P1, N=40, Recruiting, Kaken Pharmaceutical

Although 3 µM dasatinib reduced 100 µM OHP accumulation in hOCT2-HEK293 cells, co-incubation with dasatinib and OHP did not prevent OHP toxicity, possibly due to dasatinib-induced cell viability reduction. In summary, this study demonstrates OHP as an OCT2 substrate and dasatinib as a non-transported inhibitor and regulator of OCT2, offering potential for OIPN mitigation.

This study investigated the interaction between the already approved cationic drugs disopyramide, imipramine, and orphenadrine with hOCT2 that is stably expressed in human embryonic kidney cells. In conclusion, certain interventions targeting hOCT2 have demonstrated the ability to reduce CDDP cytotoxicity, at least in vitro. Further investigations in in vivo systems are warranted to ascertain their potential applicability as co-treatments for mitigating undesired toxicities associated with CDDP in patients.

CircSLC22A23 regulated the transcription of EGFR through activation of HNRNPU in GC cells, suggesting that circSLC22A23 may serve as a potential therapeutic target for the treatment of GC.

Therefore, in mice, CDDP uptake by both OCT1 and 2 contributes to the development of CDDP undesired side effects. OCT seem to be suitable targets for establishing treatment protocols aimed at decreasing unwanted CDDP toxicity and improving anticancer treatment with CDDP.

OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients.

OCT2 mediates the interaction of the major active components in SMF. Ginsenosides Rd, Re and schizandrin B are the potential inhibitors of OCT2, while ginsenosides Rb1 and methylophiopogonanone A are the potential substrates of OCT2. There is an OCT2-mediated compatibility mechanism among these active ingredients of SMF.

The 7-SLC-gene prognostic signature established in this study helped predict the prognosis, and was also correlated with the tumor immune status and infiltration of different immune cells in the tumor microenvironment. The current findings may provide important clinical indications for proposing a novel combination therapy consists of targeted anti-SLC therapy and immunotherapy for HCC patients.

It is shown here, for the first time, that the rs316019 gene variant of the SLC22A2 gene may be associated with the hematological toxicity of oxaliplatin. Patients with genotype CA/AA of rs316019 are more likely to develop serious hematological adverse effects.

Finally, our analyses raise the possibility that current approaches may undertreat certain kidney cancer patients with low SLC22 expression and only localized disease while possibly overtreating more advanced disease in patients with higher SLC22 expression. Clinical studies are needed to investigate these possibilities.

Our novel findings can contribute to solving the diagnostic challenges in TNBC and the 10-gene signature may serve as a novel biomarker for risk-based patient care.

In stratification analysis, SLC22A2 rs316003, SLC2A1 rs4658 were related to PFS and AQP9 rs1867380, SLC2A1 rs3820589, SLC22A2 rs316003 indicated were related to OS of platinum-based chemotherapy prognosis. Genetic polymorphisms of rs1448784 in ABCG2 might be potential clinical marker for predicting the prognosis of lung cancer patients treated with platinum-based chemotherapy.

Moreover, we found that treatment of DNA methyltransferase (DNMT) inhibitors, decitabine or 5-azacytidine recover OCT2 expression and oxaliplatin sensitivity in PANC-1/GR cells, and DNMT1 level has inverse correlation with OCT2 expression in PDAC cells and tumors. Our findings jointly suggest that OCT2 expression is a potential and predictive marker for evaluating oxaliplatin sensitivity and developing alternative treatments for PDAC patients with gemcitabine resistance.

Overall, the drug-drug interaction and safety profiles of trilaciclib in these studies support its continued use in patients with extensive-stage small-cell lung cancer.

Rhein oriented itself in the site of Keap1, inhibiting the Keap1-Nrf2 interaction. Rhein ameliorated VIN mainly through regulating the expressions of renal transporters and acting on Nrf2 pathway.

NET, OCT and MATE transporters play differential roles in mIBG tumor targeting, systemic elimination, and accumulation in normal tissues. The clinical use of mIBG as a radiopharmaceutical in cancer diagnosis and treatment can be further improved by taking a holistic approach considering mIBG transporters in both cancer and normal tissues.

Frequency of FGFR fusions Fusions Fusion region N (%) FGFR3-TACC3 EX18E:EX11 3(7.14%) EX17:EX8 3(7.14%) EX17:EX10 2(4.76%) EX18E:EX13 1(2.38%) EX8:EX9 1(2.38%) FGFR3-LETM1 EX8:Promoter 1(2.38%) FGFR3-SZT2 EX7:EX61 1(2.38%) FGFR3-PCDH7(intergenic) EX8:intergenic 1(2.38%) FAM53A(intergenic)-FGFR3 intergenic:EX18E,intergenic:EX8 2(4.76%) FGFR3-chr20 55284041 EX18E:chr20 55284041 1(2.38%) FGFR2-FAM184B EX17:EX8 1(2.38%) FGFR2-GRK5 EX17:EX1 1(2.38%) FGFR2-SORBS1 EX17:EX24 1(2.38%) FGFR2-PROM1 EX18:EX11 1(2.38%) FGFR2-chr10 122732846 EX17:chr10 122732846 1(2.38%) FGFR2-NPVF(intergenic) EX14:intergenic 1(2.38%) OPALIN-FGFR2 EX6E:EX2 1(2.38%) ATE1-FGFR2 EX11:EX2,EX5:EX17 2(4.76%) chr10 123156582-FGFR2 chr10 123156582:EX18 1(2.38%) DEC1(intergenic)-FGFR2 intergenic:EX6 1(2.38%) FGFR1-TACC1 EX1:EX2 1(2.38%) FGFR1-STAU1 EX1:EX7 1(2.38%) FGFR1-LETM2 EX12:EX8 1(2.38%) FGFR1-KCNU1(intergenic) EX3:intergenic 1(2.38%) FGFR1-SLC22A23 EX13:EX10 1(2.38%) FGFR1-ISL1(intergenic) EX8:intergenic,EX4:intergenic 2(4.76%) DDHD2-FGFR1 EX5:EX2 1(2.38%) ZMAT4-FGFR1 EX2:EX2 1(2.38%) HELZ-FGFR1 EX33E:EX6 1(2.38%) chr8 76149982-FGFR1 EX0:EX2 1(2.38%) chr8 138590655-FGFR1 EX0:EX2 1(2.38%) UNC5D(intergenic)-FGFR1 intergenic:EX2 1(2.38%) LOC100996508-FGFR1 EX1:EX2 1(2.38%) TACC1(intergenic)-FGFR1 intergenic:EX2 1(2.38%) Total 42(100%) Conclusion We report the prevalence of FGFR aberrations in a large lung cancer pts, including mutations, gene amplifications, gene deletion and one novel FGFR fusion. Our results revealed the potential therapeutic strategies with FGFR inhibitors for Chinese patients with lung cancer.

OCTs might play a significant role in the transport of fluoxetine across the BBB. In addition, P-gp, BCRP, and MRPs seemed not to mediate the efflux transport of fluoxetine.

The urinary excretion of enerisant within 48 h after administration was 64.5% to 89.9% of the dose, indicating that most of the absorbed enerisant was excreted in the urine without being metabolized.Based on the plasma concentrations at the estimated clinical dose, enerisant is unlikely to cause CYP-mediated, clinically relevant DDI. Although the possibility of transporter-mediated, clinically relevant DDI cannot be ruled out, there is little or no risk of side effects.

Corroborating this finding, cisplatin delivery to the 4T1 primary tumor was enhanced upon OMO-1 treatment, increasing cisplatin DNA-adduct levels and tumor cell death. Although verification in additional cell lines is warranted, our findings provide initial evidence that TNBC patients may benefit from OMO-1 treatment, even in cases of non-c-MET addicted tumors.

In vitro, tucatinib inhibited OCT2-, MATE1-, and MATE2-K-mediated transport of metformin, with IC values of 14.7, 0.340, and 0.135 µM, respectively. GFR and eGFR, which are unaffected by OCT2 and/or MATE1/2-K transport, were unchanged with tucatinib. These data demonstrate that tucatinib inhibits OCT2- and MATE1/2-K-mediated tubular secretion of creatinine, which may manifest as mild SCr elevations that are not indicative of renal impairment.

Of 433 patients assessed in this study, 26.8% developed nephrotoxicity after bleomycin-etoposide-cisplatin treatment. A clinical and genomics-based machine learning algorithm improved the ability to identify patients at risk of nephrotoxicity compared with using clinical variables alone. Novel genetics associations with cisplatin-induced nephrotoxicity were found for NAT1, NAT2, CNTN6, and CNTN4 that require replication in larger studies before application to clinical practice.

It is concluded that the ameliorative effect of curcumin in cisplatin-induced reproductive disorders was due to the modulation of testosterone and androgen receptors.

The epigenetic activation of OCT2 by decitabine (DAC) reversed this resistance in normoxic conditions. Hypoxia-mediated repression of ENT1 led to the inability of DAC to upregulate the expression of OCT2 under hypoxia. H-NPs could alleviate resistance to oxaliplatin and DAC in RCC cells under hypoxia and may have potential clinical applications.

In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, albeit with different catalytic efficiency. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but support that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.

Consistently, there was a significant correlation between plasma cadmium level and alteration of renal function in cervical cancer patients who underwent chemotherapy with cisplatin. Thus, our studies suggest that membrane transporter distribution induced by cadmium exposure is a previously unrecognized factor for the broad variation in renal drug disposition and response.

This study assessed the in vitro and clinical inhibition of renal transporters by abemaciclib and its metabolites using metformin (a clinically relevant transporter substrate), in a clinical study that quantified glomerular filtration and iohexol clearance, In vitro, abemaciclib inhibited metformin uptake by OCT2, MATE1 and MATE2-K transporters with an IC50 of 0.4-3.8 μM. Clinically abemaciclib significantly increased metformin exposure but did not significantly affect measured glomerular filtration rate, serum NGAL, serum cystatin C or the urinary markers of kidney tubular injury, NGAL and KIM-1,.