxic effects in a CRL4CRBN-dependent fashion that leads ultimately to the induction of apoptosis, even in the context of low or mutated CRBN protein. Additionally, similar to lenalidomide, CC-92480 conserves immunomodulatory activity against MM cells. These data support the clinical investigation of CC-92480 in patients with RRMM. Disclosures Lopez-Girona: Celgene Corporation: Employment. Havens:Pfizer: Employment, Equity Ownership; Celgene: Equity Ownership. Lu:Celgene Corporation: Employment, Equity Ownership. Rychak:Celgene Corporation: Employment, Equity Ownership. Mendy:Celgene Corporation: Employment. Gaffney:Celgene: Employment. Surka:Celgene: Employment, Equity Ownership. Lu:Celgene Corporation: Employment, Equity Ownership. Matyskiela:Celgene corporation: Employment. Khambatta:Celgene: Employment. Wong:Celgene Corporation: Employment, Equity Ownership. Hansen:Celgene Corporation: Employment. Pierce:Celgene Corporation: Employment, Equity Ownership. Cathers:Global Blood Therapeutics (GBT): Employment; Celgene Corporation: Equity Ownership. Carmichael:Celgene plc: Employment, Equity Ownership.

scholarly journals Pretargeted delivery of PI3K/mTOR small-molecule inhibitor–loaded nanoparticles for treatment of non-Hodgkin’s lymphoma

2020 ◽  
Vol 6 (14) ◽  
pp. eaaz9798 ◽  
Author(s):  
Kin Man Au ◽  
Andrew Z. Wang ◽  
Steven I. Park
Keyword(s):  
Small Molecule ◽  
Hodgkin’S Lymphoma ◽  
Kinase Inhibitor ◽  
Drug Carrier ◽  
Hodgkin's Lymphoma ◽  
Therapeutic Window ◽  
Non Hodgkin’S Lymphoma ◽  
Hla Dr ◽  
Non Hodgkin's Lymphoma

Overactivation of the PI3K/mTOR signaling has been identified in non-Hodgkin’s lymphoma. BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity. Here, we developed a nanoparticle (NP)–based pretargeted system for the therapeutic delivery of BEZ235 to CD20- and HLA-DR–expressing lymphoma cells for targeted therapy. The pretargeted system is composed of dibenzocyclooctyne-functionalized anti-CD20 and anti-Lym1 antibodies as the tumor-targeting components and azide-functionalized BEZ235-encapsulated NPs as the effector drug carrier. Using lymphoma cell lines with different CD20 and HLA-DR antigen densities as examples, we demonstrate that the dual antibody pretargeted strategy effectively raises the number of NPs retained on the target tumor cells and improves the in vitro and in vivo antitumor activity of BEZ235 through the inhibition of the PI3K/mTOR pathway. Our data demonstrate that the NP-based pretargeted system improves the therapeutic window of small-molecule kinase inhibitor.

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