Browsing by Subject "Proteasome inhibitors"

Now showing 1 - 3 of 3
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    CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis
    (American Society for Cell Biology, 2013) Teske, Brian F.; Fusakio, Michael E.; Zhou, Donghui; Shan, Jixiu; McClintick, Jeanette N.; Kilberg, Michael S.; Wek, Ronald C.; Biochemistry and Molecular Biology, School of Medicine
    Environmental stresses that disrupt protein homeostasis induce phosphorylation of eIF2, triggering repression of global protein synthesis coincident with preferential translation of ATF4, a transcriptional activator of the integrated stress response (ISR). Depending on the extent of protein disruption, ATF4 may not be able to restore proteostatic control and instead switches to a terminal outcome that features elevated expression of the transcription factor CHOP (GADD153/DDIT3). The focus of this study is to define the mechanisms by which CHOP directs gene regulatory networks that determine cell fate. We find that in response to proteasome inhibition, CHOP enhances the expression of a collection of genes encoding transcription regulators, including ATF5, which is preferentially translated during eIF2 phosphorylation. Transcriptional expression of ATF5 is directly induced by both CHOP and ATF4. Knockdown of ATF5 increases cell survival in response to proteasome inhibition, supporting the idea that both ATF5 and CHOP have proapoptotic functions. Transcriptome analysis of ATF5-dependent genes reveals targets involved in apoptosis, including NOXA, which is important for inducing cell death during proteasome inhibition. This study suggests that the ISR features a feedforward loop of stress-induced transcriptional regulators, each subject to transcriptional and translational control, which can switch cell fate toward apoptosis.
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    P947: Comparative Effectiveness of Oral Ixazomib-Lenalidomide-Dexamethasone (Ird) After Initial Bortezomib (V)-Based Induction vs. Parenteral V-Based Therapy in Newly Diagnosed Multiple Myeloma (Ndmm)
    (Wolters Kluwer, 2022-06-23) Rifkin, R.M.; Costello, C.L.; Birhiray, R.E.; Kambhampati, S.; Richter, J.; Abonour, R.; Lee, H.C.; Kim, Y.J.; Ren, K.; Stull, D.M.; Cherepanov, D.; Bogard, K.; Noga, S.J.; Girnius, S.; Medicine, School of Medicine
    Background: Long-term proteasome inhibitor (PI)-based treatment can improve outcomes for patients (pts) with multiple myeloma (MM). However, prolonged parenteral PI therapy (e.g. with V) can be challenging to achieve in routine clinical practice, and outcomes for pts are often poorer in this setting compared with clinical trials. The phase IV, community-based, single-arm US MM-6 study (NCT03173092) is assessing in-class transition (iCT) from V-based induction to all-oral IRd in transplant ineligible NDMM pts treated in routine clinical practice, with the objective of increasing the duration of PI-based treatment while maintaining quality of life. INSIGHT MM is the largest global, prospective, observational study of MM pts (>4,200), and provided a subset of patients as the comparator cohort. This enabled assessment of iCT vs V-based therapy in NDMM pts in routine clinical practice in the US. Aims: To examine the comparative effectiveness of IRd following initial V-based induction (3 cycles; US MM-6 pts; ‘IRd’ cohort) vs continued V-based therapy (INSIGHT MM pts; ‘V-based’ cohort) in NDMM pts. Methods: A secondary analysis of non-transplant eligible US NDMM pts with ≥stable disease after 3 cycles of V-based induction and baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1 or 2 from the US MM-6 (Manda CLML 2020) and INSIGHT MM (Costello Future Onc 2019) studies was performed. Study outcomes included first-line duration of treatment (DOT), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and reasons for treatment discontinuation. All analyses were weighted using the inverse probability of treatment weighting (IPTW) approach to reduce the imbalance of potential confounding factors between the two cohorts (adjusted analyses). Kaplan–Meier methods were used to examine DOT, PFS, OS, and associated 95% confidence intervals (CIs); the log-rank test was used to compare distribution of time to events. The Clopper-Pearson method was applied to estimate 95% CIs for ORR. Statistical significance was evaluated at alpha=0.05. Results: 100 pts from the IRd cohort (MM-6) and 111 pts from the V-based cohort (INSIGHT) were included. After IPTW, in the IRd vs V-based cohorts: median age was 75.0 vs 74.8 yrs; 56.7 vs 51.3% of pts were male; 37.4 vs 29.1% had an ECOG PS of ≥2; 48.8 vs 41.4% had International Staging System stage III at initial diagnosis, and 79.5/17.7/2.8 vs 77.3/19.5/3.1% pts had received VRd/ V-cyclophosphamide-d (VCd)/ VRCd as initial induction therapy. Adjusted ORRs in the IRd vs V-based cohorts were 74.1 (95% CI 66.0–82.2) vs 57.5% (95% CI 47.9–67.1; p<0.0001). After a median follow-up of 20.3 and 15.8 months in the IRd and V-based cohorts, respectively, DOT was 10.8 (95% CI 6.5–24.4) vs 5.3 months (95% CI 4.3–7.0; p<0.0001) (see Figure). Median PFS was not estimable (NE) in either cohort; 24-month PFS rates were 85.7 (95% CI 68.1–94.0; IRd cohort) vs 76.5% (95% CI 62.6–85.8; V-based cohort). Median OS was NE in either cohort; 24-month OS rates were 94.0 (95% CI 77.7–98.5; IRd cohort) vs 84.9% (95% CI 70.6–92.6; V-based cohort). In the IRd and V-based cohorts, 16.8 and 16.9% of pts discontinued IRd and V, respectively, due to an adverse event. Summary/Conclusion: US MM-6 NDMM pts who transitioned to IRd after 3 initial cycles of V-based induction had a significantly higher ORR and longer DOT compared with pts who received continued V-based therapy in INSIGHT MM. The results suggest that iCT from continued V-based therapy to all-oral IRd may improve outcomes in pts treated at community oncology clinics.
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    Pharmacologic targeting of the p62 ZZ domain enhances both anti-tumor and bone-anabolic effects of bortezomib in multiple myeloma
    (Ferrata Storti Foundation, 2024-05-01) Marino, Silvia; Petrusca, Daniela N.; Bishop, Ryan T.; Anderson, Judith L.; Sabol, Hayley M.; Ashby, Cody; Layer, Justin H.; Cesarano, Annamaria; Davé, Utpal P.; Perna, Fabiana; Delgado-Calle, Jesus; Chirgwin, John M.; Roodman, G. David; Medicine, School of Medicine
    Multiple myeloma (MM) is a malignancy of plasma cells whose antibody secretion creates proteotoxic stress relieved by the N-end rule pathway, a proteolytic system that degrades N-arginylated proteins in the proteasome. When the proteasome is inhibited, protein cargo is alternatively targeted for autophagic degradation by binding to the ZZ-domain of p62/ sequestosome-1. Here, we demonstrate that XRK3F2, a selective ligand for the ZZ-domain, dramatically improved two major responses to the proteasome inhibitor bortezomib (Btz) by increasing: i) killing of human MM cells by stimulating both Btz-mediated apoptosis and necroptosis, a process regulated by p62; and ii) preservation of bone mass by stimulating osteoblast differentiation and inhibiting osteoclastic bone destruction. Co-administration of Btz and XRK3F2 inhibited both branches of the bimodal N-end rule pathway exhibited synergistic anti-MM effects on MM cell lines and CD138+ cells from MM patients, and prevented stromal-mediated MM cell survival. In mice with established human MM, co-administration of Btz and XRK3F2 decreased tumor burden and prevented the progression of MM-induced osteolytic disease by inducing new bone formation more effectively than either single agent alone. The results suggest that p62-ZZ ligands enhance the anti- MM efficacy of proteasome inhibitors and can reduce MM morbidity and mortality by improving bone health.