Citations

Abstract Glioblastoma (GBM) is among the most aggressive and lethal primary brain cancers. A major therapeutic challenge is that the standard chemotherapeutic agent temozolomide (TMZ) is associated with drug resistance and lacks tumor-specificity. The development of targeted drug delivery systems encapsulating new chemotherapeutic agents may overcome these limitations. Fucoidan has been reported to exhibit tumor-targeting properties through its high binding affinity for P-selectin overexpressed on both GBM cells and activated brain microvascular endothelial cells (BMECs) within and surrounding tumors. Verteporfin (VP), a benzoporphyrin derivative, has been reported to suppress Yes-associated protein (YAP) activity, inhibit tumor angiogenesis, and exhibit antitumor activity in heterogeneous GBM. However, the hydrophobic nature of VP limits its bioavailability, reducing therapeutic efficacy and necessitating high doses that may increase the risk of adverse effects. To address this challenge, we synthesized VP-laden, fucoidan-coated nanoparticles (VP@NP-F), and VP-laden nanoparticles without fucoidan coating (VP@NP). Their capability of enhancing VP delivery and antitumor efficacy was evaluated using human BMECs and patient-derived primary GBM cells (GBM1a). VP@NP-F exhibits ∼4-fold and ∼1.8-fold greater uptake in BMECs and GBM1a than VP@NP, demonstrating the fucoidan coating enhances targeting and internalization. The half-maximal inhibitory concentration (IC50) value of VP@NP-F is ∼12.3-fold and ∼3-fold lower than that of free VP and VP@NP, respectively. These data suggest the therapeutic advantage of the VP-laden, fucoidan-coated nanoparticles in vitro, which warrants further in vivo investigation in the future.

Purpose Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients and Methods Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Results Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations. Conclusion Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives.