Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma

Kang, Yubin; Sundaramoorthy, Pasupathi; Gasparetto, Cristina; Feinberg, Daniel; Fan, Shengjun; Long, Gwynn D.; Sellars, Emily; Garrett, Anderson; Tuchman, Sascha A.; Reeves, Brandi; Li, Zhiguo; Liu, Bei; Öğretmen, Besim; Maines, Lynn W.; Ben-Yair, Vered Katz; Smith, Charles D.; Plasse, Terry F

doi:10.1007/s00277-022-05056-7

Cited by 9 publications

(10 citation statements)

References 58 publications

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“…Plasma concentrations of opaganib peaked at 1-2 h, and declined with a mean half-time of 5-15 h. Doses of opaganib that have therapeutic efficacy in mouse xenograft models provide a C max of ~3.5 µg/mL [37], a drug level that was achieved by 33%, 75%, and 100% of patients treated with 250, 500, and 750 mg of opaganib, respectively. In a second clinical trial of opaganib, 58% of patients with refractory multiple myeloma achieved stable disease or better, and patients had decreased plasma levels of TNFα, EGF, and VEGF [50]. Opaganib has also been assessed in hospitalized patients with severe COVID-19 and is completing Phase 2 clinical testing in patients with cholangiocarcinoma (ClinicalTrials.gov Identifier: NCT03377179) or prostate cancer (ClinicalTrials.gov Identifier: NCT04207255).…”

Section: Discussionmentioning

confidence: 99%

Opaganib Downregulates N-Myc Expression and Suppresses In Vitro and In Vivo Growth of Neuroblastoma Cells

Maines,

Keller,

Smith

et al. 2024

Cancers

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Neuroblastoma (NB), the most common cancer in infants and the most common solid tumor outside the brain in children, grows aggressively and responds poorly to current therapies. We have identified a new drug (opaganib, also known as ABC294640) that modulates sphingolipid metabolism by inhibiting the synthesis of sphingosine 1-phosphate (S1P) by sphingosine kinase-2 and elevating dihydroceramides by inhibition of dihydroceramide desaturase. The present studies sought to determine the potential therapeutic activity of opaganib in cell culture and xenograft models of NB. Cytotoxicity assays demonstrated that NB cells, including cells with amplified MYCN, are effectively killed by opaganib concentrations well below those that accumulate in tumors in vivo. Opaganib was shown to cause dose-dependent decreases in S1P and hexosylceramide levels in Neuro-2a cells, while concurrently elevating levels of dihydroceramides. As with other tumor cells, opaganib reduced c-Myc and Mcl-1 protein levels in Neuro-2a cells, and also reduced the expression of the N-Myc protein. The in vivo growth of xenografts of human SK-N-(BE)2 cells with amplified MYCN was suppressed by oral administration of opaganib at doses that are well tolerated in mice. Combining opaganib with temozolomide plus irinotecan, considered the backbone for therapy of relapsed or refractory NB, resulted in increased antitumor activity in vivo compared with temozolomide plus irinotecan or opaganib alone. Mice did not lose additional weight when opaganib was combined with temozolomide plus irinotecan, indicating that the combination is well tolerated. Opaganib has additive antitumor activity toward Neuro-2a tumors when combined with the checkpoint inhibitor anti-CTLA-4 antibody; however, the combination of opaganib with anti-PD-1 or anti-PD-L1 antibodies did not provide increased antitumor activity over that seen with opaganib alone. Overall, the data demonstrate that opaganib modulates sphingolipid metabolism and intracellular signaling in NB cells and inhibits NB tumor growth alone and in combination with other anticancer drugs. Amplified MYCN does not confer resistance to opaganib, and, in fact, the drug attenuates the expression of both c-Myc and N-Myc. The safety of opaganib has been established in clinical trials with adults with advanced cancer or severe COVID-19, and so opaganib has excellent potential for treating patients with NB, particularly in combination with temozolomide and irinotecan or anti-CTLA-4 antibody.

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Section: Discussionmentioning

confidence: 99%

Opaganib Downregulates N-Myc Expression and Suppresses In Vitro and In Vivo Growth of Neuroblastoma Cells

Maines,

Keller,

Smith

et al. 2024

Cancers

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“…ABC294640 is currently undergoing phase I/II clinical trials for myeloma (see trial NCT01410981) [ 32 , 60 ]. ABC294640 induces proteasome degradation and the downregulation of Mcl-1 and c-Myc but has no effect on Bcl-2 expression [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Sphingosine Kinase 2 Results in PARK2-Mediated Mitophagy and Induces Apoptosis in Multiple Myeloma

Fan

Feinberg

et al. 2023

Current Oncology

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Mitophagy plays an important role in maintaining mitochondrial homeostasis by clearing damaged mitochondria. Sphingosine kinase 2 (SK2), a type of sphingosine kinase, is an important metabolic enzyme involved in generating sphingosine-1-phosphate. Its expression level is elevated in many cancers and is associated with poor clinical outcomes. However, the relationship between SK2 and mitochondrial dysfunction remains unclear. We found that the genetic downregulation of SK2 or treatment with ABC294640, a specific inhibitor of SK2, induced mitophagy and apoptosis in multiple myeloma cell lines. We showed that mitophagy correlates with apoptosis induction and likely occurs through the SET/PP2AC/PARK2 pathway, where inhibiting PP2AC activity may rescue this process. Furthermore, we found that PP2AC and PARK2 form a complex, suggesting that they might regulate mitophagy through protein–protein interactions. Our study demonstrates the important role of SK2 in regulating mitophagy and provides new insights into the mechanism of mitophagy in multiple myeloma.

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“…Therefore, the development of therapies targeting S1P signaling requires the selection of target patient groups, the development of S1P signaling inhibitors, and consideration of combination therapy with anti-cancer drugs and molecular-targeted drugs. A variety of agents have been developed to regulate S1P signaling, each with different targets, and clinical development strategies must be tailored to the pathophysiology of the cancer [ 181 , 226 , 227 , 228 , 229 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , 242 , 243 , 244 , 245 , 246 , 247 ]. S1P signaling inhibitors developed to date, which could be applied to cancer therapy, are listed in Table 1 .…”

Section: Targeting S1p As Therapy For Advanced Breast Cancermentioning

confidence: 99%

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer

Nagahashi,

Miyoshi

2024

IJMS

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In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary. Sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including involvement in cancer cell proliferation, invasion, and metastasis. S1P also contributes to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system. In this article, we outline the basic mechanism of action of S1P, summarize previous findings on the function of S1P in cancer cells and the cancer microenvironment, and discuss the clinical significance of S1P in breast cancer and the therapeutic potential of targeting S1P signaling.

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Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma

Cited by 9 publications

References 58 publications

Opaganib Downregulates N-Myc Expression and Suppresses In Vitro and In Vivo Growth of Neuroblastoma Cells

Opaganib Downregulates N-Myc Expression and Suppresses In Vitro and In Vivo Growth of Neuroblastoma Cells

Inhibition of Sphingosine Kinase 2 Results in PARK2-Mediated Mitophagy and Induces Apoptosis in Multiple Myeloma

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer

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