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Triple-negative breast cancer (TNBC) is traditionally treated with systemic chemotherapy, often resulting in significant off-target toxicity. In this study, we assess the efficacy of intraductal chemotherapeutic delivery, aimed at reducing systemic side effects. Using an in situ TNBC model, created by intraductal injection of 4T1-luc cells, we identified day 3 post-tumor implantation as an optimal early intervention point. Echocardiographic analysis confirmed that intraductal administration of eribulin (ERI) or doxorubicin (DOX) did not cause cardiac dysfunction or apoptosis. Our results demonstrate that intraductal delivery of ERI and DOX significantly enhances anti-tumor and anti-metastatic effects. Mechanistically, ERI followed by DOX increased intratumoral perfusion, improved drug concentration, reversed epithelial-mesenchymal transition, and inhibited tumor cell invasion and metastasis. Additionally, this approach triggered immunogenic cell death and activated a systemic anti-tumor immune response. These findings underscore the potential of intraductal chemotherapy as a safe, highly effective approach, offering a preclinical foundation for minimally invasive TNBC therapies.

In preclinical mouse models of triple-negative breast cancer (TNBC), we show that a combination of chemotherapy with cisplatin (CDDP) and eribulin (Eri) was additive from an immunological point of view and was accompanied by the induction of an intratumoral immune and inflammatory response favored by the immunogenic cell death induced by CDDP, as well as by the vascular and tumor stromal remodeling induced by each chemotherapy. Unexpectedly, despite the favorable immune context created by this immunomodulatory chemotherapy combination, our models remained refractory to the addition of anti–PD-L1 immunotherapy. These surprising observations led us to discover that CDDP chemotherapy was simultaneously responsible for the production of TGF-β by several populations of cells present in tumors, which favored the emergence of different subpopulations of immune cells and cancer-associated fibroblasts characterized by immunosuppressive properties. Accordingly, co-treatment with anti–TGF-β restored the immunological synergy between this immunogenic doublet of chemotherapy and anti–PD-L1 in a CD8-dependent manner. Translational studies revealed the unfavorable prognostic effect of the TGF-β pathway on the immune response in human TNBC, as well as the ability of CDDP to induce this cytokine also in human TNBC cell lines, thus highlighting the clinical relevance of targeting TGF-β in the context of human TNBC treated with chemoimmunotherapy.

Background The PI3K/AKT pathway is frequently altered in advanced triple-negative breast cancer (aTNBC), representing a promising target. Ipatasertib, a pan-AKT inhibitor, has shown activity with taxane-based chemotherapy and acceptable safety. This study evaluated the safety and efficacy of ipatasertib with non-taxane chemotherapy for aTNBC. Methods The PATHFINDER trial was a multicenter, open-label, non-comparative, phase IIa study with a safety run-in phase. Eligible patients had TNBC pretreated in the advanced setting with one or two chemotherapy regimens, including a taxane, and no prior exposure to PI3K/mTOR/AKT inhibitors. Patients received 21-day cycles of ipatasertib combined with capecitabine (arm A), eribulin (arm B), or carboplatin plus gemcitabine (arm C). The safety run-in phase determined feasibility and phase IIa doses. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The analysis was exploratory without formal hypothesis testing. Results A total of 54 patients were assigned to arms A ( N  = 22), B ( N  = 25), and C ( N  = 7). Arm C was discontinued due to toxicity during the safety run-in phase. At data cut-off (November 2023), the overall median follow-up was 12.1 (range: 0.2–35.6) months. Common TEAEs in arm A were diarrhea (59.1%, 0.0% G ≥ 3), fatigue (36.4%, 0.0% G ≥ 3), and nausea (36.4%, 0.0% G ≥ 3); in arm B neutropenia (52.0%; 32.0% G ≥ 3), diarrhea (52.0%, 4.0% G3) and stomatitis (44.0%; 8.0% G3); and in arm C thrombocytopenia (85.7%, 85.7%G ≥ 3), anemia (85.7%, 57.1% G ≥ 3), neutropenia (71.4%, 71.4% G ≥ 3). No treatment-related deaths occurred. Median PFS was 2.7 (95%CI, 1.5–4.1) and 3.8 (95%CI, 1.5–9.6) months; median OS was 15.5 (95%CI, 11.8–19.3) and 11.5 (95%CI, 8.8–25.1) months; and ORR was 9.1% and 36.0% for arms A and B, respectively. No significant differences in efficacy were observed by PIK3CA mutational status. Conclusions Ipatasertib combined with capecitabine or eribulin showed acceptable safety but was not tolerable with carboplatin plus gemcitabine. The addition of ipatasertib to capecitabine or eribulin shows a potential efficacy signal in this patient population, compared to historical monotherapy data of these treatments. Identifying biomarkers to predict response to AKT inhibitors in TNBC is crucial. Trial registration www.clinicaltrials.gov , NCT04464174. Registered 09 July 2020.

Background Inflammatory breast cancer (IBC) is an aggressive and highly angiogenic disease. Eribulin is a microtubule inhibitor with anti-angiogenic properties. Methods In a phase II trial, we examined the efficacy of an eribulin-containing neoadjuvant regimen (eribulin- > doxorubicin plus cyclophosphamide (AC) or AC- > eribulin) for patients with newly diagnosed HER2-negative IBC. Pathologic complete response (pCR: ypT0/Tis ypN0) was the primary endpoint; residual cancer burden (RCB) categories were also recorded. Five patients from each cohort underwent dynamic contrast enhanced MRI (DCE-MRI) and diffusion weighted MRI. All patients had research breast biopsies for transcriptomic, differential gene expression, and cell subset analysis at baseline and one week after the first dose of therapy. Results 19/22 (86.4%) patients had hormone receptor-positive disease. All patients were able to undergo planned curative-intent surgery and radiation. One patient had a pCR, and long-term outcomes were encouraging: after median follow up of 76 months, 3 patients experienced disease recurrence. Five-year event-free survival (EFS) was 85.6%. The regimen was tolerated with expected side effects—the most common grade 1 or 2 AEs were fatigue (95.5%), nausea (68.2%), and alopecia (63.6%). Seven out of 22 (31.8%) patients experienced any grade 3 or 4 AE, with neutropenia (22.7%) being the most common. DCE-MRI showed decreased tumor vascularization after 1 week of treatment versus baseline. Transcriptomic analysis using quantification of synthesized dsDNA libraries and tumor microenvironment analysis of paired baseline and on-treatment samples showed residual cancer burden (RCB)-III tumors were more likely to have genes associated with adipogenesis/fatty acid metabolism and cells associated with immunosuppression. Conclusions Despite the low pCR rate, all patients were able to undergo curative surgery, and long-term outcomes were encouraging with 5-year EFS 85.6%. Decreases in tumor vascularization with treatment were detected by DCE-MRI parameters irrespective of initial chemotherapy received. Adipogenesis/fatty acid metabolism and cells associated with immunosuppression are potential mechanisms of resistance and targets for future investigation in this unique patient population. Trial registration ClinicalTrials.gov (NCT02623972)(Registration date: 12/02/15).

Salinomycin (Sal) has been recently discovered as a novel chemotherapeutic agent against various cancers including prostate cancer which is one of the most commonly diagnosed cancers affecting male populations worldwide. Herein we designed salinomycin nanocarrier (Sal-NPs) to extend its systemic circulation and to increase its anticancer potential. Prepared nanoform showed high encapsulation and sustained release profile for salinomycin. The present study elucidated the cytotoxicity and mechanism of apoptotic cell death of Sal-NPs against prostate cancer both in vitro and in vivo . At all measured concentrations, Sal-NPs showed more significant cytotoxicity to DU145 and PC3 cells than Sal alone. This effect was mediated by apoptosis, as confirmed by ROS generation, loss of MMP and cell cycle arrest at the G1 phase in both cells. Sal-NPs efficiently inhibited migration of PC3 and DU145 cells via effectively downregulating the epithelial mesenchymal transition. Also, the results confirmed that Sal-NPs can effectively inhibit the induction of Prostate adenocarcinoma in male Wistar rats. Sal-NPs treatment exhibited a decrease in tumour sizes, a reduction in prostate weight, and an increase in body weight, which suggests that Sal-NPs is more effective than salinomycin alone. Our results suggest that the molecular mechanism underlying the Sal-NPs anticancer effect may lead to the development of a potential therapeutic strategy for treating prostate adenocarcinoma. Graphical Abstract

The antibody‐drug conjugate (ADC) MORAb‐202, consisting of farletuzumab paired with a cathepsin B–cleavable linker and eribulin, targets folate receptor alpha (FRA), which is frequently overexpressed in various tumor types. MORAb‐202 was highly cytotoxic to FRA‐positive cells in vitro, with limited off‐target killing of FRA‐negative cells. Furthermore, MORAb‐202 showed a clear in vitro bystander cytotoxic effect in coculture with FRA‐positive/negative cells. In vivo antitumor efficacy studies of MORAb‐202 were conducted with a single administration of MORAb‐202 in triple‐negative breast cancer (TNBC) patient–derived xenograft (PDx) models expressing low and high levels of FRA. MORAb‐202 exhibited durable efficacy proportional to tumor FRA expression. Toxicology studies (Q3Wx2) in nonhuman primates suggested that the major observed toxicity of MORAb‐202 is hematologic toxicity. Overall, these findings support the concept that MORAb‐202 represents a promising investigational ADC for the treatment of TNBC patients. The antibody‐drug conjugate (ADC) MORAb‐202, consisting of farletuzumab with cleavable linker, is the first ADC that carries clinically validated eribulin as a payload and exhibits direct antitumor efficacy and a strong bystander effect. As a result, the therapeutic window of MORAb‐202 is much wider than other nonvalidated payloads. Importantly, its well validated safety profile is minimizes risk in the clinic. Thus, MORAb‐202 represents promising investigational therapeutics for TNBC patients.

Oxaliplatin (OXA) is widely used for colorectal cancer (CRC) as a first-line chemotherapy. However, drug resistance and peripheral neurotoxicity prevail in colorectal cancer therapy. Salinomycin (SAL) makes cancer cells sensitive to ionizing radiation and chemotherapeutic drugs. Chemotherapy regimens that combine more than two drugs can improve the outcome of patients. In the present study, we detected apoptosis and mitochondrial function in CRC cells through MTT assays, Annexin V-FITC/PI staining, colony-forming assays, intracellular reactive oxygen species (ROS) measurements, western blotting and so on. We used CompuSyn software to calculate combination index (CI). The effect of SAL and OXA was synergistic. The combination treatment inhibited cell proliferation, migration and colony formation but increased the expression of proapoptotic proteins and promoted cell apoptosis of CRC cells. In vitro experiments demonstrated that the SAL and OXA cotreatment increased intracellular ROS levels in CRC cell lines, decreased the MMP and activated the mitogen-activated protein kinase (MAPK) pathway, thus inhibiting the proliferation of CRC cells and promoting the apoptosis of CRC cells. Pretreatment with N-acetylcysteine (NAC) reversed this effect. Cotreatment with SAL and OXA increases the apoptotic effects in OXA-treated CRC cell lines. In vivo, combined treatment of SAL and OXA markedly inhibited the tumor growth compared to either drug alone. SAL enhances OXA-induced antitumor effects in CRC both in vitro and in vivo by ROS-mediated mitochondrial apoptosis and activation of the MAPK pathway. These results may provide a rationale for combining SAL with OXA for CRC treatment.

Our understanding of neoadjuvant treatment with microtubule inhibitors (MTIs) for triple negative breast cancer (TNBC) remains limited. To advance our understanding of the role of breast cancer driver genes' mutational status with pathological complete response (pCR; ypT0/isypN0) prediction and to identify distinct gene sets for MTIs like eribulin and paclitaxel, we carried out targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) of TNBC tumor samples from the Japan Breast Cancer Research Group 22 (JBCRG‐22) clinical trial. Lower PIK3CA, PTEN, and HRAS mutations were found in homologous recombination deficiency (HRD)‐high (HRD score ≥ 42) tumors with higher pCR rates. When HRD‐high tumors were stratified by tumor BRCA mutation status, the pCR rates in BRCA2‐mutated tumors were higher (83% vs. 36%). Transcriptomic profiling of TP53‐positive tumors identified downregulation of FGFR2 (false discovery rate p value = 2.07e‐7), which was also the only common gene between HRD‐high and ‐low tumors with pCR/quasi‐pCR treated with paclitaxel and eribulin combined with carboplatin, respectively. Differential enrichment analysis of the HRD‐high group posttreatment tumors revealed significant correlation (p = 0.006) of the glycan degradation pathway. FGFR2 expression and the differentially enriched pathways play a role in the response and resistance to MTIs containing carboplatin treatment in TNBC patients. Our study hypothesizes FGFR2's potential role in response to microtubule inhibitors containing neoadjuvant chemotherapy in TP53 mutated and microtubule genes in homologous recombination deficiency‐high triple negative breast cancer tumors.

Purpose Although changes in circulating tumour DNA (ctDNA) in breast cancer are well described, the kinetics of their fluctuations has not been described over short timescales. We investigated ctDNA dynamics during alternating cycles of chemotherapy and hormonal treatment in pre-treated patients with oestrogen receptor-positive metastatic breast cancer. Methods Patients received alternating, 9-week cycles of eribulin and aromatase inhibitors (AIs). The clinical primary endpoint, progression-free survival (PFS), was monitored at 3, 6 and 9 months; secondary endpoints, clinical benefit rate (CBR), safety and tolerability profiles, were also assessed. Importantly, ctDNA fluctuations were monitored using the Oncomine™ Breast cfDNA assay to test whether biomarkers may change rapidly between chemotherapy and aromatase inhibitor (AI) treatment in the setting of advanced breast cancer, potentially reflecting disease dynamics. Results The median PFS was 202 days (95% CI: 135-undefined) and 235 days (95% CI: 235-undefined) at 6 and 9 months, respectively, with a 50% CBR at both 6 and 9 months. Dynamic changes in ctDNA were observed in short timescales between chemotherapy and AI treatment and support the clinical benefit (CB) seen in individual patients and, critically, appear informative of acquired resistance in real time. Conclusion Changes in ctDNA can occur rapidly and reflect changes in patients’ clinical tumour responses (NCT02681523).

Background Pre-clinical data suggests a potential synergistic effect of eribulin and platinum. However, clinical data on the combination for metastatic breast cancer (mBC) is lacking. We evaluated the efficacy and safety of eribulin plus carboplatin (ErCb) in patients with mBC. Patients and methods This multicenter, real-world cohort study included patients with pre-treated metastatic triple negative breast cancer (TNBC) or endocrine-refractory hormone receptor (HR) positive, HER2-negative mBC who received ErCb. Eribulin (1.4 mg/m2) and carboplatin (target AUC = 2) were administered intravenously on day 1 and 8 of 21-day cycle. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. Results From March 2022 to December 2023, a cohort of 37 patients were recruited to the study. Among them, 22 patients have TNBC and 15 have HR + HER2 − mBC. Of the 22 patients with TNBC, 8 had an initial diagnosis of the HR + HER2 − subtype. The median treatment was 6 cycles (range, 2 − 8 cycles). In the full cohort, TNBC, and HR + HER2 − subgroup, the ORR were 51.4%, 54.5% and 46.7%, the DCR were 81.1%, 81.8% and 80%, and the median PFS were 5 months, 5 months, and 5.2 months, respectively. The median OS was 12.7 months in the entire cohort and 12.8 months in TNBC subgroup. The most common grade 3/4 hematological AEs were neutropenia (37.8%), leukopenia (35.1%), febrile neutropenia (10.8%), thrombocytopenia (5.4%), and anemia (2.7%). No grade 3/4 non-hematological AEs were observed. Conclusion ErCb demonstrated favorable efficacy and tolerability in patients with heavily pre-treated mBC, especially TNBC. The findings of the current study warrant further investigation of the application of this combination in earlier lines of mBC treatment.