Abstract
Plitidepsin is a marine-derived anticancer compound isolated from the Mediterranean tunicate Applidium albicans. It exerts pleiotropic effects on cancer cells, most likely by binding to the eukaryotic translation eEF1A2. This ultimately leads to cell-cycle arrest, growth inhibition and induction of apoptosis via multiple pathway alterations. Recently, a Phase III randomized trial in patients with relapsed/refractory multiple myeloma reported outcomes for plitidepsin plus dexamethasone compared with dexamethasone. Median progression-free survival was 3.8 months in the plitidepsin arm and 1.9 months in the dexamethasone arm (HR: 0.611; p = 0.0048). Here, we review preclinical data regarding plitidepsins mechanism of action, give an overview of clinical trial results across different tumor types as well as the latest results in multiple myeloma.
Papers of special note have been highlighted as: • of interest
References
- 1 . Cancer statistics, 2018. CA Cancer J. Clin. 68(1), 7–30 (2018).
- 2 Global Burden of Disease Cancer Collaboration; Global, regional and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 3(4), 524–548 (2017).
- 3 . How I treat myeloma with new agents. Blood 130(13), 1507–1513 (2017).
- 4 Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 28(Suppl. 4), iv52–iv61 (2017).
- 5 Randomized Phase III study (ADMYRE) of plitidepsin in combination with dexamethasone versus dexamethasone alone in patients with relapsed/refractory multiple myeloma. Blood 130, 1886 (2017). • Includes the most recent Phase III data in multiple myeloma.
- 6 . Where we were, where we are, where we are going: progress in multiple myeloma. Am. Soc. Clin. Oncol. Educ. Book 2014, 199–203 (2014).
- 7 ClinicalTrials.gov.com (2018). www.clinicaltrials.gov.
- 8 Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated cytotoxicity in multiple myeloma. Br. J. Haematol. 174(6), 911–922 (2016).
- 9 Didemnins: antiviral and antitumor depsipeptides from a caribbean tunicate. Science 212(4497), 933–935 (1981).
- 10 . Biochemical and cellular effects of didemnins A and B. Cancer Res. 44(5), 1796–1801 (1984).
- 11 . GTP-dependent binding of the antiproliferative agent didemnin to elongation factor 1α. J. Biol. Chem. 269(22), 15411–15414 (1994).
- 12 Phase II clinical trial of didemnin B in previously treated small-cell lung cancer. Invest. New Drugs 12(3), 243–249 (1994).
- 13 . Phase II trail of didemnin B in previously treated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group (ECOG) Study. Am. J. Clin. Oncol. 23(3), 273–277 (2000).
- 14 Structure–activity relationships of the didemnins. J. Med. Chem. 39(14), 2819–2834 (1996).
- 15 Aplidin synergizes with cytosine arabinoside: functional relevance of mitochondria in aplidin-induced cytotoxicity. Leukemia 21(12), 2399–2405 (2007).
- 16 Translation elongation factor eEF1A2 is a novel anticancer target for the marine natural product plitidepsin. Sci. Rep. 6, 35100 (2016). • Contains recent insights into the mechanism of action of plitidepsin.
- 17 . Mouse translation elongation factor eEF1A-2 interacts with Prdx-I to protect cells against apoptotic death induced by oxidative stress. J. Cell. Biochem. 100(2), 267–278 (2007).
- 18 . Upregulation of eEF1A2 promotes proliferation and inhibits apoptosis in prostate cancer. Biochem. Biophys. Res. Commun. 450(1), 1–6 (2014).
- 19 Interaction of the eukaryotic elongation factor 1A with newly synthesized polypeptides. J. Biol. Chem. 277(21), 18545–18551 (2002).
- 20 Eef1a2 promotes cell growth, inhibits apoptosis and activates JAK/STAT and AKT signaling in mouse plasmacytomas. PLoS ONE 5(5), e10755 (2010).
- 21 Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C delta. Oncogene 21(49), 7533–7544 (2002).
- 22 Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK. J. Biol. Chem 278(1), 241–250 (2003).
- 23 . JNK activation is critical for aplidin-induced apoptosis. Oncogene 23(27), 4673–4680 (2004).
- 24 Aplidin induces JNK-dependent apoptosis in human breast cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation and MKP-1 phosphatase downregulation. Cell Death Differ. 13(11), 1968–1981 (2006).
- 25 JNK-dependent release of mitochondrial protein, smac, during apoptosis in multiple myeloma (MM) cells. J. Biol. Chem. 278(20), 17593–17596 (2003).
- 26 . Rapid and selective apoptosis in human leukemic cells induced by aplidine through a Fas/CD95- and mitochondrial-mediated mechanism. Clin. Cancer Res. 9(4), 1535–1545 (2003).
- 27 . Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy. J. Biol. Chem. 280(12), 11641–11647 (2005).
- 28 Constitutive expression of Fas (Apo-1/CD95) ligand on multiple myeloma cells: a potential mechanism of tumor-induced suppression of immune surveillance. Blood 90(1), 12–20 (1997).
- 29 Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4. Leukemia 17(1), 52–59 (2003).
- 30 Antiangiogenic activity of aplidine, a new agent of marine origin. Br. J. Cancer 90(12), 2418–2424 (2004).
- 31 . VEGF inhibition and cytotoxic effect of aplidin in leukemia cell lines and cells from acute myeloid leukemia. Ann. Oncol. 16(10), 1667–1674 (2005).
- 32 Aplidin reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes. Cancer Chemother. Pharmacol. 57(1), 7–14 (2006).
- 33 The cytotoxic activity of aplidin in chronic lymphocytic leukemia (CLL) is mediated by a direct effect on leukemic cells and an indirect effect on monocyte-derived cells. Invest. New Drugs 30(5), 1830–1840 (2012).
- 34 Aplidin, a marine organism-derived compound with potent antimyeloma activity in vitro and in vivo. Cancer Res. 68(13), 5216–5225 (2008). • Contains in vitro experiments with plitidepsin in multiple myeloma.
- 35 . Establishment and characterisation of a human carcinoma cell line with acquired resistance to aplidin. Br. J. Cancer 91(7), 1405–1413 (2004).
- 36 Proteomic analysis of the resistance to aplidin in human cancer cells. J. Proteome Res. 6(4), 1286–1294 (2007).
- 37 Phase I clinical and pharmacokinetic study of plitidepsin as a 1-h weekly intravenous infusion in patients with advanced solid tumors. Clin. Cancer Res. 14(10), 3105–3112 (2008).
- 38 Metabolite profiling of the novel anticancer agent, plitidepsin, in urine and faeces in cancer patients after administration of (14) C-plitidepsin. Cancer Chemother. Pharmacol. (2018) (Epub ahead of print).
- 39 Phase I and pharmacokinetic study of Aplidine, a new marine cyclodepsipeptide in patients with advanced malignancies. J. Clin. Oncol. 23(31), 7871–7880 (2005). • First in human trial of plitidepsin.
- 40 Phase I study of aplidine in a dailyx5 1-hour infusion every 3 weeks in patients with solid tumors refractory to standard therapy National Cancer Institute of Canada Clinical Trials Group study: NCIC CTG IND 115. Ann. Oncol. 17(9), 1371–1378 (2006).
- 41 Phase I clinical and pharmacokinetic study of the marine compound aplidin (APL) administered as a 3-hour infusion every 2 weeks. Proc. Am. Soc. Clin. Oncol. 21, Abstract 422 (2002).
- 42 . Phase I and pharmacokinetic (PK) study of aplidin (APL) using a 24-hour weekly schedule. Proc. Am. Soc. Clin. Oncol. 19, Abstract 734 (2000).
- 43 Phase II study of plitidepsin in pretreated patients with locally advanced or metastatic non-small cell lung cancer. Lung Cancer 60(3), 374–380 (2008).
- 44 Phase II randomized study of plitidepsin (aplidin), alone or in association with L-carnitine, in patients with unresectable advanced renal cell carcinoma. Mar. Drugs 7(1), 57–70 (2009).
- 45 Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer. Lung Cancer 64(1), 60–65 (2009).
- 46 Phase II study of biweekly plitidepsin as second-line therapy in patients with advanced malignant melanoma. Melanoma Res. 19(3), 185–192 (2009).
- 47 Phase II study of biweekly plitidepsin as second-line therapy for advanced or metastatic transitional cell carcinoma of the urothelium. Mar. Drugs 7(3), 451–463 (2009).
- 48 . Phase II study of plitidepsin 3-hour infusion every 2 weeks in patients with unresectable advanced medullary thyroid carcinoma. Am. J. Clin. Oncol. 33(1), 83–88 (2010).
- 49 Evaluation of plitidepsin in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical studies and a Phase II clinical trial. Blood Cancer J. 5, e286 (2015).
- 50 Aplidin in patients with advanced dedifferentiated liposarcomas: a French Sarcoma Group single-arm Phase II study. Ann. Oncol. 26(7), 1465–1470 (2015).
- 51 Multicenter Phase II study of plitidepsin in patients with relapsed/refractory non-Hodgkin's lymphoma. Haematologica 98(3), 357–363 (2013).
- 52 Phase I study of weekly plitidepsin as 1-hour infusion combined with carboplatin in patients with advanced solid tumors or lymphomas. Invest. New Drugs 29(6), 1406–1413 (2011).
- 53 Phase I dose-escalation study of plitidepsin in combination with bevacizumab in patients with refractory solid tumors. Anticancer Drugs 27(10), 1021–1027 (2016).
- 54 Phase II clinical and pharmacokinetic study of plitidepsin 3-hour infusion every two weeks alone or with dexamethasone in relapsed and refractory multiple myeloma. Clin. Cancer Res. 16(12), 3260–3269 (2010). • The first Phase II trial in MM.
- 55 Phase I–II study of plitidepsin and dacarbazine as first-line therapy for advanced melanoma. Br. J. Cancer 109(6), 1451–1459 (2013).
- 56 Phase I dose-escalation study of plitidepsin in combination with sorafenib or gemcitabine in patients with refractory solid tumors or lymphomas. Anticancer Drugs 28(3), 341–349 (2017).
- 57 . Carnitine palmitoyltransferase II deficiency: molecular and biochemical analysis of 32 patients. Neurology 60(8), 1351–1353 (2003).
- 58 Adjusting survival time estimates to account for treatment switching in randomized controlled trials: an economic evaluation context: methods, limitations and recommendations. Med. Decis. Making 34(3), 387–402 (2014).
- 59 . Cytotoxicity and neurocytotoxicity of new marine anticancer agents evaluated using in vitro assays. Cancer Chemother. Pharmacol. 44(4), 312–318 (1999).
- 60 . In vitro toxicity of three new antitumoral drugs (trabectedin, aplidin, and kahalalide F) on hematopoietic progenitors and stem cells. Exp. Hematol. 31(11), 1104–1111 (2003).
- 61 . In vitro toxicity of ET-743 and aplidine, two marine-derived antineoplastics, on human bone marrow haematopoietic progenitors. Comparison with the clinical results. Eur. J. Cancer 38(10), 1395–1404 (2002).
- 62 . Aplidine: a paradigm of how to handle the activity and toxicity of a novel marine anticancer poison. Curr. Pharm. Des. 13(33), 3427–3439 (2007).
- 63 Plitidepsin has a safe cardiac profile: a comprehensive analysis. Mar. Drugs 9(6), 1007–1023 (2011).
- 64 European Medicines Agency (2018). www.ema.europa.eu.
- 65 Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomized, open-label, Phase III trial. Lancet Oncol. 14(11), 1055–1066 (2013).