plocabulin (PM184) / PharmaMar - LARVOL DELTA

Total Syntheses of Plocabulin and Its C2-Analogues. (PubMed, Org Lett) - "In this study, we present a convergent synthetic strategy for plocabulin and its C2-analogues. Our approach enabled the synthesis of 1.23 g of plocabulin through a longest linear sequence of 12 steps and a total of 24 steps, achieving an overall yield of 19.7%."

Journal • Oncology

A phase I safety and efficacy clinical trial of plocabulin and gemcitabine in patients with advanced solid tumors. (PubMed, Invest New Drugs) - "No PK drug-drug interaction was found. The most encouraging outcome occurred in ovarian cancer patients."

Journal • Metastases • P1 data • Fatigue • Gastrointestinal Disorder • Hematological Disorders • Neutropenia • Oncology • Ovarian Cancer • Pain • Solid Tumor • Thrombocytopenia

Safety and efficacy of PM060184 plus gemcitabine in advanced solid tumors (ESMO 2023) - P1 | "No PK drug-drug interaction was found. While ORR was modest overall, the most encouraging outcome occurred in ovarian cancer pts."

Clinical • Metastases • Oncology • Ovarian Cancer • Solid Tumor

Effect of the Marine Polyketide Plocabulin on Tumor Progression. (PubMed, Mar Drugs) - "Plocabulin showed potent antitumor activity, in both in vitro and in vivo models of different types of cancers, mediated not only by its antitubulin activity, but also by its ability to block endothelial cell migration and invasion. The objective of this review is to offer a description of plocabulin's mechanisms of action, with special emphasis on the antiangiogenic signals and the latest progress on its development as an anticancer agent."

Journal • Review • Oncology

From seaside to bedside: Current evidence and future perspectives in the treatment of breast cancer using marine compounds. (PubMed, Front Pharmacol) - "The main marine-derived drugs that have been studied for the treatment of BC are tubulin-binding agents (eribulin and plocabulin), DNA-targeting agents (cytarabine and minor groove binders-trabectedin and lurbinectedin) and Antibody-Drug Conjugates (ADCs)...Among these, clinical data are available on ladiratuzumab vedotin and glembatumumab vedotin in TNBC, and on disitamab vedotin and ALT-P7 in HER2-positive patients. A deeper knowledge of the mechanism of action and of the potential predictive factors for response to marine-derived drugs is important for their rational and effective use, alone or in combination. In this narrative review, we discuss the role of marine-derived drugs for the treatment of BC, although most of them are not approved, and the opportunities that could arise from the potential treasure trove of the sea for novel BC therapeutics."

Journal • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • HER-2

Plocabulin, a Novel Tubulin Inhibitor, Has Potent Antitumour Activity in Patient-Derived Xenograft Models of Soft Tissue Sarcoma. (PubMed, Int J Mol Sci) - "The treatment lasted 22 days, and the efficacy of the drug was assessed and compared to the doxorubicin and vehicle groups by volumetric analysis, histopathology and immunohistochemistry. Our results demonstrate the in vivo efficacy of plocabulin in the preclinical models of soft tissue sarcoma and corroborate the findings of our previous study, which demonstrated similar vascular-disruptive effects in gastrointestinal stromal tumours-another subtype of soft tissue sarcoma. Our data provide a convincing rationale for further clinical exploration of plocabulin in soft tissue sarcomas."

Journal • Preclinical • Gastrointestinal Cancer • Gastrointestinal Disorder • Leiomyosarcoma • Liposarcoma • Oncology • Rare Diseases • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Antitumoral Effect of Plocabulin in High Grade Serous Ovarian Carcinoma Cell Line Models. (PubMed, Front Oncol) - "First line treatment with a carboplatin/paclitaxel regime is initially effective in the majority of patients, but most advanced OC will recur and develop drug resistance. We did not observe any synergistic combination of plocabulin with cisplatin, doxorubicin, gemcitabine or trabectedin. In conclusion, plocabulin has a potent antitumoral effect in HGSOC cell lines that warrants further clinical investigation."

Journal • Preclinical • Gynecologic Cancers • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

Synthesis of the analogs of plocabulin and their preliminary structure-activity relationship study. (PubMed, Bioorg Med Chem Lett) - "The preliminary results indicate that the right aliphatic chain in plocabulin is allowed to remove with a little loss of activity, the carbamate group plays a role in the activity, and particularly, the enamide unit has an important effect on the activity. This new finding will aid the design of novel potent tubulin-binding agents based on plocabulin."

Journal

Marine Natural Products: A Potential Source of Anti-hepatocellular Carcinoma Drugs. (PubMed, J Med Chem) - "Here, we discuss marine-derived compounds, including PM060184 and bryostatin-1, with demonstrated anti-cancer activity in vitro or in vivo. Based on the marine source (sponges, algae, coral, bacteria, and fungi), we introduce pharmacological parameters, compound-induced cytotoxicity, effects on apoptosis and metastasis, and potential molecular mechanisms. Cumulatively, this review provides insights into anti-HCC research conducted to date in the field of marine natural products and marine-derived compounds, as well as the potential pharmacological mechanisms of these compounds and their status in drug development."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Clinical Trial of PM60184 in Advanced Colorectal Cancer After Standard Treatment (clinicaltrials.gov) - P2; N=32; Completed; Sponsor: PharmaMar; Active, not recruiting ➔ Completed; N=60 ➔ 32

Clinical • Enrollment change • Trial completion • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM060184 in Combination With Gemcitabine in Selected Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=57; Completed; Sponsor: PharmaMar; Recruiting ➔ Completed; N=36 ➔ 57

Clinical • Combination therapy • Enrollment change • Trial completion • Biliary Tract Cancer • Breast Cancer • Endometrial Cancer • Gastrointestinal Cancer • Germ Cell Tumors • Head and Neck Cancer • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor

Tubulin Maytansine Site Binding Ligands and Their Applications as MTAs and ADCs for Cancer Therapy. (PubMed, Curr Med Chem) - "The maytansine site binding agents are powerful MTAs for cancer chemotherapy. The maytansine site ligands-based ADCs are used in clinic or under clinical trials as cancer targeted therapy to improve their selectivity and to reduce their side effects. Further improvements in the delivery efficiency of the ADCs will benefit the patients in cancer targeted therapy."

Journal • Oncology

"The tubulin inhibiting cytotoxic compound plocabulin has potent ant-tumor activity in our patient-derived mouse models of GIST, disrupts the tumor vasculature and should be explored in the clinic, alone or in combination with TKIs. See Wang et al . Transl Oncol 2020;13(11):100832" (@schoffski)

Combination therapy • Oncology

[VIRTUAL] Plocabulin, a novel tubulin inhibitor, has antitumor activity in various patient-derived xenograft models of soft tissue sarcoma (AACR-II 2020) - "Doxorubicin (DOX)-based chemotherapy has been the standard of care for patients with advanced and metastatic STS, despite providing low response rates and poor disease control in this disease. PLO is a novel anti-tubulin agent showing potent antitumor activity in a variety of PDX modes of STS. The drug induces cytotoxicity mainly through necrosis and is more active than DOX. This study provides strong arguments to study PLO further in STS and to explore the compound in clinical trials involving mesenchymal malignancies."

Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor • CD31

Interdimeric Curvature in Tubulin-Tubulin Complexes Delineates the Microtubule-Destabilizing Properties of Plocabulin. (PubMed, J Chem Inf Model) - "The applicability of these findings to the rational discovery of novel MT destabilizers was tested using MD and MM/GBSA calculations as filtering tools to narrow the results of Virtual Screening among a FDA-approved drug database. Our results confirmed that tight-binding ligands do not necessarily exert the expected conformational and energetic effects on longitudinal tubulin-tubulin interactions, which is a matter to consider in future design strategies."

Journal • Oncology

Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors. (PubMed, Transl Oncol) - "We then used these well characterized models with distinct sensitivity to imatinib to evaluate the efficacy of the novel tubulin inhibitor. Our results demonstrated the in vivo efficacy of the novel tubulin inhibitor plocabulin in PDX models of GIST and challenge the established view that GIST are resistant to cytotoxic agents in general and to tubulin inhibitors in particular. Our findings provide a convincing rationale for early clinical exploration of plocabulin in GIST and warrant further exploration of this class of drugs in the management of this common sarcoma subtype."

Journal • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor

Plocabulin, a tubulin inhibitor, presents antitumor activity in patient-derived xenograft (PDX) models of gastrointestinal stromal tumor (GIST) (AACR 2018) - "Introduction: Advanced GIST is commonly treated with tyrosine kinase inhibitors (TKI) [e.g. imatinib (IMA)]...The aim of our study was to test plocabulin (PLO; PM060184, PharmaMar), a potent cytotoxic tubulin-dynamics modifier, in two PDX models of GIST, characterized by different sensitivity to IMA.Experimental set-up: NMRI nu/nu mice (n=34) were transplanted bilaterally with human xenografts UZLX-GIST3sens (KIT: exon 11 p.W557_V559delinsF; IMA-sensitive) or -GIST9res (KIT: exon 11+17: p.P577del;W557LfsX5;D820G; IMA-resistant)... PLO is the first anti-tubulin agent showing antitumor activity in GIST PDX, both in models sensitive or resistant to IMA. The drug causes cytotoxicity in GIST, mainly through necrosis, without affecting KIT signaling. Due to the different modes of action of PLO and established TKI our work provides a scientific rationale to combine PLO and IMA to overcome resistance to small molecule TKI."

Clinical • Gastrointestinal Cancer • Sarcoma

Exploratory testing of PM060184 compound in high-grade serous ovarian carcinoma cell lines (AACR 2018) - "PM060184 is a new tubulin-binding agent with a potent antitumor activity in a panel of HGS ovarian cancer cell lines, with different ranges of sensitivity to cisplatin and paclitaxel. Additionally, this effect is more potent than that exerted by other tubulin-binding compounds, such as paclitaxel. However, the underlying mechanism of PM060184 action on ovarian HGS cell lines will need to be further elucidated."

Preclinical • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Plocabulin Displays Strong Cytotoxic Activity in a Personalized Colon Cancer Patient-Derived 3D Organoid Assay. (PubMed, Mar Drugs) - "The cytotoxicity of plocabulin was an order of magnitude higher than that of the active irinotecan derivative SN38 (7-ethyl-10-hydroxy-camptothecin) in tumor organoids at different passages. Moreover, plocabulin maintained its strong cytotoxic activity in wash-out experiments, in which a short pulse treatment of tumor organoids was as efficient as continuous treatment. Our data show that plocabulin has a very potent cytotoxic action in CRC patient-derived tumor organoids, supporting ongoing clinical trials with plocabulin and the use of organoid assays to provide personalized validation of antitumor drugs."

Clinical • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

First-in-human phase I study of the microtubule inhibitor plocabulin in patients with advanced solid tumors. (PubMed, Invest New Drugs) - "Conclusion The main DLT of plocabulin was PSN, as anticipated for a tubulin-binding agent. Since encouraging antitumor activity was observed, efforts to improve toxicity and to find the RD were planned in other trials evaluating D1&D8 and D1-D3 plus D15-D17 schedules."

Clinical • Journal • P1 data

PharmaMar has presented results of its antitumor compounds trabectedin and plocabulin at the CTOS Congress (Pharmamar Press Release) - “PharmaMar…announces that the results of clinical and pre-clinical studies on Yondelis® (trabectedin) and plocabulin (PM184), compounds of a marine origin, have been presented at the International Congress of the Connective Tissue Oncological Society (CTOS). The Congress was held in Tokyo, Japan, from 13th to 16th November.”

P2 data • P3 data • Preclinical • Retrospective data

Marine-Derived Anticancer Agents: Clinical Benefits, Innovative Mechanisms, and New Targets. (PubMed, Mar Drugs) - "Approximately 50 years since the approval of cytarabine, the marine-derived anticancer pharmaceutical pipeline includes four approved drugs and eighteen agents in clinical trials, six of which are in late development. Thus, the dynamic pharmaceutical pipeline consisting of approved and developmental marine-derived anticancer agents offers new hopes and new tools in the treatment of patients afflicted with previously intractable types of cancer."

Clinical • Journal • Review

Enriching Cancer Pharmacology with Drugs of Marine Origin. (PubMed, Br J Pharmacol) - "In this scenario, innovation from marine-based pharmaceuticals has helped advance cancer chemotherapy in many aspects, as most of these are designated as first-in-class drugs. Herein, by examining the path from discovery to development of clinically approved drugs of marine origin for cancer treatment - cyrabine (Cytosar-U®), trabectedin (Yondelis®), eribulin (Halaven®), brentuximab vedotin (Adcetris®) and plitidepsin (Aplidin®) - plus those in late clinical trial phases - lurbinectedin, plinabulin, marizomib and plocabulin -, the present review offers a critical analysis of the contributions given by these new compounds to cancer pharmacotherapy."

Journal • Review

Molecular basis of resistance to the microtubule-depolymerizing antitumor compound plocabulin. (PubMed, Sci Rep) - "Resistance mutations resulted in amino acid substitutions in (1) two subunits of the eukaryotic translation initiation factor eIF2B activating the General Amino Acid Control, (2) TIM44, an essential component of the inner mitochondrial membrane translocase, (3) two transcription factors of the binuclear zinc cluster family potentially interfering with the uptake or efflux of plocabulin. Given the conservation of some of the identified proteins and their respective cellular functions in the tumor environment, our results pinpoint candidates to be tested as potential biomarkers for determination of drug efficiency."

Biomarker • Journal