Pharmacodynamic markers and clinical results from the phase 2 study of the <scp>SMAC</scp> mimetic birinapant in women with relapsed platinum‐resistant or ‐refractory epithelial ovarian cancer

Noonan, Anne; Bunch, Kristen; Chen, Jin‐Qiu; Herrmann, Michelle A.; Lee, Jung‐Min; Kohn, Elise C.; O’Sullivan, Ciara C.; Jordan, Elizabeth; Houston, Nicole; Takebe, Naoko; Kinders, Robert J.; Cao, Liang; Peer, Cody J.; Figg, William D.; Annunziata, Christina M.

doi:10.1002/cncr.29783

Cited by 78 publications

(69 citation statements)

References 31 publications

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“…To focus on physiologically achievable concentrations of the IAP antagonists, we set the upper limit of their concentrations at 10 μM, slightly higher than the GDC-0152 peak plasma concentration (7 μM [24]). Pharmacokinetic data have not been published for SM-164, but the levels of LCL-161 [31] and Birinapant [61] detected in the blood of treated patients resembled those of GDC-0152, so it seems likely that SM-164 may also reach similar levels in vivo .…”

Section: Resultsmentioning

confidence: 99%

IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

et al. 2016

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Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors.

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Section: Resultsmentioning

confidence: 99%

IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

et al. 2016

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“…The Smac mimetic, Birinapant is undergoing clinical evaluation to treat refractory haematological and solid tumours, including lymphoma (Amaravadi et al, 2015) and epithelial ovarian cancer (Noonan et al, 2016). Flavopiridol decreases XIAP and is under investigation for the treatment of chronic lymphocytic leukemia (Awan et al, 2016; Blachly et al, 2016).…”

Section: Pro-apoptotic Compounds To Clear Hiv Latently Infected T-cellsmentioning

confidence: 99%

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Kim

Anderson

Lewin

2018

Cell Host & Microbe

298

351

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Despite the success of antiretroviral therapy (ART), there is currently no HIV cure and treatment is lifelong. HIV persists during ART due to long lived and proliferating latently infected CD4+ T-cells. One strategy to eliminate latency is to activate virus production using latency reversing agents (LRAs) with the goal of triggering cell death through virus-induced cytolysis or immune-mediated clearance. However, multiple studies have demonstrated that activation of viral transcription alone is insufficient to induce cell death and some LRAs may counteract cell death by promoting cell survival. Here, we review new approaches to induce death of latently infected cells through apoptosis and inhibition of pathways critical for cell survival, which are often hijacked by HIV proteins. Given advances in the commercial development of compounds that induce apoptosis in cancer chemotherapy, these agents could move rapidly into clinical trials, either alone or in combination with LRAs, to eliminate latent HIV infection.

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“…In the phase 2 setting, prospectively collected correlative studies demonstrated good penetration of drug into tumors, and consistent target downregulation of cIAP1 protein in tumor tissue (61). Similar compounds are moving forward in clinical development in combination regimens with standard chemotherapy and novel therapeutic agents.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: The Balance between Cancer and the Immune System Challenges the Therapeutic Specificity of Targeting Nuclear Factor-κB Signaling for Cancer Treatment

Zeligs

Neuman

Annunziata

2016

Clinical Cancer Research

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The Nuclear Factor-κB (NF-κB) signaling pathway is a complex network linking extracellular stimuli to cell survival and proliferation. Cytoplasmic signaling to activate NF-kB can occur as part of the DNA damage response or in response to a large variety of activators including viruses, inflammation, and cell death. NF-κB transcription factors play a fundamental role in tumorigenesis and are implicated in the origination and propagation of both hematologic and solid tumor types, including melanoma, breast, prostate, ovarian, pancreatic, colon, lung, and thyroid cancers. On the other hand, NF-kB signaling is key to immune function, and is likely necessary for anti-tumor immunity. This presents a dilemma when designing therapeutic approaches to target NF-kB. There is growing interest in identifying novel modulators to inhibit NF-κB activity since impeding different steps of the NF-κB pathway has potential to slow tumor growth, progression, and resistance to chemotherapy. Despite significant advances in our understanding of this pathway, our ability to effectively clinically block key targets for cancer therapy remains limited due to on-target effects in normal tissues. Tumor specificity is critical to developing therapeutic strategies targeting this anti-apoptotic signaling pathway in order to maintain anti-tumor immune surveillance when applying such therapy to patients.

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Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum‐resistant or ‐refractory epithelial ovarian cancer

Cited by 78 publications

References 31 publications

IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Molecular Pathways: The Balance between Cancer and the Immune System Challenges the Therapeutic Specificity of Targeting Nuclear Factor-κB Signaling for Cancer Treatment

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