Small‐Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy with a poor prognosis. Here, we focus on the neuroendocrine SCLC subtypes, SCLC‐A and SCLC‐N, whose transcription addiction was driven by ASCL1 and NEUROD1 transcription factors which target E‐box motifs to activate up to 40% of total genes, the promoters of which are maintained in a steadily open chromatin environment according to ATAC and H3K27Ac signatures. This leverage is used by the marine agent lurbinectedin, which preferentially targets the CpG islands located downstream of the transcription start site, thus arresting elongating RNAPII and promoting its degradation. This abrogates the expression of ASCL1 and NEUROD1 and of their dependent genes, such as BCL2 , INSM1 , MYC , and AURKA , which are responsible for relevant SCLC tumorigenic properties such as inhibition of apoptosis and cell survival, as well as for a part of its neuroendocrine features. In summary, we show how the transcription addiction of these cells becomes their Achilles’s heel, and how this is effectively exploited by lurbinectedin as a novel SCLC therapeutic endeavor.

Vascular supply of tumors is one of the main targets for cancer therapy. Here, we investigated if plocabulin (PM060184), a novel marine-derived microtubule-binding agent, presents antiangiogenic and vascular-disrupting activities. The effects of plocabulin on microtubule network and dynamics were studied on HUVEC endothelial cells. We have also studied its effects on capillary tube structures formation or destabilization in three-dimensional collagen matrices. In vivo experiments were performed on different tumor cell lines. In vitro studies show that, at picomolar concentrations, plocabulin inhibits microtubule dynamics in endothelial cells. This subsequently disturbs the microtubule network inducing changes in endothelial cell morphology and causing the collapse of angiogenic vessels, or the suppression of the angiogenic process by inhibiting the migration and invasion abilities of endothelial cells. This rapid collapse of the endothelial tubular network in vitro occurs in a concentration-dependent manner and is observed at concentrations lower than that affecting cell survival. The in vitro findings were confirmed in tumor xenografts where plocabulin treatment induced a large reduction in vascular volume and induction of extensive necrosis in tumors, consistent with antivascular effects. Altogether, these data suggest that an antivascular mechanism is contributing to the antitumor activities of plocabulin.

Lurbinectedin is a selective inhibitor of oncogenic transcription approved for the treatment of adult patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. Preclinical data provide evidence for lurbinectedin exerting its actions in a unique manner that involves oncogenic transcription inhibition, DNA damage, reshaping of the tumor microenvironment, and inducing anticancer immunity. Understanding the mechanism of action has facilitated the rational combination of lurbinectedin and anticancer therapies with complementary modes of action, in order to obtain synergistic effects that could potentially lead to improved efficacy. This review evaluates the mechanism of action for lurbinectedin and provides an overview of the therapeutic landscape with regards to lurbinectedin combination therapies for the treatment of small cell lung cancer based on data from preclinical and clinical studies.

PM742 (1), a new chemical entity, has been isolated from the sponge Discodermia du Bocage collected in the Pacific Ocean. This compound showed strong in vitro cytotoxicity against several human tumor cell lines as well as a tubulin depolymerization mechanism of action, which led us to conduct an extensive Structure-Activity-Relationship study through the synthesis of different analogs. As a result, a derivatively named PM534 (2) is currently in its first human Phase I clinical trial. Herein, we present a comprehensive review of the isolation, structural elucidation, and antitumor activities of the parent compound PM742.

This study evaluates PM534, a novel colchicine-binding domain inhibitor, for its potential in cancer therapy. PM534 exhibited potent in vitro efficacy against a panel of 14 human cancer cell lines, including breast, ovarian, and prostate cancers, with concentration needed to reduce the growth of treated cells to half that of untreated cells values in the low nanomolar range. Both continuous (72 hours) and short-term (1–24 hours) exposure led to irreversible effects, inducing G2–M cell cycle arrest and multinucleation. Additionally, PM534 also impaired angiogenic process. It effectively inhibited HUVEC functions, including adhesion, with an IC50 of 2.3 nmol/L, markedly more potent than colchicine (IC50 = 1,800 nmol/L). At concentrations as low as 1.6 nmol/L, PM534 delayed wound closure in migration assays, completely inhibiting migration above 4 nmol/L. Additionally, PM534 abrogated invasion and disrupted capillary-like network formation at concentrations starting from 0.5 nmol/L without inducing cytotoxicity. In vivo PM534 demonstrated robust antitumor efficacy across six xenograft models, including ovarian (A2780 and ES-2), triple-negative breast (MDA-MB-231 and HCC1937), and prostate (VCaP and 22Rv1) tumors. This treatment also led to statistically significant increases in median survival times across all models, without inducing signs of systemic toxicity. Mechanistically, PM534 induced apoptosis, mitotic catastrophe, and necrosis in tumor tissues. Importantly, PM534 retained efficacy in models overexpressing multidrug resistance proteins P-glycoprotein or β-III tubulin, overcoming common resistance mechanisms that limit the effectiveness of other tubulin-binding agents. Collectively, these findings highlight PM534 as a promising antitumor agent with potent activity against diverse and treatment-resistant malignancies. A phase I clinical trial (NCT#5835609) is underway to assess the therapeutic potential of PM534 in patients with advanced solid tumors.

This study evaluates PM534, a novel colchicine-binding domain inhibitor, for its potential in cancer therapy. PM534 exhibited potent in vitro efficacy against a panel of 14 human cancer cell lines, including breast, ovarian, and prostate cancers, with concentration needed to reduce the growth of treated cells to half that of untreated cells values in the low nanomolar range. Both continuous (72 hours) and short-term (1–24 hours) exposure led to irreversible effects, inducing G2–M cell cycle arrest and multinucleation. Additionally, PM534 also impaired angiogenic process. It effectively inhibited HUVEC functions, including adhesion, with an IC50 of 2.3 nmol/L, markedly more potent than colchicine (IC50 = 1,800 nmol/L). At concentrations as low as 1.6 nmol/L, PM534 delayed wound closure in migration assays, completely inhibiting migration above 4 nmol/L. Additionally, PM534 abrogated invasion and disrupted capillary-like network formation at concentrations starting from 0.5 nmol/L without inducing cytotoxicity. In vivo PM534 demonstrated robust antitumor efficacy across six xenograft models, including ovarian (A2780 and ES-2), triple-negative breast (MDA-MB-231 and HCC1937), and prostate (VCaP and 22Rv1) tumors. This treatment also led to statistically significant increases in median survival times across all models, without inducing signs of systemic toxicity. Mechanistically, PM534 induced apoptosis, mitotic catastrophe, and necrosis in tumor tissues. Importantly, PM534 retained efficacy in models overexpressing multidrug resistance proteins P-glycoprotein or β-III tubulin, overcoming common resistance mechanisms that limit the effectiveness of other tubulin-binding agents. Collectively, these findings highlight PM534 as a promising antitumor agent with potent activity against diverse and treatment-resistant malignancies. A phase I clinical trial (NCT#5835609) is underway to assess the therapeutic potential of PM534 in patients with advanced solid tumors.