Cancer Communications最新文献

Prostate cancer is a common cancer among men worldwide. Large-scale clinical studies of the 1,000 mg daily dosing of abiraterone acetate (AA) have confirmed its antitumor efficacy in patients with metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC), regardless of their cancer's response to androgen deprivation therapy (ADT) or treatment duration. However, this dosage was indirectly justified based on the absence of dose-limiting toxicities (DLTs) in prior phase I dose-escalation trials, where a plateau in the increase of upstream steroids relating to secondary mineralocorticoid excess was observed at doses greater than 750 mg and up to 2,000 mg daily [1, 2]. Notably, prostate specific antigen (PSA) levels declined at all investigated doses (250 to 1,000 mg) [1, 2].

Cytochrome P450 17A1 (CYP17A1) is involved in both adrenal and de novo intratumoural androgen biosynthesis. We previously identified that abiraterone targeted CYP17A1 via a two-step binding mechanism [3]. Our subsequent pharmacokinetic/pharmacodynamic (PK/PD) simulations found that both the 1,000 mg and 500 mg doses of AA achieved comparable > 80% apparent target CYP17A1 enzyme occupancy and equipotent reduction of downstream plasma dehydroepiandrostenedione-sulfate (DHEA-S) levels, despite the difference in systemic exposure of abiraterone [3]. In addition, we developed physiologically-based pharmacokinetic (PBPK) models for AA and abiraterone via a middle-out approach [4], which enabled the prospective prediction of abiraterone systemic exposure at different doses.

Our research group participated in a global phase II study that demonstrated a 250 mg dose of AA taken with a low-fat meal achieved comparable PSA metrics to the standard 1,000 mg AA dose taken in a fasting state in patients with CRPC [5]. However, the fat content of food could significantly impact the relative bioavailability of abiraterone [4], and controlling food intake poses a challenge in outpatient settings and during the long-term use of abiraterone. By analyzing the PK data, we observed that the systemic exposure of a lower dose of 500 mg of AA (fasted) is comparable to that of a 250 mg dose of AA with a low-fat meal. Furthermore, our modeling studies revealed that 500 mg AA is promising in achieving optimal antitumor efficacy, and diminishing mineralocorticoid-related adverse outcomes simultaneously. In addition, patients will pay less with a half-reduced dose. Currently, data on the administration of 500 mg AA in prostate cancer patients remains insufficient. To address this gap, we conducted a proof-of-concept phase I study in mCRPC and mHSPC patients newly initiated on 500 mg once daily AA. Simultaneous PBPK/PD simulations of the low-dose AA were performed to further support the unique relationship between systemic exposure and pharmacological

Ascites formation in solid tumor patients is associated with an increased risk of death [1, 2]. The lack of pathophysiological insight limited the development of targeted treatment so far. With advances in immune modulating therapies, the inflammatory component of ascites moved into focus. Experimental approaches targeting immunologic dysregulation have shown only limited success [3, 4]. Therefore, we investigated inflammatory processes of ascites, taking the presence of tumor cells into account, while focusing on gastrointestinal tract malignancies due to their underrepresentation in literature.

A total of 63 patients were included in this study. Among these patients, 55 (87.3%) underwent paracentesis for ascites caused by advanced solid tumors, of which 30/63 (47.6%) patients had negative tumor cell cytology (paramalignant ascites) and 25/63 (39.7%) had positive tumor cell cytology (malignant ascites). Additionally, 8/63 (12.7%) patients with non-malignant ascites due to liver cirrhosis were included. Patients’ characteristics are displayed in Supplementary Table S1.

To study differences in the inflammatory profiles based on tumor cells within ascites, nine cytokines (interleukin-6 [IL-6], IL-8, IL-10, IL-17, tumor necrosis factor-alpha [TNF-α], C-reactive protein [CRP], Eotaxin, vascular endothelial growth factor [VEGF], and the soluble programmed death ligand-1 [sPD-L1]) were measured in ascitic supernatant. Malignant ascites showed increased levels of IL-6, IL-8, VEGF, and sPD-L1, compared to paramalignant and non-malignant ascites, respectively (Figure 1A-D). In contrast, no differences in cytokine levels were observed between non-malignant and paramalignant ascites in all measured cytokines, indicating that the inflammatory composition of ascites correlates with the presence of tumor cells.

To correlate systemic inflammatory processes with local inflammation in ascites supernatant in patients with advanced solid tumors, we measured cytokine levels in serum samples obtained at the timepoint of paracentesis. Strong correlations between ascitic and serum cytokine levels were evident for IL-8 and IL-17 (Figure 1E-F). Additionally, strong correlation was evident for CRP levels (Figure 1G), while no or weak correlations were detected in other cytokines. CRP as well as levels sPD-L1were decreased in ascites compared to serum (Supplementary Table S2). Compared to serum, ascitic IL-6 was significantly elevated (Supplementary Table S2) without a correlation to systemic IL-6 levels (ρ = 0.16, P > 0.05), suggesting IL-6 signaling may be important for local inflammation.

To tie the link between soluble inflammatory markers and the cellular inflammatory compartment, we investigated correlations between cytokine levels and leukocyte as well as cell count for 19 overlapping samples. While no associations between leukocyte count and cytokine levels were observed, strong correlations betw

Neutrophils are important components of the immune system and play a key role in defending against pathogenic infections and responding to inflammatory cues, including cancer. Their dysregulation indicates potential disease risk factors. However, their functional importance in disease progression has often been underestimated due to their short half-life, especially as there is limited information on the role of intratumoral neutrophils. Recent studies on their prominent role in cancer have led to a paradigm shift in our understanding of the functional diversity of neutrophils. These studies highlight that neutrophils have emerged as key components of the tumor microenvironment, where they can play a dual role in promoting and suppressing cancer. Moreover, several approaches to therapeutically target neutrophils have emerged, and clinical trials are investigating their efficacy. In this review, we discussed the involvement of neutrophils in cancer initiation and progression. We summarized recent advances in therapeutic strategies targeting neutrophils and, most importantly, suggested future research directions that could facilitate the manipulation of neutrophils for therapeutic purposes in cancer patients.

The cover image is based on the article A strong internal promoter drives massive expression of YEATS-domain devoid MLLT3 transcripts in HSC and most lethal AML by Chloé Bessière et al., https://doi.org/10.1002/cac2.12650.

Despite advances in breast cancer therapy, effective targeting of cancer stem cells (CSCs) remains a challenge. CSCs, which have self-renewal, tumorigenic and metastatic properties, are often quiescent and located in hypoxic regions of tumors [1], making them resistant to conventional chemo- and radiotherapies [2]. These characteristics allow CSCs to survive, leading to relapse and metastasis. Studying CSCs under conditions similar to their hypoxic niche is essential for evaluating therapies that target these cells.

We show that CSCs can be targeted via binding to externalized phosphatidylserine (PS). PS, a negatively charged lipid, is typically confined to the inner leaflet of cell membranes [3]. However, its externalization occurs on dying and diseased cells, and as we demonstrated, on stem cells [4]. PS-targeting agents like Annexin V (AnnV) [5] and the monoclonal antibody bavituxumab (Bavi) [6] are under investigation for cancer therapy, but these are limited in their use as they remain surface bound and do not deliver payloads into cells. In contrast, we have found that a truncated protein S comprised of the PS-binding γ-carboxyglutamate (Gla) domain and four epidermal growth factor (EGF) domains (collectively referred to as GlaS), binds PS on the outer leaflet and is internalized after binding [4] enabling delivery of payloads to the cytoplasm of cells with externalized PS, which would include CSC in the hypoxic regions of tumors.

We used patient derived models of human breast cancer which are enriched in CD44⁺CD24⁻ CSCs (Supplementary Materials and Methods). Following isolation, the CSC were propogated in mice and engineered so they express bioluminescent and fluorescent reporters. Cells collected from the CSC enriched tumors [7] were exposed to an oxygen level in culture that mimics the tumor microenvironment (TME) [8, 9], 4% O₂ (hypoxia), and compared to cells exposed to 7% O₂ (physoxia) and 21% O₂ (hyperoxia, typical cell culture). The percentage of CD44⁺ cells did not show significant differences at different oxygen levels (F_2,36 = 1.32, P = 0.28, Figure 1A-B, Supplemental Figure S1A). However, the percentage of CD44⁺GlaS⁺ cells (indicating GlaS binding) varied significantly (F_2,36 = 27.69, P < 0.001, Figure 1C-D, Supplemental Figure S1B). Hypoxic conditions showed increased GlaS binding, with 61% of cells being CD44⁺GlaS⁺ under hypoxic conditions, compared to 47% in physoxia (P = 0.01) and 28% in hyperoxia (P < 0.001). There were no significant differences in GlaS binding in CD44⁻ cells (P = 0.054), suggesting that oxygen dependent binding is specific to CD44⁺ cells (Figure 1E-F). These findings were also validate

Mutations in the oncogene NRAS that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling pathways [1]. These mutations occur in approximately 20% of melanomas and very rarely coexist with BRAF V600 mutations. NRAS-mutant melanoma is associated with poor survival [2] and represents an unmet clinical need, with no effective therapies available following immunotherapy failure.

Identification of contextual essential genes that exert stronger fitness effects on NRAS-mutant melanoma cells presents an opportunity for the discovery of targeted therapies. In this study, we employed CRISPR-Cas9-mediated whole-genome dropout screens to identify genetic dependencies in NRAS-mutant melanoma. Typically, melanoma cell lines are cultured under ambient (∼20%) O₂ conditions, despite O₂ concentrations of < 8% at the epidermal-dermal junction where melanocytes reside, resulting in adaptations in gene and protein expression [3]. Therefore, for our screens, we used a panel of early-passage New Zealand Melanoma (NZM) cell lines that were established and cultured under physiological (5%) O₂ conditions [4].

Six NRAS-mutant and seven NRAS-wildtype (five BRAF-mutant, two BRAF/NRAS/NF1-wildtype) NZM cell lines (Supplementary Table S1) were transduced in multiple replicates with the Brunello single guide RNA (sgRNA) library at a multiplicity of infection of approximately 0.3 and screened at 5% O₂ for up to 35 days (Supplementary Methods and Materials). All NZM lines were cultured for transduction at fewer than 10 passages from derivation. The representation of the sgRNA libraries was assessed to evaluate transducibility, with any cell lines exhibiting poor sgRNA representation (< 80% of sgRNAs detected with ≥1 count) excluded from further analyses (Supplementary Table S2). Moderate to high representation was observed in nine of the 13 NZM cell lines, whereas four cell lines were excluded due to < 80% of sgRNAs being detected (Figure 1A). Reduced sgRNA representation was accompanied by dropout of non-targeting control (NTC) sgRNAs (Figure 1A), greater read count inequality (Supplementary Figure S1, Supplementary Table S2) and reduced correlation with the Brunello library plasmids and between individual cell line replicates (Supplementary Figure S2), suggesting stochastic evolution rather than knockout-induced fitness effects.

We used BAGEL2 to estimate gene essentiality relative to reference sets of common essential and nonessential genes. Typically, tissue-agnostic gene sets are used for this purpose [5], but we established a combined essential gene set incorporating both tissue-agnostic and melanoma-sp