Cancer Therapy Research Articles

An Updated Review on Molecular Biomarkers in Diagnosis and Therapy of Colorectal Cancer.

Colorectal cancer is one of the most common cancer types worldwide. Since colorectal cancer takes time to develop, its incidence and mortality can be treated effectively if it is detected in its early stages. As a result, non-invasive or invasive biomarkers play an essential role in the early diagnosis of colorectal cancer. Many experimental studies have been carried out to assess genetic, epigenetic, or protein markers in feces, serum, and tissue. It may be possible to find biomarkers that will help with the diagnosis of colorectal cancer by identifying the genes, RNAs, and/or proteins indicative of cancer growth. Recent advancements in the molecular subtypes of colorectal cancer, DNA methylation, microRNAs, long noncoding RNAs, exosomes, and their involvement in colorectal cancer have led to the discovery of numerous new colorectal cancer biomarkers. In small-scale investigations, most biomarkers appear promising. However, large-scale clinical trials are required to validate their effectiveness before routine clinical implementation. Hence, this review focuses on small-scale investigations and results of big data analysis that may provide an overview of the biomarkers for the diagnosis, therapy, and prognosis of colorectal cancer.

Recent Advances in the Development of RET Inhibitors

Background: Rearranged during transfection (RET) is a receptor tyrosine kinase and a bona fide oncogene that drives various cancers. Oncogenic RET induces abnormal activation of RET kinase, causing tumorigenesis. RET can be abnormally activated through RET point mutations and RET fusions. Although RET kinase has been discovered in tumors more than 30 years ago, patients with RET-altered tumors gain limited benefits from multikinase inhibitors (MKIs). In 2020, pralsetinib and selpercatinib were approved by FDA for the treatment of RET-altered tumors. Objective: Recently reported RET inhibitors were reviewed to provide an overview of the development of novel RET inhibitors. Methods: Literatures, patents, and conference proceedings published in the past five years were collected. Only RET inhibitors with novel scaffolds or in vivo efficacy were discussed in this review. The enzymebased and cell-based activities, PK profiles, antitumor activities in vivo, and clinical efficacy of the selected RET inhibitors were described. Results: Great efforts have been spent on the development of RET inhibitors, leading to increased RETtargeted therapies. Due to high potency and specificity, pralsetinib and selpercatinib resulted in a >8- month improvement in overall survival, compared to MKIs. However, solvent-front mutants emerged and contributed to the acquired resistance to pralsetinib and selpercatinib. To overcome solvent front mutants, TPX-0046, TAS0953, and LOX-260 are investigated in early clinical studies. Conclusion: Zeteletinib, SYHA1815, TPX-0046, TAS0953, and LOX-260 are potential therapies for RET-altered cancers. In addition, macrocyclic inhibitors, allosteric inhibitors, and PROTACs are three promising strategies to address the potential drug resistance of RET.

SOAT1 in gallbladder cancer: Clinicopathological significance and avasimibe therapeutics.

The aim of this investigation was to evaluate the differential expression of the sterol O-acyltransferase 1 (SOAT1) protein in gallbladder cancer tissues and cells, investigate the impact of Avastin on the proliferation, migration, invasion capabilities of gallbladder cancer cells, and its potential to induce cell apoptosis. Immunohistochemical analysis of samples from 145 gallbladder cancer patients was conducted, along with analysis of SOAT1 protein, mRNA expression levels, and cholesterol content in gallbladder cancer cell lines SGC-996, NOZ, and gallbladder cancer (GBC)-SD using Western blot and q-PCR techniques. Furthermore, the effects of Avastin on the proliferation, migration, and invasion capabilities of these gallbladder cancer cell lines were studied, and its ability to induce cell apoptosis was evaluated using flow cytometry, Western blot, and immunohistochemical methods. Additionally, gene expression and pathway analysis were performed, and the synergistic therapeutic effects of Avastin combined with gemcitabine were tested in a gallbladder cancer xenograft model. The study found that SOAT1 expression was significantly upregulated in GBC tissues and positively correlated with lymph node metastasis and TNM staging. In vitro experiments demonstrated that Avastin significantly inhibited the proliferation, migration, and invasion capabilities of SGC-996 and GBC-SD cell lines and induced apoptosis. RNA sequencing analysis revealed multiple differentially expressed genes in cells treated with Avastin, primarily enriched in biological pathways such as signaling transduction, malignant tumors, and the immune system. In vivo, experiments confirmed that Avastin could effectively suppress tumor growth in a gallbladder cancer xenograft model and enhanced the treatment efficacy when used in combination with gemcitabine. Overall, these findings provide new insights and strategies for targeted therapy in gallbladder cancer.

Focal high-intensity focused ultrasound therapy for localized prostate cancer: An interim analysis of the multinational FASST study.

High-intensity focused ultrasound (HIFU) emerged as a novel approach for the treatment of localized prostate cancer (PCa). However, prospective studies on HIFU-related outcomes and predictors of treatment failure (TF) remain scarce. We conducted a multinational prospective cohort study among patients undergoing HIFU therapy for localized, low- to intermediate-risk PCa. Follow-up data on serial prostate specific antigen (PSA), multi-parametric magnetic resonance imaging (mpMRI), targeted/systematic biopsies, adverse events and functional outcomes were collected. The primary endpoint was TF, defined as histologically confirmed PCa requiring whole-gland salvage treatment. Uni- and multi-variable adjusted hazard ratios (HRs) were calculated using Cox proportional hazard regression models. At baseline, mean (standard deviation) age was 64.14 (7.19) years, with the majority of patients showing T-stage 1 (73.9%) and International Society of Urological Pathology grading system Grade 2 (58.8%). PSA nadir (median, 1.70 ng/mL) was reached after 6 months. Of all patients recruited, 16% had clinically significant PCa, as confirmed by biopsy, of which 13.4% had TF. Notably, T-stage and number of positive cores at initial biopsy were independent predictors of TF during follow-up (HR [95% CI] 1.27 [1.02-1.59] and 5.02 [1.80-14.03], respectively). Adverse events were minimal (17% and 8% early and late adverse events, respectively), with stable or improved functional outcomes in the majority of patients. This interim analysis of a multinational study on HIFU therapy for the management of low-to-intermediate-risk PCa reveals good functional outcomes, minimal adverse events and low incidence of TF over the short-term. Data on long-term outcomes, specifically as it relates to oncological outcomes, are awaited eagerly.

Association between endocrine adjuvant therapy intake timing and disease-free survival in patients with high-risk early breast cancer: results of a sub-study of the UCBG- UNIRAD trial

Circadian rhythms regulate cellular physiology and could influence the efficacy of endocrine therapy (ET) in breast cancer (BC). We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271). 1278 patients with high-risk hormonal receptor positive (HR+)/HER2 negative (HER2-) primary BC were randomly assigned to adjuvant ET with placebo or everolimus. Patients prospectively reported in a diary the daily timing of ET intake among four 6-h slots (06:00-11:59 (morning), 12:00-17:59 (afternoon), 18:00-23:59 (evening), or 24:00-05:59 (nighttime). The association between ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial and the results of this observational study are reported here. ET timing was recorded by 855 patients (67.2%). Patients declaring morning (n=465, 54.4%) or afternoon (n=45, 5.4%) ET intake were older than those declaring evening (n=339, 39.6%) or nighttime (n=5, 0.6%) intake. With a median follow-up of 46.7 months, 118 patients had a local (n=30) or metastasis relapse (n=84), and 41 patients died. ET intake timing was not associated with DFS in the whole population (HR=0.77, 95% CI [0.53-1.12]). The association between ET intake timing and DFS according to the stratification factors revealed interactions with ET agent (tamoxifen versus Aromatase inhibitors (AI) with an increased DFS in the group of evening/nighttime versus morning/afternoon tamoxifen intake (HR=0.43, 95% CI [0.22-0.85]), while no association was found for AI intake (HR=1.07, 95% CI [0.68-1.69]). The interaction between ET intake timing and ET agent remained in multivariable analysis (HR=0.38 [0.16-0.91]). Tamoxifen intake in the evening/nighttime could be recommended in patients with high-risk HR+/HER2- BC while awaiting for results from further ET timing studies. UNIRAD was Supported by a grant from the French Ministry of Health PHRC 2012 and received funding from La Ligue contre le Cancer, Cancer Research-UK, Myriad Genetics, and Novartis.

Thrombin - A Molecular Dynamics Perspective.

Thrombin is a crucial enzyme involved in blood coagulation, essential for maintaining circulatory system integrity and preventing excessive bleeding. However, thrombin is also implicated in pathological conditions such as thrombosis and cancer. Despite the application of various experimental techniques, including X-ray crystallography, NMR spectroscopy, and HDXMS, none of these methods can precisely detect thrombin's dynamics and conformational ensembles at high spatial and temporal resolution. Fortunately, molecular dynamics (MD) simulation, a computational technique that allows the investigation of molecular functions and dynamics in atomic detail, can be used to explore thrombin behavior. This review summarizes recent MD simulation studies on thrombin and its interactions with other biomolecules. Specifically, the 17 studies discussed here provide insights into thrombin's switch between 'slow' and 'fast' forms, active and inactive forms, the role of Na+ binding, the effects of light chain mutation, and thrombin's interactions with other biomolecules. The findings of these studies have significant implications for developing new therapies for thrombosis and cancer. By understanding thrombin's complex behavior, researchers can design more effective drugs and treatments that target thrombin.

Role of TBK1 Inhibition in Targeted Therapy of Cancer.

TANK-binding kinase 1 (TBK1) is a serine/threonine protein that plays a crucial role in various biological processes like immunity, autophagy, cell survival, and proliferation. The level and kinase activity of the TBK1 protein is regulated through post-translational modifications (PTMs). TBK1 mainly mediates the activation of IRF3/7 and NF-κB signaling pathways while also participating in the regulation of cellular activities such as autophagy, mitochondrial metabolism, and cell proliferation. TBK1 regulates immune, metabolic, inflammatory, and tumor occurrence and development within the body through these cellular activities. TBK1 kinase has emerged as a promising therapeutic target for tumor immunity. However, its molecular mechanism of action remains largely unknown. The identification of selective TBK1 small molecule inhibitors can serve as valuable tools for investigating the biological function of TBK1 protein and also as potential drug candidates for tumor immunotherapy. The current research progress indicates that some TBK1 inhibitors (compounds 15,16 and 21) exhibit certain antitumor effects in vitro culture systems. Here, we summarize the mechanism of action of TBK1 in tumors in recent years and the progress of small molecule inhibitors of TBK1.

Challenges and opportunities for cancer stem cell-targeted immunotherapies include immune checkpoint inhibitor, cancer stem cell-dendritic cell vaccine, chimeric antigen receptor immune cells, and modified exosomes.

Cancer stem cells (CSCs) are associated with the tumor microenvironment (TME). CSCs induce tumorigenesis, tumor recurrence and progression, and resistance to standard therapies. Indeed, CSCs pose an increasing challenge to current cancer therapy due to their stemness or self-renewal properties. The molecular and cellular interactions between heterogeneous CSCs and surrounding TME components and tumor-supporting immune cells show synergistic effects toward treatment failure. In the immunosuppressive TME, CSCs express various immunoregulatory proteins, growth factors, metabolites and cytokines, and also produce exosomes, a type of extracellular vesicles, to protect themselves from host immune surveillance. Among these, the identification and application of CSC-derived exosomes could be considered for the development of therapeutic approaches to eliminate CSCs or cancer, in addition to targeting the modulators that remodel the composition of the TME, as reviewed in this study. Here, we introduce the role of CSCs and how their interaction with TME complicates immunotherapies, and then present the CSC-based immunotherapy and the limitation of these therapies. We describe the biology and role of tumor/CSC-derived exosomes that induce immune suppression in the TME, and finally, introduce their potentials for the development of CSC-based targeted immunotherapy in the future.

Fucoxanthin induces human melanoma cytotoxicity by thwarting the JAK2/STAT3/BCL-xL signaling axis.

Melanoma is the most lethal skin malignancy. Fucoxanthin is a marine carotenoid with significant anticancer activities. Intriguingly, Fucoxanthin's impact on human melanoma remains elusive. Signal Transducer and Activator of Transcription 3 (STAT3) represents a promising target in cancer therapy due to its persistent activation in various cancers, including melanoma. Herein, we revealed that Fucoxanthin is cytotoxic to human melanoma cell lines A2758 and A375 while showing limited cytotoxicity to normal human melanocytes. Apoptosis is a primary reason for Fucoxanthin's melanoma cytotoxicity, as the pan-caspase inhibitor z-VAD-fmk drastically abrogated Fucoxanthin-elicited clonogenicity blockage. Besides, Fucoxanthin downregulated tyrosine 705-phosphorylated STAT3 (p-STAT3 (Y705)), either inherently present in melanoma cells or inducible by interleukin 6 (IL-6) stimulation. Notably, ectopic expression of STAT3-C, a dominant-active STAT3 mutant, abolished Fucoxanthin-elicited melanoma cell apoptosis and clonogenicity inhibition, supporting the pivotal role of STAT3 blockage in Fucoxanthin's melanoma cytotoxicity. Moreover, Fucoxanthin lowered BCL-xL levels by blocking STAT3 activation, while ectopic BCL-xL expression rescued melanoma cells from Fucoxanthin-induced killing. Lastly, Fucoxanthin was found to diminish the levels of JAK2 with dual phosphorylation at tyrosine residues 1007 and 1008 in melanoma cells, suggesting that Fucoxanthin impairs STAT3 signaling by blocking JAK2 activation. Collectively, we present the first evidence that Fucoxanthin is cytotoxic selectively against human melanoma cells while sparing normal melanocytes. Mechanistically, Fucoxanthin targets the JAK2/STAT3/BCL-xL antiapoptotic axis to provoke melanoma cell death. This discovery implicates the potential application of Fucoxanthin as a chemopreventive or therapeutic strategy for melanoma management.

Preparation, Characterization, and Evaluation of the Anticancer Effect of Mesoporous Silica Nanoparticles Containing Rutin and Curcumin.

The aim of this study was the preparation of mesoporous silica nanoparticles co-loaded with rutin and curcumin (Rut-Cur-MSNs) and the assessment of its physicochemical properties as well as its cytotoxicity on the head and neck cancer cells (HN5). Besides, ROS generation of HN5 cells exposed to Rut-Cur-MSNs was evaluated. Several investigations showed that rutin and curcumin have potential effects as anticancer phytochemicals; however, their low aqueous solubility and poor bioavailability limited their applications. The assessment of physicochemical properties and anticancer effect of prepared nanoparticles was the objective of this study. The physicochemical properties of produced nanoparticles were evaluated. The toxicity of Rut-Cur-MSNs on HN5 cells was assessed. In addition, the ROS production in cells treated with Rut-Cur-MSNs was assessed compared to control untreated cells. The results showed that Rut-Cur-MSNs have mesoporous structure, nanometer size and negative surface charge. The X-ray diffraction pattern showed that the prepared nanoparticles belong to the family of silicates named MCM-41. The cytotoxicity of Rut-Cur-MSNs at 24 h was significantly higher than that of rutin-loaded MSNs (Rut-MSNs) and curcumin-loaded MSNs (Cur-MSNs) (p<0.05). The achieved results recommend that the prepared mesoporous silica nanoparticles containing rutin and curcumin can be a useful nanoformulation for the treatment of cancer. The produced nanomaterial in this study can be helpful for cancer therapy.

Hypoxia A Typical Target in Human Lung Cancer Therapy.

Lung cancer (LC) is the leading cause of cancer-related death globally. Comprehensive knowledge of the cellular and molecular etiology of LC is perilous for the development of active treatment approaches. Hypoxia in cancer is linked with malignancy, and its phenotype is implicated in the hypoxic reaction, which is being studied as a prospective cancer treatment target. The hypervascularization of the tumor is the main feature of human LC, and hypoxia is a major stimulator of neo-angiogenesis. It was seen that low oxygen levels in human LC are a critical aspect of this lethal illness. However, as there is a considerable body of literature espousing the presumed functional relevance of hypoxia in LC, the direct measurement of oxygen concentration in Human LC is yet to be determined. This narrative review aims to show the importance and as a future target for novel research studies that can lead to the perception of LC therapy in hypoxic malignancies.

A Stimulus-Responsive Ternary Heterojunction Boosting Oxidative Stress, Cuproptosis for Melanoma Therapy.

Cuproptosis, a recently discovered copper-dependent cell death, presents significant potential for the development of copper-based nanoparticles to induce cuproptosis in cancer therapy. Herein, a unique ternary heterojunction, denoted as HACT, composed of core-shell Au@Cu2O nanocubes with surface-deposited Titanium Dioxide quantum dots and modified with hyaluronic acid is introduced. Compared to core-shell AC NCs, the TiO2/Au@Cu2O exhibits improved energy structure optimization, successfully separating electron-hole pairs for redox use. This optimization results in a more rapid generation of singlet oxygen and hydroxyl radicals triggering oxidative stress under ultrasound radiation. Furthermore, the HACT NCs initiate cuproptosis by Fenton-like reaction and acidic environment, leading to the sequential release of cupric and cuprous ions. This accumulation of copper induces the aggregation of lipoylated proteins and reduces iron-sulfur proteins, ultimately initiating cuproptosis. More importantly, HACT NCs show a tendency to selectively target cancer cells, thereby granting them a degree of biosecurity. This report introduces a ternary heterojunction capable of triggering both cuproptosis and oxidative stress-related combination therapy in a stimulus-responsive manner. It can energize efforts to develop effective melanoma treatment strategies using Cu-based nanoparticles through rational design.

A prospective single-center, single-arm, open-label, phase II study of sintilimab and anlotinib combined with chemotherapy in neoadjuvant treatment of resectable esophageal cancer.

Antiangiogenic treatment and immunochemotherapy effectively treat patients with advanced esophageal cancer. However, there remains a dearth of studies concerning neoadjuvant therapy for resectable esophageal cancer. The study focused on patients with T2-4NxM0 resectable esophageal carcinoma. Neoadjuvant treatment involved administering anlotinib (10 mg orally, once a day, 2 weeks on and 1 week off) for antiangiogenesis and sintilimab (200 mg) and chemotherapy for three cycles. Surgical treatment was performed 4-6 weeks after the last chemotherapy cycle was completed. The primary endpoints assessed were pathological complete response (pCR) and safety. Out of the 34 screened patients, 17 were successfully enrolled in the study, and 14 completed the entire treatment process. The pCR was 35.3% (6/17). However, two patients experienced mortality. The occurring rate of grade 3 or higher complications after the surgery was 78.6% (11/14) according to Clavien-Dindo classification. Specifically, anastomotic leakage was observed in 57.1% (8/14) of the patients. Compared to neoadjuvant chemotherapy, the current regimen demonstrated improved pCR. However, it did not show significant improvement compared to immunochemotherapy. It is essential to exercise caution when using this treatment approach in patients with esophageal cancer as it might increase postoperative complications, especially anastomotic leakage.

Survival outcomes of radium-223 therapy for metastatic castration-resistant prostate cancer following national health insurance reimbursement in Taiwan.

Radium-223 dichloride (Ra-223) prolongs overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) with symptomatic bone metastases. However, there is considerable variation in outcomes among individuals. We aimed to evaluate the prognostic determinants associated with patient survival following National Health Insurance (NHI) reimbursement for Ra-223 therapy in Taiwan. Patients with mCRPC who underwent Ra-223 treatment at Taipei Veterans General Hospital were retrospectively enrolled. Each intravenous Ra-223 dose was administered at 55 kBq/kg at four-week intervals. Clinical outcomes were obtained from medical records; potential prognostic factors for survival were assessed. Kaplan-Meier analysis was used to generate cumulative survival curves; between-group differences were evaluated using the Chi-squared test. Statistical significance was set at p < 0.05. Seventy-six patients underwent Ra-223 therapy; 62 patients received NHI reimbursement and the remainder self-paid. Fifty patients (65.8%) completed six cycles of treatment; 26 (34.2%) received 1‒5 cycles. Mortality occurred in 47 patients. Factors significantly associated with survival included ≦ five bone metastases (p = 0.0018), baseline prostate-specific antigen (PSA) ≦ 36 ng/mL (p = 0.0004), baseline alkaline phosphate (ALP) < 115 U/L (p = 0.0007), and baseline hemoglobin (Hb) > 12 g/dL (p = 0.0029). Patients who completed six cycles of treatment achieved significantly higher OS compared to those who did not (p < 0.0001). There has been a 4.4-fold increase in the number of patients since reimbursement began; there was no significant difference in OS between patients who received NHI reimbursement and those who self-paid. Administration of Ra-223 demonstrates considerable potential to extend the survival of patients with mCRPC. Survival outcomes may be influenced by various prognostic factors. However, no significant difference in OS was observed subsequent to reimbursement of Ra-223 therapy for mCRPC through the NHI system in Taiwan.

An ultrasensitive electrochemical biosensor based on logic transcription circuit-activated DNAzyme amplifier for flap endonuclease 1 activity detection

The accurate detection of flap endonuclease 1 (FEN1) activity is crucial for early cancer diagnosis and therapy. Herein, we have established a “target-substrate double-enhanced” DNA electrochemical biosensor by integrating a cleavage-ligation logic transcription circuit-activated DNAzyme amplifier with the transition-metal carbides-gold nanoparticles (MXene-Au) composites for the accurate detection of FEN1 activity. The FEN1 can be translated into a stable transcription hairpin DNA (TH), incorporating the catalytic strand of the DNAzyme via the logic transcription circuit. Then, the TH hybridizes with the substrate strand of DNAzyme and the DNAzyme amplifier can be activated, thus producing a significant quantity of single-stranded DNA (sDNA) and achieving the efficient amplification of the FEN1. Finally, the sDNA loaded with electroactive substances is immobilized on the capture DNA-anchored MXene-Au modified electrode, significantly enhancing the electrochemical signal intensity for highly sensitive FEN1 activity detection. The excellent selectivity and sensitivity of the proposed electrochemical biosensor can facilitate the accurate detection of FEN1 activity in biological samples and aid in screening FEN1-releated drugs. Additionally, three-input concatenated logic gates (AND-AND, INHIBIT-AND, and AND-OR) are constructed for FEN1 activity detection. Particularly, the AND-AND gate achieves logic detection of FEN1 activity in complex samples. Consequently, this bidirectionally enhanced electrochemical biosensor offers a novel analytical method for FEN1 activity detection, showing substantial promise for early diagnosis and drug discovery of FEN1-related disease.

RNA Isoforms as Broad Targets for Cancer Immunotherapy.

While immunotherapy is typically reserved for cancer patients with a high mutational burden, neoantigens produced from post-transcriptional regulation provide a possible untapped reservoir of common immunogenic targets for new targeted cancer therapies. In this review, we describe new and emerging technologies, unconventional molecular targets and challenges for the precision immune targeting of diverse malignancies. In particular, we focus on the unique potential of targeting alternative mRNA isoforms as a source for broadly presented neoantigens and cell surface proteins. Finally, we discuss emerging challenges for alternative isoform immune targeting, with an emphasis in silico prioritization and high-throughput target validation.

Experimental investigation of photothermal conversion and thermal conductivity of broadband absorbing gold nanoblackbodies and graphene oxide nanoparticles for plasmonic photothermal cancer therapy

The choice of nanomaterial is crucial for achieving desired thermal ablation of a tumors, considering nanoparticle dose/concentration and near-infrared (NIR) irradiation parameters during plasmonic photothermal therapy (PPTT). Most studies prioritize use of nanoparticles with high photothermal conversion efficiency (η) for PPTT without emphasizing the thermal conductivity (κ) within a solid tumor. Herein, two broadband absorbing nanoparticles, i.e., gold nanoblackbodies (AuNBs) and graphene oxide (GO) nanoparticles, are compared for η under similar NIR irradiation and nanoparticles dose. Further, the effect of photothermal conversion and κ are studied through tumor-tissue mimicking phantoms mimicking invasive ductal carcinoma embedded with nanoparticles, surrounded by normal tissue region. Under similar conditions, η is higher in AuNBs (73.2%) than GO nanoparticles (63.7%), while κ of GO nanoparticles embedded phantom (0.62 W/mK) surpasses AuNBs embedded phantom (0.59 W/mK) by 5.08%. Photothermal response through tumor-tissue mimicking phantoms shows that GO nanoparticles achieve higher temperatures within the entire tumor region than AuNBs due to their high κ, despite having lower η. This finding suggests that η is not the sole parameter, and it is the coupled effect of η and κ for the choice/suitability of a nanoparticle to attain desired temperatures throughout the tumor for PPTT.

Metabolism characterization and toxicity of N-hydap, a marine candidate drug for lung cancer therapy by LC-MS method.

N-Hydroxyapiosporamide (N-hydap), a marine product derived from a sponge-associated fungus, has shown promising inhibitory effects on small cell lung cancer (SCLC). However, there is limited understanding of its metabolic pathways and characteristics. This study explored the in vitro metabolic profiles of N-hydap in human recombinant cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs), as well as human/rat/mice microsomes, and also the pharmacokinetic properties by HPLC-MS/MS. Additionally, the cocktail probe method was used to investigate the potential to create drug-drug interactions (DDIs). N-Hydap was metabolically unstable in various microsomes after 1h, with about 50% and 70% of it being eliminated by CYPs and UGTs, respectively. UGT1A3 was the main enzyme involved in glucuronidation (over 80%), making glucuronide the primary metabolite. Despite low bioavailability (0.024%), N-hydap exhibited a higher distribution in the lungs (26.26%), accounting for its efficacy against SCLC. Administering N-hydap to mice at normal doses via gavage did not result in significant toxicity. Furthermore, N-hydap was found to affect the catalytic activity of drug metabolic enzymes (DMEs), particularly increasing the activity of UGT1A3, suggesting potential for DDIs. Understanding the metabolic pathways and properties of N-hydap should improve our knowledge of its drug efficacy, toxicity, and potential for DDIs.

Endocrine therapy in advanced high-grade ovarian cancer: real-life data from a multicenter study and a review of the literature.

In women, ovarian cancer is the eighth most frequent cancer in incidence and mortality. It is often diagnosed at advanced stages; relapses are frequent, with a poor prognosis. When platinum resistant, subsequent lines of chemotherapy are of limited effect and often poorly tolerated, leading to quality of life deterioration. Various studies suggest a hormonal role in ovarian carcinogenesis, with a rationale for endocrine therapy in these cancers. This multicenter, retrospective study assessed the use of endocrine treatment for high-grade ovarian epithelial carcinomas treated between 2010 and 2020. Eighty-one patients with ovarian cancers were included. The median duration of platinum sensitivity was 29 months. We observed a 35% disease control rate with endocrine therapy, and 10% reported symptom improvement. For 19 patients (23.5%), the disease was stabilized for more than 6 months. Median overall survival from diagnosis was 62.6 months. Regarding endocrine therapy predictive factors of response, in a multivariate analysis, 3 factors were statistically significant in favoring progression-free survival: platinum sensitivity (P = .021), an R0 surgical resection (P = .020), and the indication for hormone therapy being maintenance therapy (P = .002). This study shows real-life data on endocrine therapy in ovarian cancer. As it is a low-cost treatment with many advantages such as its oral administration and its safety, it may be an option to consider. A perspective lies in the search for cofactors to aim as future therapeutic targets to improve the effectiveness of hormone treatment by means of combination therapy.

The future of cancer therapy: exploring the potential of patient-derived organoids in drug development

Cancer therapy is on the brink of a significant transformation with the inclusion of patient-derived organoids (PDOs) in drug development. These three-dimensional cell cultures, directly derived from a patient’s tumor, accurately replicate the complex structure and genetic makeup of the original cancer. This makes them a promising tool for advancing oncology. In this review, we explore the practical applications of PDOs in clinical drug screening and pharmacognostic assessment, as well as their role in refining therapeutic strategies. We provide insights into the latest advancements in PDO technology and its implications for predicting treatment responses and facilitating novel drug discoveries. Additionally, we address the operational challenges associated with incorporating PDOs into the drug development process, such as scaling up organoid cultures, ensuring consistent results, and addressing the ethical use of patient-derived materials. Aimed at researchers, clinicians, and key stakeholders in oncology, this article aims to succinctly present both the extraordinary potential and the obstacles to integrating PDOs, thereby shedding light on their prospective impact on the future of cancer treatment.