Phase 1b study of first-line fuzuloparib combined with modified FOLFIRINOX followed by fuzuloparib maintenance monotherapy in pancreatic adenocarcinoma.

BACKGROUND: Chemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting. METHODS: This was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8-12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D). RESULTS: As of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0-74.0) and disease control rate of 94.4% (95% CI, 72.7-99.9). CONCLUSIONS: First-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04228601.

Histone methyltransferase KMT2C plays an oncogenic role in prostate cancer.

PURPOSE: Prostate cancer (PCa) is a leading cause of morbidity and mortality in males. Epigenetic modifier abnormalities are becoming a driving event in PCa. The specific role of KMT2C, a histone methyltransferase that is frequently aberrant in various tumors, is poorly understood in PCa. This study aimed to reveal the potential carcinogenic role of KMT2C in PCa. METHODS: We first examined the expression levels of KMT2C in prostate cancer tissues. Then, we assessed the function of KMT2C in prostate cancer cell proliferation, colony formation, and migration. To explore the mechanism of the biological consequences, RNA-seq and CHIP-qPCR were performed. We also analyzed the effects of overexpression of the KMT2C downstream genes CLDN8 and ITGAV to reverse the effects of KMT2C on prostate cancer cells. RESULTS: Herein, we first confirmed KMT2C overexpression in PCa at the transcript and protein levels. Knocking down KMT2C in VCaP and LNCaP cells inhibited cell viability, colony formation, and migration. Consistently, stable KMT2C depletion effectively decreased tumor growth by approximately 70% in vivo. Mechanistically, the results suggested that CLDN8 and ITGAV are two key downstream genes of KMT2C and further regulate the MAPK/ERK and EMT pathways. CONCLUSION: Our study suggests that KMT2C plays an oncogenic role in PCa. One of the mechanisms may be the epigenetic regulation of CLDN8 and ITGAV by KMT2C to modulate tumor-signaling pathways. Therefore, KMT2C may serve as a potential therapeutic target for PCa patients.

Tracing steroidogenesis in prostate biopsy samples to unveil prostate tissue androgen metabolism characteristics and potential clinical application.

Androgens are essential for prostate cancer development. However, steroidogenesis has mainly been investigated in a limited number of prostate cancer cell lines, leading to varied conclusions and elusive clinical significance. Here, we established an ex vivo research platform with fresh biopsy samples transiently cultured with tritium- labelled androgens to trace steroidogenesis in prostate tissues and investigate its potential clinical application. DHEA was confirmed as the major precursor for androgen synthesis in the prostate. Significant amounts of oxidized DHEA and 5α-androstanedione were generated from DHEA in prostate biopsy samples. Prostatic steroidogenesis was independent of other clinical factors. Furthermore, prostatic steroidogenesis was suppressed after androgen deprivation therapy but increased upon treatment resistance, indicating that prostatic steroidogenesis was affected by clinical treatments. Overall, we provide an accessible research platform to characterize steroidogenesis in prostate tissue and indicate the correlation between prostatic steroidogenesis and disease progression.

Enhanced wild-type p53 expression by small activating RNA dsP53-285 induces cell cycle arrest and apoptosis in pheochromocytoma cell line PC12.

Malignant pheochromocytoma (PHEO) is diagnosed only when metastasis has occurred, making it less likely for patients to obtain the benefits of traditional chemotherapy. Anti-oncogene TP53 mutation has been detected in PHEO and is possibly related to disease progression. However, whether the upregulation of wild-type TP53 has antitumoral effects on PHEO remains completely unknown. In the present study, we used RNA activation (RNAa) technique to upregulate the expression of wild-type TP53 by transfecting synthetic dsP53­285 into PHEO cell line PC12. We found that the upregulation of wild-type p53 blocked the transition of PC12 cells from the G0/G1 to the S phase, with induction of apoptosis. Additionally, the above-mentioned findings were attested in vivo. Most importantly, dsP53-285-induced antitumoral effects were reversible following co-transfection with siRNA that targeted p53 mRNA. Collectively, our results revealed that the upregulation of p53 and possibly other anti-oncogenes may provide a potential effective therapeutic strategy for PHEO.

Apogossypolone (ApoG2) induces ROS-dependent apoptosis and reduces invasiveness of PC12 cells in vitro and in vivo.

Malignant pheochromocytoma is accurately diagnosed only at occurrence of metastatic foci. However, at that time, patients are less likely to get many benefits from traditional chemotherapy. Over-expression of BCL-2 family proteins is tightly correlated with progression of pheochromocytoma. ApoG2, as the most potent gossypol derivative, has exhibited anti-tumor activities in various tumors. In the present study, we found that the staining degree of Bcl-2 being stronger than Bax was more frequently observed in pheochromocytoma than adrenocorticohyperplasia, which was possibly related to shorter overall survival. In addition, ApoG2 could induce apoptosis through up-regulation of Bax and down-regulation of Bcl-2, increasing reactive oxygen species (ROS) levels, inducing cytochrome C release and cleaving caspase proteins. Most importantly, those inhibition effects were blocked by caspase activation inhibitor Z-VAD-fmk and antioxidant N-acetyl-L-cysteine. The above results were further confirmed in vivo. Furthermore, ApoG2 could effectively inhibit tumor movement capabilities. Altogether, our results indicated that ApoG2 was a potential effective target drug for pheochromocytoma.

NVP-AUY922, a novel HSP90 inhibitor, inhibits the progression of malignant pheochromocytoma in vitro and in vivo.

PURPOSE: Malignant pheochromocytoma (PCC) is a rare tumor with a very poor prognosis and no effective treatments. The aim of this study was to assess the efficacy of a novel second-generation synthetic heat-shock protein 90 (HSP90) inhibitor, NVP-AUY922, to treat malignant PCC in vitro and in vivo. MATERIALS AND METHODS: Cell Counting Kit-8 (CCK-8) and Transwell assays were used to assess the effects of NVP-AUY922 on the proliferation and migration of the PCC cell line PC12. Flow cytometry was used to determine the effects of NVP-AUY922 on apoptosis and cell-cycle progression. Activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB/AKT) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling was measured using a Western blot analysis. In vivo, a mouse xenograft model was used to test the effects of intraperitoneal injection of NVP-AUY922 on tumor growth. RESULTS: NVP-AUY922 was found to be cytotoxic in PC12 cells at lower concentrations compared with 17-allylamino-17-demethoxygeldanamcyin (17-AAG). NVP-AUY922 inhibited the proliferation of PC12 cells in a time- and concentration-dependent manner and decreased the rate of migration of PC12 cells. Furthermore, we found that HSP90 inhibition induced cell-cycle arrest and apoptosis. In vivo, administration of NVP-AUY922 reduced PCC tumor growth without significant weight loss. Finally, we observed the modulation of MEK/ERK and PI3K/AKT signaling in response to NVP-AUY922 exposure. CONCLUSION: NVP-AUY922 exhibits potent anti-PCC activities in vitro and in vivo and represents a promising therapeutic small molecule for treating malignant PCC.

Co-inhibition of EGFR and IGF1R synergistically impacts therapeutically on adrenocortical carcinoma.

PURPOSE: Adrenocortical carcinoma (ACC) is a rare tumor with very poor prognosis and no effective treatment. The aim of this study was to explore a novel therapy co-targeting EGFR and IGF1R in vitro and vivo. METHODS: The expression of EGFR and IGF1R were evaluated in a series of adrenocortical tumors by immunohistochemistry. Cell viability of ACC cell lines H295R and SW13 were determined by MTT assay after treatment with the combination of EGFR inhibitor Erlotinib and IGF1R inhibitor NVP-AEW541. Apoptosis was assessed by flow cytometry. The mechanism within intracellular signaling pathways was analyzed by Western blot. Mice bearing human ACC xenografts were treated with Erlotinib and NVP-AEW541, and the effects on tumour growth were assessed. RESULTS: Our results show a significant over-expression of EGFR (66.67%) and IGF1R (80.0%) in ACC. Besides, the co-overexpression of EGFR and IGF1R was seen in 8/15 ACCs, as compared with ACAs (P<0.05). Erlotinib and NVP-AEW541 significantly inhibited cell viability and induced apoptosis by blocking phosphorylation of MEK/ERK and AKT, respectively. Meanwhile, we found that single inhibition of IGF1R induced compensatory activation of MEK/ERK, leading to sustained activation of mTOR, which represent as aggregation of EGFR and IGF1R downstream components. More importantly, the combination of Erlotinib and NVP-AEW541 enhances anti-tumour efficacy compared to treatment with either agent alone or to untreated control in vitro and vivo. CONCLUSIONS: In conclusion, coinhibition therapy targeting EGFR and IGF1R may be considerable for treatment of ACC in the future.