Aplidin (plitidepsin)

To rationalize possible combinations, the efficacy in the Gata1low model of drugs currently used for these patients (the JAK1/2 inhibitor Ruxolitinib) was compared with that of drugs targeting other abnormalities, such as p27kip1 (Aplidin), TGF-β (SB431542, inhibiting ALK5 downstream to transforming growth factor beta (TGF-β) signaling and TGF-β trap AVID200), P-selectin (RB40.34), and CXCL1 (Reparixin, inhibiting the CXCL1 receptors CXCR1/2). None of the drugs reduced osteopetrosis. These results suggest that future therapies for myelofibrosis should consider combining JAK1/2 inhibitors with drugs targeting hematopoietic stem cells (p27Kip1) or the pro-inflammatory milieu (TGF-β or CXCL1).

Among them, plitidepsin was approved for the treatment of multiple myeloma whereas metarrestin was currently under clinical development. Despite significant achievements in these two interrelated fields, hitherto there lacks a systematic examination of the eEF1A protein in the context of cancer research. Therefore, the present work aims to delineate its clinical implications, molecular oncogenic mechanisms, and targeted therapeutic strategies as reflected in the ever expanding body of literature, so as to deepen mechanistic understanding of eEF1A-involved tumorigenesis and inspire the development of eEF1A-targeted chemotherapeutics and biologics.

However, despite the massive increase in the number of marine natural products classified as 'anticancer leads,' most of which correspond to general cytotoxic agents, and only a few have been characterized regarding their molecular targets and mechanisms of action. The current review presents a critical analysis of inhibitors of HIF-1 and HIF-2 and hypoxia-selective compounds that have been sourced from marine organisms and that might act as new chemotherapeutic candidates or serve as templates for the development of structurally similar derivatives with improved anticancer efficacy.

P2, N=37, Terminated, PharmaMar | N=150 --> 37 | Active, not recruiting --> Terminated; Significant difficulties in the recruitment of patients

P2, N=150, Active, not recruiting, PharmaMar | Recruiting --> Active, not recruiting | Trial completion date: Jul 2025 --> Apr 2024 | Trial primary completion date: Jun 2025 --> Mar 2024

P2, N=150, Recruiting, PharmaMar

EEF1A2 exhibits angiogenic potential in both normoxic and hypoxic conditions, underscoring its dual role in promoting EMT and angiogenesis, rendering it a promising target for cancer therapy.

P2, N=150, Recruiting, PharmaMar | Trial completion date: Aug 2024 --> Jul 2025 | Trial primary completion date: Jul 2024 --> Jun 2025

Sixty percent (3/5) had received 6 cycles of obitunuzumab and bendamustine (the last dose in patients 1 and 2 were administered 2 years prior to admission). Patients 2 and 5 had received rituximab maintenance, the last dose being administered in both < 2 months prior to admission for SARS-CoV-2. Patient 3 had received 6 cycles of obinutuzumab-COMP and maintenance with obinutuzumab, with the last dose administered 9 months before admission for SARS-COV-2... Plitidepsin shows a good safety profile in patients with NHL and SARS-CoV-2 infection. Four of the 5 patients presented resolution of SARS-CoV-2 infection. Prospective studies are needed to confirm the effectiveness of plitidepsin as a treatment for SARS-CoV-2 infection in patients with NHL who have received immunochemotherapy.

These data support plitidepsin as a well-tolerated treatment that might have potential clinical and antiviral efficacy in COVID-19 immunocompromised patients.

P2, N=150, Recruiting, PharmaMar | Not yet recruiting --> Recruiting | Trial completion date: Feb 2024 --> Jul 2024 | Trial primary completion date: Feb 2024 --> Jul 2024

Consistently, eEF1A has proven to be targeted by a wide assortment of small molecules with excellent anticancer activity, among which plitidepsin has been granted approval for the treatment of multiple myeloma...The present review summarizes recent advances in eEF1A-targeting anticancer agents, both naturally occurring and synthetically crafted, with regard to their discovery or design, target identification, structure-activity relationship, and mode of action. Their structural diversity and differential eEF1A-targeting mechanisms warrant continuing research in pursuit of curing eEF1A-driven malignancy.

P2, N=150, Not yet recruiting, PharmaMar

P2, N=150, Ongoing, Pharma Mar, S.A.

In respect to its potent anti-SARS-CoV-2 properties, the drug has demonstrated superior ex vivo efficacy compared to other host-directed agents and remdesivir, and it might retain its antiviral effect against the more transmittable B.1.1.7 variant. A phase III trial is being planned to compare the plitidepsin-dexamethasone regimen to the current standard of care only in moderately affected hospitalized patients. Despite plitidepsin's preclinical efficacy, current clinical evidence is inadequate for its registration in COVID-19 patients.Therefore, multicentre trials on the drug's efficacy, potentially also studying populations of emerging SARS-CoV-2 lineages, are warranted.

Large randomized clinical trials that aimed to test four repurposed drugs, hydroxychloroquine, lopinavir-ritonavir, interferon beta 1a, and remdesivir, have shown that these compounds lack an impact on the COVID-19 course. Plitidepsin has shown efficacy in animal models and Phase I/II human trials. Although plitidepsin is administered intravenously and its toxicity profile remains to be fully characterized, this compound may be a promising alternative COVID-19 therapeutic.