Search

Abstract Triple‐negative breast cancer (TNBC) often develops resistance to single‐agent treatment, which can be circumvented using targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 synergistically limits TNBC proliferation in vitro and in vivo. Mechanistically, LOXL2 interacts in the nucleus with the short isoform of BRD4 (BRD4S), MED1, and the cell cycle transcriptional regulator B‐MyB. These interactions sustain the formation of BRD4 and MED1 nuclear transcriptional foci and control cell cycle progression at the gene expression level. The pharmacological co‐inhibition of LOXL2 and BRD4 reduces BRD4 nuclear foci, BRD4‐MED1 colocalization, and the transcription of cell cycle genes, thus suppressing TNBC cell proliferation. Targeting the interaction between BRD4S and LOXL2 could be a starting point for the development of new anticancer strategies for the treatment of TNBC.

Abstract Background Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance. Methods Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi. Results AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (> 386 days vs. 90 days). Mechanistically, AZD5305 induced more replication stress and genomic instability than the PARP1/2 inhibitor olaparib in PARPi-sensitive tumors. All tumors at progression with either PARPi (39/39) showed increase of HRR functionality by RAD51 foci formation. The most prevalent resistance mechanisms identified were the acquisition of reversion mutations in BRCA1/BRCA2 and the accumulation of hypomorphic BRCA1. AZD5305 did not sensitize PDXs with acquired resistance to olaparib but elicited profound and durable responses when combined with carboplatin or ceralasertib in 3/6 and 5/5 models, respectively. Conclusions Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option.

CDK4/6 inhibitor resistance is common in breast cancer. Here, the authors show that p16 overexpression may be linked to reduced efficacy of CDK4/6 inhibition, and show that the combination with PI3K inhibitors may increase anti-tumour effects.

Abstract Poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2‐related cancers. A test to identify additional HRR‐deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient‐derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2‐related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. In clinical samples, all PALB2‐related tumors were classified as HRR‐deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi‐sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2‐related cancers.

Background: Leptospirosis is a worldwide zoonotic infection, and its management needs to be refined. This study aims to discern which antibiotic would be the best option to treat leptospirosis disease and analyze the efficacy of chemoprophylaxis regimens to prevent this illness. Methods: systematic review and meta-analysis on the efficacy of antibiotic treatment and chemoprophylaxis of leptospirosis in humans. Results: Ten clinical trials compared an antibiotic treatment with placebo or other antibiotic treatments in leptospirosis (the most recent one was published in 2007). The meta-analysis shows no effect of penicillin treatment on mortality compared to placebo (OR 1.65; 95% CI 0.76–3.57; p = 0.21). There are no differences between penicillin and cephalosporins or doxycycline. Penicillin does not reduce the time of defervescence (MD-0.16; 95% CI (−1.4) –1.08; p = 0.80) nor hospital stay (MD 0.15; 95% CI (−0.75)–1.06; p = 0.74). Besides, the data did not demonstrate any effectiveness of the use of penicillin in terms of the incidence of oliguria/anuria, the need for dialysis treatment, time to creatinine normalization, incidence of jaundice, or the liver function normalization time. Eight trials have assessed prophylactic treatment against leptospirosis with different strategies. A weekly dose of 200 mg of doxycycline does not show benefit versus placebo regarding the number of new cases of symptomatic leptospirosis (OR 0.20; 95% CI 0.02–1.87; p = 0.16). A single dose of doxycycline at exposure to flood water could have a beneficial effect (OR 0.23; 95% CI 0.07–0.77; p = 0.02). None of the other chemoprophylaxis regimens tested have shown a statistically significant effect on the number of new symptomatic cases. Conclusion: There is no evidence that antibiotics are a better treatment than placebo regarding mortality, shortening of fever, liver and kidney function, or reduction in the hospital stay. On the other hand, neither doxycycline nor penicillin, nor azithromycin have shown statistically significant differences in preventing symptomatic infection. Well-designed clinical trials, including other antibiotics such as quinolones or aminoglycosides, are urgently needed to improve our understanding of the treatment for this infection, which continues to be a neglected disease.