Aggressive Cancer Research Articles

End Binding Proteins: Drivers of Cancer Progression.

Cancer, a complex and heterogeneous disease, continues to be a major global health concern. Despite advancements in diagnostics and therapeutics, the aggressive nature of certain cancers remain a significant challenge, necessitating a deeper understanding of the underlying molecular mechanisms driving their severity and progression. Cancer severity and progression depend on cellular properties such as cell migration, cell division, cell shape changes, and intracellular transport, all of which are driven by dynamic cellular microtubules. Dynamic properties of microtubules, in turn, are regulated by an array of proteins that influence their stability and growth. Among these regulators, End Binding (EB) proteins stand out as critical orchestrators of microtubule dynamics at their growing plus ends. Beyond their fundamental role in normal cellular functions, recent research has uncovered compelling evidence linking EB proteins to the pathogenesis of various diseases, including cancer progression. As the field of cancer research advances, the clinical implication of EB proteins role in cancer severity and aggressiveness become increasingly evident. This review aims to comprehensively explore the role of microtubule-associated EB proteins in influencing the severity and aggressiveness of cancer. We also discuss the potential significance of EB as a clinical biomarker for cancer diagnosis and prognosis and as a target for therapeutic intervention.

Lack of canonical activities of connexins in highly aggressive human prostate cancer cells

Connexins (Cxs) have the ability to form channels that allow the exchange of ions/metabolites between adjacent cells (gap junction channels, GJC) or between the intra- and extra-cellular compartments (hemichannels, HC). Cxs were initially classified as tumor suppressors. However, more recently, it has been shown that Cxs exert anti- and pro-tumorigenic effects depending on the cell and tissue context. In prostate cancer (PCa), the expression and functionality of Cxs remain highly controversial. Here, we analyzed the expression pattern of Cx26, Cx32, Cx37, Cx40, Cx43 and Cx45 in PCa cell lines with increasing levels of tumor aggressiveness (LNCaP < LNCaP-C4-2 < Du-145 < PC-3). In addition, GJ and HC activities were evaluated in the PCa cell lines using dye coupling and dye uptake assays, respectively. Lastly, the cellular localization of Cx26, Cx32, and Cx43 was analyzed in LNCaP and PC-3 cell lines using immunofluorescence analyses. Our results showed a positive association between the mRNA levels of Cx26, Cx37 and Cx45 and the degree of aggressiveness of PCa cells, a negative association in the case of Cx32 and Cx43, and no clear pattern for Cx40. At the protein level, a negative relationship between the expression of Cx26, Cx32 and Cx43 and the degree of aggressiveness of PCa cell lines was observed. No significant differences were observed for the expression of Cx37, Cx40, and Cx45 in PCa cell lines. At the functional level, only LNCaP cells showed moderate GJ activity and LNCaP and LNCaP-C4-2 cells showed HC activity. Immunofluorescence analyses confirmed that the majority of Cx26, Cx32, and Cx43 expression was localized in the cytoplasm of both LNCaP and PC3 cell lines. This data indicated that GJ and HC activities were moderately detected only in the less aggressive PCa cells, which suggest that Cxs expression in highly aggressive PCa cells could be associated to channel-independent roles.

Significant association of miRNA 34a with BRCA1 expression in pancreatic ductal adenocarcinoma: an insight on miRNA regulatory pathways in the Pakistani population

BackgroundPancreatic Ductal Adenocarcinoma (PDAC) is among the most aggressive cancers, characterized by high mortality rates. Studies on various cancers across the globe indicate that regulatory miRNAs play a vital role in cellular signaling. However, the expression and interactions of these miRNAs in the Pakistani patients with PDAC is yet to be explored. Here, we aim to investigate a panel of four regulatory miRNAs (miRNA 34a, 30b, 142 and 137) in PDAC and their interaction with selected target proteins in the signaling pathway (KRAS, p53, BRCA1, APC).MethodsWe conducted a study on 109 PDAC patients to analyze the selected miRNAs and protein targets. Formalin Fixed Paraffin Embedded (FFPE) tumor samples were obtained from the hospital’s department of histopathology. After confirmation of diagnosis and appropriate tumor content, tissues were processed for RNA extraction. Based on the acceptable quality and quantity of RNA, 43 samples were proceeded for qRT-PCR. Relative expression of the miRNAs was determined through 2−[ΔΔCt] method. Further, FFPE tumor blocks were used to perform tissue sectioning followed by immunohistochemistry experiments. Stained slides were scored independently by two pathologists according to set criteria.ResultsExpression profiles revealed that miRNA 34a, 30b, and 142 showed high expression in approximately 69–70% of cases, while miRNA 137 had a lower high expression frequency (53.4%). Among protein biomarkers, KRAS, BRCA1, and APC were predominantly expressed, with high expression levels observed in 79.1%, 69.8%, and 51.2% of cases, respectively, whereas p53 showed positive expression in only 34.9% of cases. Statistical analysis showed that expression of miRNA 34a was significantly associated with the expression of BRCA1 (p = 0.034). No significant associations were observed for KRAS, p53, or APC with the selected miRNAs. Moreover, the expression of miRNA 34a independently showed significant association with miRNA 30b (p = 0.000) and miRNA 137 (p = 0.001). None of the miRNA showed an association with the overall survival, patient demographics or the clinicopathological characteristics.ConclusionOur study highlights a potential bi-directional regulatory relationship between BRCA1 and miRNA 34a, suggesting that miRNA 34a may both respond to and influence BRCA1 activity within cellular signaling pathways. This complex interaction points to a layered regulatory network that could play a crucial role in tumor suppression in PDAC, underscoring the therapeutic potential of targeting this miRNA-protein crosstalk.

BCAT1 Associates with DNA Repair Proteins KU70 and KU80 and Contributes to Regulate DNA Repair in T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Increased expression of branched-chain amino acid (BCAA) transaminase 1 (BCAT1) often correlates with tumor aggressiveness and drug resistance in cancer. We have recently reported that BCAT1 was overexpressed in a subgroup of T-cell acute lymphoblastic (T-ALL) samples, especially those with NOTCH1 activating mutations. Interestingly, BCAT1-depleted cells showed pronounced sensitivity to DNA-damaging agents such as etoposide; however, how BCAT1 regulates this sensitivity remains uncertain. Here, we provide further clues on its chemo-sensitizing effect. Indeed, BCAT1 protein regulates the non-homologous end joining (c-NHEJ) DNA repair pathway by physically associating with the KU70/KU80 heterodimer. BCAT1 inhibition during active repair of DNA double-strand breaks (DSBs) led to increased KU70/KU80 acetylation and impaired c-NHEJ repair, a dramatic increase in DSBs, and ultimately cell death. Our results suggest that, in T-ALL, BCAT1 possesses non-metabolic functions that confer a drug resistance mechanism and that targeting BCAT1 activity presents a novel strategy to improve chemotherapy response in T-ALL patients.

LAG3 immune inhibitors: a novel strategy for melanoma treatment

Melanoma, a highly aggressive skin cancer, poses significant challenges in treatment, particularly for advanced or metastatic cases. While immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-1, has transformed melanoma management, many patients experience limited responses or develop resistance, highlighting the need for new therapeutic strategies. Lymphocyte activation gene 3 (LAG-3) has emerged as a promising target in cancer immunotherapy. LAG-3 inhibitors have shown potential in restoring T cell functions and enhancing anti-tumor immunity, particularly when used in combination with existing ICIs. This review discusses the latest advancements in LAG-3 inhibition for advanced melanoma, emphasizing its role in overcoming resistance and improving patient outcomes.

Impact of prolactin treatment on enhancing the cellular responses of MCF7 breast cancer cells to tamoxifen treatment

Breast cancer remains one of the most challenging diseases to treat due to its heterogeneity, propensity to recur, capacity to spread to distant vital organs, and, ultimately, patient death. Estrogen receptor-positive illness comprises the most common breast cancer subtype. Preclinical progress is hampered by the scarcity of medication-naïve estrogen receptor-positive tumour models that recapitulate metastatic development and treatment resistance. It is becoming increasingly clear that loss of differentiation and increased cellular stemness and plasticity are important causes of cancer evolution, heterogeneity, recurrence, metastasis, and treatment failure. Therefore, it has been suggested that reprogramming cancer cell differentiation could offer an effective method of reversing cancer through terminal differentiation and maturation. In this context, the hormone prolactin is well recognized for its pivotal involvement in the development of the mammary glands lobuloalveolar tissue and the terminal differentiation that drives the production of the milk protein gene and lactation. Additionally, numerous studies have examined the engagement of prolactin in breast cancer as a differentiation player that resulted in the ablation of tumour growth and progression. Here, we showed that a pre-treatment of the estrogen-positive breast cancer cell line with prolactin led to a considerable improvement in the sensitivity of this cancer cell to Tamoxifen endocrine therapy. We also showed a favourable prognostic value of prolactin receptors/estrogen receptors 1 (or alpha) co-expression on breast cancer patients outcomes, and this co-expression is highly correlated with the well-differentiated breast tumour type. Our results revealed a fruitful aspect of the effects of prolactin in improving the responses of breast cancer cells to conventional endocrine therapy. Moreover, these findings further validated the ability of prolactin as a persuader of a more differentiated and less aggressive breast cancer phenotype. Hence, it suggested a potential implication of prolactin as a therapeutic candidate.

Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer.

The mitochondrial unfolded protein response (UPRmt) maintains mitochondrial quality control and proteostasis under stress conditions. However, the role of UPRmt in aggressive and resistant prostate cancer is not clearly defined. We show that castration-resistant neuroendocrine prostate cancer (CRPC-NE) harbored highly dysfunctional oxidative phosphorylation (OXPHOS) Complexes. However, biochemical and protein analyses of CRPC-NE tumors showed upregulation of nuclear-encoded OXPHOS proteins and UPRmt in this lethal subset of prostate cancer suggestive of compensatory upregulation of stress signaling. Genetic deletion and pharmacological inhibition of the main chaperone of UPRmt heat shock protein 60 (HSP60) reduced neuroendocrine prostate cancer (NEPC) growth in vivo as well as reverted NEPC cells to a more epithelial-like state. HSP60-dependent aggressive NEPC phenotypes was associated with upregulation of β-catenin signaling both in cancer cells and in vivo tumors. HSP60 expression rendered enrichment of aggressive prostate cancer signatures and metastatic potential were inhibited upon suppression of UPRmt. We discovered that UPRmt promoted OXPHOS functions including mitochondrial bioenergetics in CRPC-NE via regulation of β-catenin signaling. Mitochondrial biogenesis facilitated cisplatin resistance and inhibition of UPRmt resensitizes CRPC-NE cells to cisplatin. Together, our findings demonstrated that UPRmt promotes mitochondrial health via upregulating β-catenin signaling and UPRmt represents viable therapeutic target for NEPC.

The Potential Therapeutic Value of Aspirin in Anaplastic Thyroid Cancer

Background: several experimental findings and epidemiological observations indicated that aspirin/acetylsalicylic acid (ASA) may be endowed with anticancer effects against a variety of human malignancies, including thyroid carcinomas. Among these, undifferentiated/anaplastic thyroid carcinoma (ATC) is one of the most aggressive and lethal human cancers, refractory to all currently available therapies. Methods: we here evaluated in a preclinical setting the effects of ASA on a panel of three ATC-derived cell lines: the CAL-62, the 8305C, and the 8505C. Results: the data obtained demonstrated the ability of ASA to inhibit, in a dose- and time-dependent manner, the proliferation of all ATC cell lines investigated, with IC50 values comprised between 2.0 and 4.3 mM. Cell growth was restrained with the same efficacy when the ASA treatment was applied to three-dimensional soft-agar cultures. In addition, ASA significantly reduced migration and invasion in two of the three ATC cell lines. We finally investigated the effects of ASA on the MAPK and PI3K/Akt signaling pathways, which are often altered in ATC. The results showed that the phosphorylation status of the Akt1/2/3 kinases was significantly reduced following ASA treatment, while ERK1/2 phosphorylation was either unaffected or slightly upregulated. Conclusions: our findings support epidemiological evidence on the anticancer potential of ASA. On this basis, further investigations should be carried out to assess the usefulness of ASA as adjuvant therapy in patients affected by ATC.

Neuroendocrine prostate cancer (clinical case)

Neuroendocrine prostate cancer is a rare and aggressive cancer with a poor prognosis. This type of cancer is often diagnosed at an advanced stage and exhibits rapid resistance to standard therapeutic methods. Taking into account the low occurrence of this phenomenon, a description of poorly differentiated neuroendocrine (small cell) prostate cancer with extremely aggressive forms is given.

Machine Learning-based Prognostic Subgrouping of Glioblastoma: A Multi-center Study.

Glioblastoma is the most aggressive adult primary brain cancer, characterized by significant heterogeneity, posing challenges for patient management, treatment planning, and clinical trial stratification. We developed a highly reproducible, personalized prognostication and clinical subgrouping system using machine learning (ML) on routine clinical data, MRI, and molecular measures from 2,838 demographically diverse patients across 22 institutions and 3 continents. Patients were stratified into favorable, intermediate, and poor prognostic subgroups (I, II, III) using Kaplan-Meier analysis (Cox proportional model and hazard ratios [HR]). The ML model stratified patients into distinct prognostic subgroups with HRs between subgroups I-II and I-III of 1.62 (95%CI: 1.43-1.84, p<0.001) and 3.48 (95%CI: 2.94-4.11, p<0.001), respectively. Analysis of imaging features revealed several tumor properties contributing unique prognostic value, supporting the feasibility of a generalizable prognostic classification system in a diverse cohort. Our ML model demonstrates extensive reproducibility and online accessibility, utilizing routine imaging data rather than complex imaging protocols. This platform offers a unique approach for personalized patient management and clinical trial stratification in glioblastoma.

Receipt of guideline-concordant care and survival among young adult women with non-metastatic breast cancer.

Adolescent and young adults (AYA) with breast cancer, compared to older adults, are diagnosed with more aggressive cancers, at more advanced stages and may undergo more aggressive treatment but have worse survival. Despite this, no research has studied the effects of the receipt of National Comprehensive Cancer Network (NCCN) defined guideline-concordant care (GCC) for breast cancer on AYA survival. We examined the association of GCC with survival among young adult (20-39 years old) breast cancer survivors. We used the Patterns of Care Study; a stratified random sample of 952 young adult women diagnosed with Stage I-III breast cancer in 2013. NCCN guidelines were used to categorize treatment as GCC or non-GCC. We used Kaplan-Meier curves, log-rank tests, and Cox-proportional hazards models to evaluate the effect of GCC on breast cancer-specific survival, stratifying by triple-negative breast cancer (TNBC) and non-TNBC, and adjusting for sociodemographic and clinical factors. All univariate analyses showed that non-GCC was associated with worse survival than GCC. The association was statistically significant for non-TNBC (Hazard ratio: 3.45, CI 1.64-7.29) and TNBC (Hazard ratio: 3.70, CI 1.02-13.43) in multivariable Cox models adjusted for sociodemographic variables and for non-TNBC (Hazard ratio: 3.13, CI 1.13-8.72) when the model was adjusted for sociodemographic and clinical variables. Among young adult women with non-metastatic breast cancer, while receipt of NCCN GCC is univariately associated with better survival for both TNBC and non-TNBC, the effect of sociodemographic and clinical factors on the association differs by TNBC status. Further investigation with larger TNBC samples is needed.

Plasma cell-free DNA chromatin immunoprecipitation profiling depicts phenotypic and clinical heterogeneity in advanced prostate cancer.

Cell phenotype underlies prostate cancer presentation and treatment resistance and can be regulated by epigenomic features. However, the osteotropic tendency of prostate cancer limits access to metastatic tissue, meaning most prior insights into prostate cancer chromatin biology are from preclinical models that do not fully represent disease complexity. Noninvasive chromatin immunoprecipitation of histones in plasma cell-free in humans may enable capture of disparate prostate cancer phenotypes. Here, we analyzed activating promoter- and enhancer-associated H3K4me2 from cfDNA in metastatic prostate cancer enriched for divergent patterns of metastasis and diverse clinical presentation. H3K4me2 density across prostate cancer genes, accessible chromatin, and lineage-defining transcription factor binding sites correlated strongly with circulating tumor DNA (ctDNA) fraction-demonstrating capture of prostate cancer-specific biology and informing the development of a statistical framework to adjust for ctDNA fraction. Chromatin hallmarks mirrored synchronously measured clinico-genomic features: bone versus liver-predominant disease, serum PSA, biopsy-confirmed histopathological subtype, and RB1 deletions convergently indicated phenotype segregation along an axis of differential androgen receptor activity and neuroendocrine identity. Detection of lineage switching after sequential progression on systemic therapy in select patients indicates potential utility for individualized resistance monitoring. Epigenomic footprints of metastasis-induced normal tissue destruction were evident in bulk cfDNA from two patients. Finally, a public epigenomic resource was generated using a distinct chromatin marker that has not been widely investigated in prostate cancer. These results provide insight into the adaptive molecular landscape of aggressive prostate cancer and endorse plasma cfDNA chromatin profiling as a biomarker source and biological discovery tool.

Clear Cell Sarcoma of the Parotid Gland: Case Report and Review of the Literature.

Clear cell sarcoma (CCS) of the parotid gland is a rare and aggressive cancer, predominantly affecting the deep soft tissues of the lower extremities, and is more frequently observed in the elderly. Its occurrence in the head and neck area, particularly in the parotid gland, is exceedingly rare. This study presents a 75-year-old male who exhibited a substantial, swiftly-enlarging mass on the left side of the mandible, which was diagnosed as CCS of the parotid gland. Morphologically and immunohistochemically, CCS shares characteristics with melanomas, and Ewing sarcoma, complicating differential diagnosis. The primary treatment for localized CCS typically involves surgical excision with clear margins. However, due to its resistance to conventional chemotherapy, there is ongoing research regarding the efficacy of adjuvant therapies such as chemoradiation, lymphadenectomy as well as immunotherapies such as immune checkpoint inhibitors. Further research is imperative to enhance our understanding of CCS and to develop more effective treatment strategies.

FAHD1 and mitochondrial metabolism: a decade of pioneering discoveries.

This review consolidates a decade of research on fumarylacetoacetate hydrolase domain containing protein 1 (FAHD1), a mitochondrial oxaloacetate tautomerase and decarboxylase with profound implications in cellular metabolism. Despite its critical role as a regulator in mitochondrial metabolism, FAHD1 has remained an often-overlooked enzyme in broader discussions of mitochondrial function. After more than 12 years of research, it is increasingly clear that FAHD1's contributions to cellular metabolism, oxidative stress regulation, and disease processes such as cancer and aging warrant recognition in both textbooks and comprehensive reviews. The review delves into the broader implications of FAHD1 in mitochondrial function, emphasizing its roles in mitigating reactive oxygen species (ROS) levels and regulating complex II activity, particularly in cancer cells. This enzyme's significance is further highlighted in the context of aging, where FAHD1's activity has been shown to influence cellular senescence, mitochondrial quality control, and the aging process. Moreover, FAHD1's involvement in glutamine metabolism and its impact on cancer cell proliferation, particularly in aggressive breast cancer subtypes, underscores its potential as a therapeutic target. In addition to providing a comprehensive account of FAHD1's biochemical properties and structural insights, the review integrates emerging hypotheses regarding its role in metabolic reprogramming, immune regulation, and mitochondrial dynamics. By establishing a detailed understanding of FAHD1's physiological roles and therapeutic potential, this work advocates for FAHD1's recognition in foundational texts and resources, marking a pivotal step in its integration into mainstream metabolic research and clinical applications in treating metabolic disorders, cancer, and age-related diseases.

Explainable machine learning for predicting recurrence-free survival in endometrial carcinosarcoma patients

ObjectivesEndometrial carcinosarcoma is a rare, aggressive high-grade endometrial cancer, accounting for about 5% of all uterine cancers and 15% of deaths from uterine cancers. The treatment can be complex, and the prognosis is poor. Its increasing incidence underscores the urgent requirement for personalized approaches in managing such challenging diseases.MethodIn this work, we designed an explainable machine learning approach to predict recurrence-free survival in patients affected by endometrial carcinosarcoma. For this purpose, we exploited the predictive power of clinical and histopathological data, as well as chemotherapy and surgical information collected for a cohort of 80 patients monitored over time. Among these patients, 32.5% have experienced the appearance of a recurrence.ResultsThe designed model was able to well describe the observed sequence of events, providing a reliable ranking of the survival times based on the individual risk scores, and achieving a C-index equals to 70.00% (95% CI, 59.38–84.74).ConclusionAccordingly, machine learning methods could support clinicians in discriminating between endometrial carcinosarcoma patients at low-risk or high-risk of recurrence, in a non-invasive and inexpensive way. To the best of our knowledge, this is the first study proposing a preliminary approach addressing this task.

Preclinical evaluation of an anchored immunotherapy strategy with aluminum hydroxide-tethered interleukin-12 in dogs with advanced malignant melanoma.

Melanoma is an aggressive cancer in dogs involving skin and mucosa similar to people. Anchored immunotherapeutics offer a novel approach to increase intratumoral retention of therapeutic payloads while decreasing systemic exposure, and this strategy can be critically evaluated through a comparative oncology approach. JEN-101 is an anchored canine interleukin-12 (IL-12) tethered to aluminum hydroxide administered by local injection. A Phase I study was conducted to determine the tolerability, activity, and immune responses of JEN-101 in dogs with advanced melanoma. A 3+3 dose escalation design was used to evaluate intratumoral injection of JEN-101 at 1, 3, 10, or 20 μg/kg every three weeks for four cycles. A second course was allowable in the absence of disease progression or toxicity. Peripheral blood, serum, and tumor biopsies were collected at baseline and at pre-specified timepoints for pharmacokinetic and immune analyses, which included serum cytokines, immunohistochemistry, and gene expression assessment. JEN-101 was well tolerated with adverse events being fever, lethargy, and isolated elevated liver enzymes. Five dogs experienced grade 3 events and no grade 4 events were observed. Pharmacokinetic analysis showed a trend towards dose-related Cmax within 8 hours of injection. Responding dogs demonstrated increased systemic interferon-γ and IL-10 AUC levels and local recruitment of CD3+ T cells. Increased pro-inflammatory and antigen processing gene expressions were identified in responding lesions. JEN-101 was well tolerated with evidence of biologic and therapeutic activities. Anchored IL-12 immunotherapy merits further investigation in dogs with melanoma and our approach represents an immune competent model to inform human clinical trials.

BUD23 promote the cell proliferation ability by affecting the PPAR signaling pathways: evidence from the online dataset and cell experiment

IntroductionProstate cancer is a major public health challenge for men worldwide, being the second most common cancer diagnosis and the fifth leading cause of cancer-related deaths among men. The etiology of prostate cancer is multifactorial, with age, genetic predispositions, and lifestyle factors playing critical roles. The role of the peroxisome proliferator-activated receptors (PPARs) in prostate cancer remains complex and not fully elucidated.MethodsTranscriptomic data from The Cancer Genome Atlas (TCGA) were utilized for this study. The data were analyzed using single-sample Gene Set Enrichment Analysis (ssGSEA), Gene Ontology (GO) enrichment analysis, KEGG pathway analysis, and Gene Set Enrichment Analysis (GSEA). A prognosis-prediction model was constructed using Cox regression and LASSO analysis. Functional experiments, including Western blotting, quantitative PCR (qPCR), Cell Counting Kit-8 (CCK-8) assays, and EdU incorporation assays, were performed to validate the role of BUD23 in prostate cancer.ResultsSignificant differences were observed in the immune microenvironment and HLA gene expression profiles between high and low PPAR expression groups in prostate cancer. The high PPAR group exhibited a less active immune microenvironment with higher fractions of immunosuppressive T regulatory cells (Tregs). A robust prognostic model identified key genes, including BUD23, associated with patient survival. Elevated BUD23 expression was correlated with more aggressive clinical features such as advanced pathological stages, nodal metastasis, and higher Gleason scores. Knockdown of BUD23 in PC-3 and LNCaP prostate cancer cell lines significantly inhibited cell proliferation. Western blotting and qPCR confirmed effective BUD23 knockdown, and CCK-8 and EdU assays demonstrated reduced cell proliferation. BUD23 knockdown resulted in significant reductions in PPAR-α, PPAR-β, and PPAR-γ protein levels, suggesting a regulatory axis between BUD23 and PPARs in prostate cancer.ConclusionThe study highlights the distinct roles of PPARα, PPARβ/δ, and PPARγ in prostate cancer progression and their potential as therapeutic targets. Elevated BUD23 expression is associated with aggressive prostate cancer features and patient survival, making it a potential prognostic biomarker. The knockdown of BUD23 not only inhibited cell proliferation but also reduced the expression of PPAR-related proteins, indicating a potential regulatory axis between BUD23 and PPARs. These findings suggest that targeting BUD23 could modulate PPAR signaling and inhibit tumor growth in prostate cancer.

Androgen receptor inhibition increases MHC Class I expression and improves immune response in prostate cancer.

Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression. To uncover the mechanism, we performed a whole genome CRISPRi screen and identified AR as a repressor of the MHCI pathway. Syngeneic mouse models of aggressive prostate cancer deficient in AR also demonstrated increased tumor immunogenicity and promoted T cell mediated tumor-control. Notably, the increase in MHCI expression upon androgen receptor blockade is transient and correlates with resistance to AR inhibition. Mechanistic studies identified androgen response elements upstream of MHCI transcription start sites which increased MHCI expression when deleted. Together, this body of work highlights another mechanism by which hormones can promote immune escape.

Targeting Nudix Hydrolase 5 with Bioactive Flavonoids: Molecular Dynamics and Docking Studies for Breast Cancer Therapy.

Breast cancer (BC) is the most prevalent malignancy among women globally and the leading cause of cancer-related mortality. Consequently, there is an urgent need for new, effective treatment strategies for breast cancer. Research has shown that the enzyme nudix hydrolase 5 (NUDT5) plays a critical role in promoting breast cancer aggressiveness and serves as a key regulator of oncogenic pathways. The development of NUDT5 inhibitors presents a viable strategy for enhancing treatment results in managing BC. The ability of the flavonoids to modulate key biochemical pathways and improve therapeutic outcomes highlights their promise in developing novel breast cancer treatments. Hence, the main objective of the present investigation is to identify the potential interaction of structurally diverse bioactive flavonoids with the active site of the target NUDT5. Our docking analysis revealed that the flavonoids such as naringin and genistein have shown a significant binding association with residues Arg51, Asp60, Gln82, Arg84, Ala96, Leu98, Glu112, Glu116, Met132, Cys139, Ile141, and Glu166 of NUDT5, suggesting its potential as a potent inhibitor. The stabilizing effects of these leads (naringin and genistein) were further validated using molecular dynamics investigations, including RMSD, RMRF, Rg, SASA, PCA, and FEL. The results of the MD simulation studies evidenced a more significant interaction between genistein and NUDT5, indicating a steady and robust affinity, making genistein a more promising inhibitor. In conclusion, the flavonoid genistein has a strong potential as a therapeutic agent for targeting NUDT5 in breast cancer treatment making it viable candidates for further preclinical and clinical investigations.

Alkyne‐ and Azide‐Functionalised Cyclophellitol Derivatives for Selective Glucuronidase Targeting

AbstractHeparanase is an endo‐acting β‐glucuronidase responsible for the degradation of heparan sulfate structures in the extracellular matrix. The enzyme is found to be significantly upregulated in aggressive cancer types, aiding cell proliferation by liberation of growth factors, increasing angiogenesis and metastasis. Despite much interest in the development of inhibitors to control this activity, no compound targeting heparanase has yet been approved as a drug. While mechanism‐based inhibitors derived from the natural product cyclophellitol are very potent enzyme inactivators through their reactive epoxide, one challenge in their development is in achieving selectivity for heparanase over related glycosidases while also maintaining a balance of appropriate pharmacological properties. We present here the synthesis of three cyclophellitol scaffolds presenting azide and alkyne handles at key positions, which are amenable to facile elaboration via copper‐catalysed azide‐alkyne cycloadditions to aid in exploring the structure‐activity relationship for selective inhibitors of heparanase.