-
Asian Pacific Journal of Cancer... Jun 2024There have been several reports on rechallenge with docetaxel, cabazitaxel, abiraterone acetate, or ethinylestradiol for metastatic castration-resistant prostate cancer...
OBJECTIVE
There have been several reports on rechallenge with docetaxel, cabazitaxel, abiraterone acetate, or ethinylestradiol for metastatic castration-resistant prostate cancer (mCRPC). However, the efficacy of enzalutamide rechallenge for mCRPC has not been evaluated.
METHODS
We retrospectively reviewed 63 consecutive patients who received enzalutamide for mCRPC at our institution between 2014 and 2022. Eight of these patients underwent rechallenge with enzalutamide after disease progression on prior enzalutamide and other therapy and were the focus of this study. The prostate-specific antigen (PSA) response (PSA decrease >50%), PSA progression-free survival, treatment duration, overall survival (OS) after CRPC, and treatment-related adverse events were evaluated.
RESULTS
PSA decline to enzalutamide rechallenge was observed in 6 patients (75%), of which 2 patients had a PSA response. The median treatment duration was 4 months (range 1-12) and median PSA progression-free survival was 3 months (range 1-7). Median OS after CRPC was 41 months. OS after CRPC was not increased in patients with a PSA response. No toxicities were worse than grade ≥3.
CONCLUSION
Enzalutamide rechallenge achieved a PSA response in a quarter of our patients with mCRPC after disease progression on prior enzalutamide. However, no improvement of OS was identified in these patients.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Phenylthiohydantoin; Nitriles; Benzamides; Retrospective Studies; Aged; Middle Aged; Prostate-Specific Antigen; Follow-Up Studies; Survival Rate; Prognosis; Aged, 80 and over; Antineoplastic Agents
PubMed: 38918645
DOI: 10.31557/APJCP.2024.25.6.1863 -
Annals of Translational Medicine Jun 2024Zoledronic acid (ZA) improved outcomes in breast cancer. In pre-clinical studies, ZA increased tumour regression in combination chemotherapy and anti-human epidermal...
BACKGROUND
Zoledronic acid (ZA) improved outcomes in breast cancer. In pre-clinical studies, ZA increased tumour regression in combination chemotherapy and anti-human epidermal growth factor receptor 2 (HER2) target therapy. The Zo-NAnTax study, a clinical trial combining ZA with neoadjuvant therapy for HER2-positive tumours met the primary endpoint, showing a higher pathological complete response (pCR) rate than predicted in patients receiving surgery. Here, we report the exploratory relapse-free survival (RFS) and overall survival (OS) analysis after five years of follow-up.
METHODS
Adult women with HER2-positive breast cancer amendable to curative surgery who consented to the study received four cycles of ZA at 4 mg + doxorubicin 60 mg/m + cyclophosphamide 600 mg/m followed by four cycles of ZA at 4 mg + docetaxel 100 mg/m + trastuzumab 6 mg/kg (8 mg/kg as a loading dose), all in a 21 days-cycle, totalizing 8 cycles before surgery. To achieve the primary endpoint of pCR rate between 22% and 35%, 56 patients were needed. The secondary endpoints included safety, gene expression according to treatment response, prediction of pCR rate by an interim breast magnetic resonance imaging (bMRI).
RESULTS
Beyond the overall pCR rate of 42%, alongside a good safety profile, we showed similar pCR rates in both hormonal receptor (HR) positive (40%) and HR-negative (44%). RFS and OS at five years were evaluated in 58 subjects, and the overall rate was 79.3% and 86.2%, respectively. Numerically higher values of both RFS and OS were observed in patients achieving pCR . non-achieving, respectively 83.3% . non-pCR 76.5% (P=0.57) and 95.8% . non-pCR 79.4% (P=0.08). Although not statistically significant, OS was numerically equivalent according to HR status, respectively 85.7% . 87.5% for HR-positive and HR-negative (P=0.91), which contrasted with RFS, HR-positive 81% . HR-negative 75% (P=0.58). None of the assessed clinicopathological biomarkers significantly correlated with survival.
CONCLUSIONS
ZA plus neoadjuvant therapy in HER2-positive breast cancer shows provoking survival outcomes. Clinical and pre-clinical investigation with dual anti-HER2 blockage is warranted.
PubMed: 38911562
DOI: 10.21037/atm-23-1880 -
Diagnostic Pathology Jun 2024Catenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of...
BACKGROUND
Catenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of β-catenin, with consequent hyperactivation of the Wnt/β-catenin signaling pathway, implicated in PCa progression and treatment resistance. To date, successful targeted treatment options for Wnt/β-catenin - driven PCa are lacking.
METHODS
We report a rare histologic transformation of a CTNNB1 (β-catenin) mutated metastatic castration resistant prostate cancer (mCRPC), clinically characterized by highly aggressive disease course. We histologically and molecularly characterized the liver metastatic tumor samples, as well as successfully generated patient-derived organoids (PDOs) and patient-derived xenograft (PDX) from a liver metastasis. We used the generated cell models for further molecular characterization and drug response assays.
RESULTS
Immunohistochemistry of liver metastatic biopsies and PDX tumor showed lack of expression of typical PCa (e.g., AR, PSA, PSAP, ERG) or neuroendocrine markers (synaptophysin), compatible with double-negative CRPC, but was positive for nuclear β-catenin expression, keratin 7 and 34βE12. ERG rearrangement was confirmed by fluorescent in situ hybridization (FISH). Drug response assays confirmed, in line with the clinical disease course, lack of sensitivity to common drugs used in mCRPC (e.g., enzalutamide, docetaxel). The casein kinase 1 (CK1) inhibitor IC261 and the tankyrase 1/2 inhibitor G700-LK showed modest activity. Moreover, despite harbouring a CTNNB1 mutation, PDOs were largely insensitive to SMARCA2/4- targeting PROTAC degraders and inhibitor.
CONCLUSIONS
The reported CTNNB1-mutated mCRPC case highlights the potential challenges of double-negative CRPC diagnosis and underlines the relevance of further translational research to enable successful targeted treatment of rare molecular subtypes of mCRPC.
Topics: Humans; Male; beta Catenin; Mutation; Prostatic Neoplasms, Castration-Resistant; Liver Neoplasms; Animals; Biomarkers, Tumor; Aged; Disease Progression
PubMed: 38907236
DOI: 10.1186/s13000-024-01511-3 -
Discover Oncology Jun 2024To develop a prognostic risk model for Bladder Cancer (BLCA) based on mitochondrial-related long non-coding RNAs (lncRNAs).
OBJECTIVE
To develop a prognostic risk model for Bladder Cancer (BLCA) based on mitochondrial-related long non-coding RNAs (lncRNAs).
METHODS
Transcriptome and clinical data of BLCA patients were retrieved from the TCGA database. Mitochondrial-related lncRNAs with independent prognostic significance were screened to develop a prognostic risk model. Patients were categorized into high- and low-risk groups using the model. Various methods including Kaplan-Meier (KM) analysis, ROC curve analysis, Gene Set Enrichment Analysis (GSEA), immune analysis, and chemotherapy drug analysis were used to verify and evaluate the model.
RESULTS
A mitochondrial-associated lncRNA prognostic risk model with independent prognostic significance was developed. High-risk group (HRG) patients exhibited significantly shorter survival periods compared to low-risk group (LRG) patients (P < 0.01). The risk score from the model was an independent predictor of BLCA prognosis, correlating with tumor grade, pathological stage, and lymph node metastasis (P < 0.05). The HRG showed significant positive correlations with high expressions of immune checkpoints (CTLA4, LAG3, PD-1, TIGIT, PD-L1, PD-L2, and TIM-3) and lower IC50 for chemotherapy drugs (cisplatin, docetaxel, paclitaxel, methotrexate, and vinblastine) (P < 0.001).
CONCLUSIONS
The mitochondrial-related lncRNA-based prognostic risk model effectively predicts BLCA prognosis and can guide individualized treatment for BLCA patients.
PubMed: 38907134
DOI: 10.1007/s12672-024-01108-8 -
Nature Communications Jun 2024Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in...
Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.
Topics: Humans; Docetaxel; Drug Resistance, Neoplasm; Nasopharyngeal Carcinoma; Cell Line, Tumor; Nasopharyngeal Neoplasms; Pyroptosis; Ubiquitination; Animals; Ubiquitin-Protein Ligases; Mice; Mice, Nude; Female; Dynamins; Reactive Oxygen Species; Phosphoprotein Phosphatases; Male; Xenograft Model Antitumor Assays; Mice, Inbred BALB C; Antineoplastic Agents; Phosphorylation; Mitochondrial Proteins; Fluorouracil; Gene Expression Regulation, Neoplastic; Mitochondria; Cisplatin; Middle Aged; Gasdermins
PubMed: 38906860
DOI: 10.1038/s41467-024-49675-2 -
Biomedicine & Pharmacotherapy =... Jun 2024Aberration of Notch signaling is one of the key events involved in the development and progression of head and neck squamous cell carcinoma (HNSCC). The Notch pathway...
Aberration of Notch signaling is one of the key events involved in the development and progression of head and neck squamous cell carcinoma (HNSCC). The Notch pathway controls the tissue-specific differentiation of normal squamous epithelial cells and is frequently altered in squamous carcinomas, thus affecting their proliferation, growth, survival, and chemosensitivity or resistance against anti-cancer agents. In this study, we show that the use of novel, small-molecule inhibitors of Notch signaling, such as FLI-06, can have a beneficial effect on increasing the chemosensitivity of HNSCC to taxane-based chemotherapy. Inhibition of Notch signaling by FLI-06 alone virtually blocks the proliferation and growth of HNSCC cells in both 2D and 3D cultures and the zebrafish model, which is accompanied by down-regulation of key Notch target genes and proteins. Mechanistically, FLI-06 treatment causes cell cycle arrest in the G-phase and induction of apoptosis in HNSCC, which is accompanied by increased c-Jun phosphorylation. Combining FLI-06 with Docetaxel shows a synergistic effect and partially blocks the cell growth of aggressive HNSCC cells via enhanced apoptosis and modification of c-Jun phosphorylation via GSK-3β inhibition. In conclusion, inhibition of Notch signaling in HNSCC cells that retain active Notch signaling significantly supports taxane-based anticancer activities via modulation of both the GSK-3β and the c-Jun.
PubMed: 38906029
DOI: 10.1016/j.biopha.2024.116822 -
Cureus May 2024Prostate cancer (PC) is one of the leading causes of cancer death among men worldwide. Brain metastases from PC are very rare, often presenting in advanced stages of the...
Prostate cancer (PC) is one of the leading causes of cancer death among men worldwide. Brain metastases from PC are very rare, often presenting in advanced stages of the disease, and are associated with a poor prognosis. Treatment is complex and may involve surgery or radiotherapy. We present the case of a 64-year-old male diagnosed with localized prostate adenocarcinoma, initially treated with pelvic radiotherapy associated with long-term hormonal treatment. While on this hormonal treatment, around one year after radical treatment initiation, he developed bilateral pulmonary metastases, histologically proven to be related to PC, defining a state of metastatic castration-resistant PC. He was asymptomatic and therefore treatment with enzalutamide was initiated. A partial response to the lung lesions was obtained and maintained for more than a year, at which time new mediastinal lymph node metastases were identified. An endobronchial ultrasound biopsy revealed metastases from carcinoma with neuroendocrine differentiation, favoring lung small-cell carcinoma. The patient started chemotherapy with carboplatin and etoposide, with a response. Due to the progression of the mediastinal lymph nodes after eight months, the patient had to undergo chemotherapy again, this time in combination with atezolizumab, with once again partial response. Given the possibility of drug interactions, enzalutamide was suspended during both cycles of chemotherapy and successfully reintroduced afterward. Three months after restarting enzalutamide, he began complaining of headaches. Brain imaging revealed a single frontobasal lesion, without evidence of simultaneous extracerebral progression. Considering the epileptogenic potential of enzalutamide, it was again suspended. The patient underwent surgery and histology revealed metastases of prostate adenocarcinoma, a very rare finding. Systemic re-staging after surgery revealed the progression of cerebral and extra-cerebral disease. The patient is currently proposed for treatment with whole brain radiotherapy and chemotherapy with docetaxel. This case demonstrates the difficulties associated with the diagnosis and treatment of a patient with two distinct neoplasms. Therapy choices were necessarily adjusted because of significant drug interactions. The diagnosis of brain lesions was the last complication, and it proved to be a challenge as it is a rare entity, with optimal management options not being well established.
PubMed: 38903358
DOI: 10.7759/cureus.60728 -
Nature Communications Jun 2024This phase II trial aimed to determine the efficacy and safety of induction chemoimmunotherapy of camrelizumab plus modified TPF in locally advanced hypopharyngeal...
This phase II trial aimed to determine the efficacy and safety of induction chemoimmunotherapy of camrelizumab plus modified TPF in locally advanced hypopharyngeal squamous cell carcinoma (LA HSCC) (NCT04156698). The primary endpoint was objective response rate (ORR), and secondary endpoints were 3-year overall survival (OS), progression-free survival (PFS), larynx preservation rate (LPR), and metastasis-free survival (MFS). Patients (cT3-4aN0-2M0), regardless of sex, received induction chemoimmunotherapy for three cycles: camrelizumab 200 mg d1, docetaxel 75 mg/m d1, cisplatin 25 mg/m d1-3, and capecitabine 800 mg/m bid d1-14, q21d. Patients were assigned to radioimmunotherapy if they had a complete or partial response, those with stable or progressive disease underwent surgery and adjuvant (chemo)radiotherapy. Camrelizumab was maintained post-radioimmunotherapy. Fifty-one patients were enrolled with a median follow-up duration of 23.7 months. After induction therapy, the ORR was 82.4% (42/51), meeting the prespecified endpoint. Grade 3/4 adverse events occurred in 26 patients, and no treatment-related death occurred. As three-year outcomes were immature, two-year OS, PFS and LPR were reported. As no distant metastatic event had occurred, MFS was not reported here. The two-year OS, PFS, and LPR rates were 83.0%, 77.1%, and 70.0%, respectively. The induction chemoimmunotherapy of camrelizumab plus TPF showed a high ORR rate with an acceptable safety profile in LA HSCC.
Topics: Humans; Male; Female; Middle Aged; Antibodies, Monoclonal, Humanized; Aged; Hypopharyngeal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Adult; Immunotherapy; Neoplasm Staging; Cisplatin; Progression-Free Survival; Induction Chemotherapy; Treatment Outcome
PubMed: 38898018
DOI: 10.1038/s41467-024-49121-3 -
European Urology Jun 2024Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer.
Corrigendum to "Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostat Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial" [Eur. Eurol. 84(2) (2023) 156-163].
BACKGROUND
Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer.
OBJECTIVE
To provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT.
DESIGN, SETTING, AND PARTICIPANTS
High-risk localized prostate cancer patients (>50% of patients had Gleason 9-10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS).
RESULTS AND LIMITATIONS
After 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval [CI] 0.70-1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73-1.14), DM (HR = 0.84, 95% CI 0.73-1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74-1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm.
CONCLUSIONS
After a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers.
PATIENT SUMMARY
No significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.
PubMed: 38897867
DOI: 10.1016/j.eururo.2024.06.009 -
Molecules (Basel, Switzerland) May 2024Breast cancer is a major health concern and the leading cause of death among women worldwide. Standard treatment often involves surgery, radiotherapy, and chemotherapy,...
Breast cancer is a major health concern and the leading cause of death among women worldwide. Standard treatment often involves surgery, radiotherapy, and chemotherapy, but these come with side effects and limitations. Researchers are exploring natural compounds like baicalin and baicalein, derived from the plant, as potential complementary therapies. This study investigated the effects of baicalin and baicalein on the cytotoxic, proapoptotic, and genotoxic activity of doxorubicin and docetaxel, commonly used chemotherapeutic drugs for breast cancer. The analysis included breast cancer cells (MCF-7) and human endothelial cells (HUVEC-ST), to assess potential effects on healthy tissues. We have found that baicalin and baicalein demonstrated cytotoxicity towards both cell lines, with more potent effects observed in baicalein. Both flavonoids, baicalin (167 µmol/L) and baicalein (95 µmol/L), synergistically enhanced the cytotoxic, proapoptotic, and genotoxic activity of doxorubicin and docetaxel in breast cancer cells. In comparison, their effects on endothelial cells were mixed and depended on concentration and time. The results suggest that baicalin and baicalein might be promising complementary agents to improve the efficacy of doxorubicin and docetaxel anticancer activity. However, further research is needed to validate their safety and efficacy in clinical trials.
Topics: Humans; Flavonoids; Flavanones; Docetaxel; Doxorubicin; MCF-7 Cells; Apoptosis; Breast Neoplasms; Female; DNA Damage; Drug Synergism; Antineoplastic Agents; Cell Survival; Human Umbilical Vein Endothelial Cells
PubMed: 38893380
DOI: 10.3390/molecules29112503