Cancer Chemotherapy and Pharmacology最新文献

Purpose: Relapsed and/or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome continue to have a poor prognosis with limited treatment options despite advancements in rational combination and targeted therapies. Belinostat (an HDAC inhibitor) and Pevonedistat (a NEDD8 inhibitor) have each been independently studied in hematologic malignancies and have tolerable safety profiles with limited single-agent activity. Preclinical studies in AML cell lines and primary AML cells show the combination to be highly synergistic, particularly in high-risk phenotypes such as p53 mutant and FLT-3-ITD positive cells. Here, we present the safety, pharmacokinetics and pharmacodynamics of belinostat and pevonedistat in a dose escalation Phase I study in AML and High-Risk MDS.

Methods: Eighteen patients (16 with AML, 2 with MDS) were treated at 5 dose levels (belinostat 800-1000 mg/m², pevonedistat 20-50 mg/m²). Safety and tolerability were assessed according to protocol defined dose limiting toxicities (DLTs). Correlative pharmacokinetic and pharmacodynamic analyses were performed.

Results: No dose limiting toxicities were noted. Most Grade 3 or 4 toxicities were hematologic in nature. The best response was stable disease in four patients, and complete remission in one patient who qualified as an exceptional responder. Pharmakokinetic studies revealed no association between drug exposure and best response. Pharmacodynamic RT-PCR studies demonstrated post-treatment increases in several proteins, including quantitative increases in the oxidative stress protein NQO1, ferroptosis protein SLC7A11, and GSR, linked to glutathione metabolism and oxidative stress, as did the anti-oxidants SRXN1 and TXNRD1.

Conclusions: Patterns of post-treatment changes in correlative pharmacodynamic parameters may suggest possible mechanistic changes in the DNA damage response, oxidative damage, and ferroptosis pathways. The combination of pevonedistat plus belinosat is safe in an adult relapsed and/or refractory AML/High-Risk MDS population with modest but notable activity in this heavily treated, high risk population. Our findings also raise the possibility that certain extremely poor prognosis AML patients may respond to a regimen combining two targeted agents that have little or no activity when administered individually.

Trial registration: ClinicalTrials.gov ID NCT03772925, first posted 12/12/2018; CTEP Identifier 10246.

Purpose: After initial approval of lenvatinib for radioiodine-refractory differentiated thyroid cancer (DTC), it has also shown promising outcomes in among others metastatic renal cell carcinoma (mRCC). Given that trial populations typically do not represent routine clinical care populations, questions arise about how applicable trial outcomes are in clinical practice. This study aims to compare the pharmacokinetics (PK), toxicity patterns, and survival data of lenvatinib in a real-world cohort with DTC and mRCC to those observed in pivotal clinical trials.

Materials and methods: Patients were included when diagnosed with DTC or mRCC, had received current or prior treatment with lenvatinib, and had at least one available lenvatinib plasma concentration measurement. A descriptive comparison was made between the baseline characteristics, PK data, toxicity and survival data in this real-world cohort and those described in the phase III trials.

Results: Overall, 29 patients with mRCC and 35 patients with DTC were included. For mRCC, median time to treatment discontinuation (mTTD) was shorter than observed in the phase III trial (7.5 versus 11.0 months) with fewer dose-limiting toxicities, likely because 66% of the patients started with a reduced dose. mRCC patients were more pretreated and had a worse performance status than trial participants. This was resembled in overall lower PK exposure in mRCC patients. For DTC, mTTD was longer in our cohort (17.1 versus 13.8 months), with similar toxicity patterns and PK exposure as in the phase III trial.

Conclusions: Our data suggests that patient characteristics and outcomes in routine clinical care deviate from clinical trials and show the need for alternative treatment strategies to manage tolerability to lenvatinib.

Purpose: Ovarian clear cell carcinoma is a highly malignant gynecological tumor characterized by a high rate of chemotherapy resistance and poor prognosis. The PI3K/AKT/mTOR pathway is well-known to be closely related to the progression of various malignancies, and recent studies have indicated that this pathway may play a critical role in the progression and worsening of OCCC.

Methods: In this study, we investigated the combined effects of WX390, a dual inhibitor of PI3K/mTOR, and cisplatin on OCCC through both in vitro and in vivo experiments to further elucidate their therapeutic effects.

Results: WX390 significantly inhibited the proliferation of human OCCC cell lines ES2 and OVISE, while promoting apoptosis. Furthermore, the combination of WX390 with CDDP exhibited a synergistic effect, markedly increasing the sensitivity of OCCC cells to chemotherapeutic agents and significantly suppressing tumor growth in PDX models. Western blot and RNA-seq analyses revealed that WX390 robustly inhibited the PI3K/AKT/mTOR pathway, interrupt autophagy, altered cell cycle dynamics, and induced apoptosis.

Conclusion: This study comprehensively assessed the efficacy of WX390 across multiple models of OCCC, laying a solid foundation for the development of new therapeutic strategies for this challenging malignancy.

Objective: Based on our previous research, which demonstrated that elevated plasma endoglin (ENG) levels in lung cancer patients were associated with a better prognosis, increased sensitivity to pemetrexed, and enhanced tumor suppression, this study aims to validate these findings at the cellular level. The focus is on membrane and extracellular ENG and their influence on drug response and tumor cell behavior in non-small cell lung cancer (NSCLC) cells.

Methods: The correlation between ENG expression and pemetrexed-induced cytotoxicity in eight human non-squamous subtype NSCLC cell lines was analyzed. ENG in A549 and H1975 cells was knocked down using shRNA. MTT assay, cell cycle assay, western blot analysis, and boyden chamber assay were used to detect the effect of ENG on pemetrexed-induced cytotoxicity, cell cycle distribution, and cell migration.

Results: The expression of membrane ENG was positively correlated with pemetrexed-induced cytotoxicity in human NSCLC cells. Compared to pemetrexed-sensitive A549 cells, the A549/a400 (pemetrexed-resistant subline) cells exhibited a reduced accumulation of cells in the S phase, making them less susceptible to cell death. ENG knockdown also alleviated pemetrexed-induced S phase arrest and regulated G1/S phase-related proteins (p53, p21, CDK2, and Cyclin A). Additionally, co-treatment with recombinant ENG enhanced pemetrexed-induced migration inhibition in the sensitive cel1 line and cytotoxicity in the resistance cell line.

Conclusion: The present results strengthened our prior clinical findings, showing that higher membrane ENG expression enhances pemetrexed-induced cytotoxicity and S phase arrest, which may involve the ENG-p21 pathway. Additionally, microenvironmental ENG enhanced the anti-migration of pemetrexed. These findings highlight the potential of ENG as a biomarker and therapeutic target, opening new avenues to improve the outcomes of non-squamous cell NSCLC treatment.

Purpose: PLB1004, developed by Beijing Avistone Biotechnology Co., Ltd., is a safe, highly selective, and efficient irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) employed in treating non-small-cell-lung-cancer (NSCLC). This study investigated its pharmacokinetics, mass balance, and metabolism in 6 healthy Chinese male subjects treated with 160 mg (70 µCi) [¹⁴C]PLB1004.

Methods: Following drug administration, samples of blood, urine and feces were collected for quantitative determination of total radioactivity and metabolites were identified through radioactivity detection coupled with UHPLC-MS/MS.

Results: Following drug administration, the median radioactive T_max was 4.17 h in plasma, with the average t_1/2 of PLB1004-related components in plasma of approximately 54.3 h. Over 264 h post-administration, the average cumulative excretion among the six subjects was 95.01% of the administered dose, with 84.71% and 10.30% excreted in feces and urine, respectively. Nine metabolites were characterized and identified and the parent drug PLB1004 was detected in plasma, urine, and feces. Among these metabolites, M689 was the most prevalent one in plasma, urine, and feces, constituting 25.37% of the total plasma radioactivity, and 55.88% and 1.73% of the administrated dose in feces and urine, respectively.

Conclusion: Fecal excretion emerged as PLB1004 excretion route, while urinary excretion via the kidneys served as the secondary route. The primarily metabolic pathways are oxidation, demethylation, dehydrogenation, and cysteine conjugation in humans.

As development of new oncology small molecule therapies is focused mainly on molecularly targeted agents, the dose selection paradigm has shifted from the maximum tolerated dose (MTD)-based approach traditionally utilized with cytotoxic drugs towards determining an optimal dose with long-term tolerability while maintaining efficacy. To assess overall tolerability in recently approved oncology small molecules, we surveyed 54 compounds approved by the FDA since March 2017 with respect to dose intensity, dose modifications, and treatment emergent adverse events (TEAEs). Of the 54 new molecular entities surveyed, only 15 were approved at a label dose equal to the MTD (Label Dose = MTD). Compared to compounds where the label dose was less than the MTD, compounds where the Label Dose = MTD reported overall lower dose intensity and higher dose modifications due to adverse events, though treatment discontinuations due to adverse events were similar. A post-marketing requirement (PMR) for dose optimization was issued for 7 compounds in the dataset, of which 3 were at the Label Dose = MTD. None of these 7 compounds reported a positive exposure-response relationship in efficacy and only 4 reported an exposure-response in safety events. Overall, dose intensity was lower, and incidence of dose modifications, discontinuations, and Grade ≥ 3 TEAEs were higher in compounds issued a PMR vs. the latter. This analysis suggests that while recently approved oncology small molecules have a reasonable relative dose intensity (RDI), the higher incidence of Grade ≥ 3 TEAEs and dose modifications where Label Dose = MTD highlight the continuing need for dose optimization while developing oncology therapeutics.

Introduction: Gynecological cancers, such as ovarian, cervical, and endometrial malignancies, are notoriously challenging due to their intricate biology and the critical need for precise diagnostic and therapeutic approaches. In recent years, groundbreaking advances in nanotechnology and nanobots have emerged as game-changers in this arena, offering the promise of a new paradigm in cancer management. This comprehensive review delves into the revolutionary potential of these technologies, showcasing their ability to transform the landscape of gynecological oncology.

Methodology: A systematic literature search spanning from March 2005 to August 2024 was conducted using major databases such as PubMed, Google Scholar, and Scopus. Keywords included "nanotechnology," "nanobots," "gynecological cancers," "ovarian cancer," "cervical cancer," and "endometrial cancer." Relevant articles published in English were selected based on their focus on nanotechnology and nanobots in the diagnosis, treatment, and management of gynecological cancers. The findings were synthesized to present a coherent overview of how nanotechnology and nanobots are reshaping gynecological cancer management. The review highlights key innovations, current applications, and future directions for research and clinical implementation.

Conclusion: The integration of nanotechnology and nanobots in gynecological cancer management represents a groundbreaking shift in the field. Recent advancements in nanoscale materials and robotic technology offer unprecedented opportunities for precision diagnosis, targeted drug delivery, and innovative therapeutic approaches. Despite promising developments, challenges such as biocompatibility, safety, and regulatory issues remain. Continued research and clinical trials are essential to overcome these hurdles and fully realize the potential of nanotechnology and nanobots.

The enzyme dihydropyrimidine dehydrogenase (DPD) is the primary catabolic pathway of fluoropyrimidines including 5 fluorouracil (5FU) and capecitabine. Cases of lethal toxicity have been reported in cancer patients with complete DPD deficiency receiving standard dose of 5FU or capecitabine. DPD is encoded by the pharmacogene DPYD in which more than 200 variants have been identified. Different approaches have been developed for screening DPD-deficiency, including DPYD genotyping and phenotyping. Plasma uracil ([U]) and dihydrouracil ([UH₂]) concentrations are routinely used as surrogate markers for systemic DPD activity: [U] ≥ 16 ng/ml and < 150 ng/ml, and [U] ≥ 150 ng/mL indicate partial and complete DPD deficient phenotype, respectively, while values of 5 or 10 for [UH2]/([U] ratio are often cited. Four clinically relevant DPYD defective variants (DPYD*13, DPYD*2A, p.Asp949Val and haplotype B3), are targeted in genetic testing via PCR. In practice, pretreatment [U], alone or combined with these 4 recommended DPYD alleles guides individual dosage selection, though this approach has limitations. This is illustrated by two cases showing discrepancy between DPD deficient phenotype and normal standard genotype. In these two cases, DPYD exome sequencing with Next Generation Sequencing identified rare inactive variants, establishing concordance between phenotype and genotype. In patient 1, [U] levels of 21.1 and 25.5 ng/mL, indicated partial deficiency though the targeted genotype was normal and 5FU dose was adjusted based on the phenotype. In patient 2, [U] levels of 16.2 and 15.2 ng/mL were near the 16 ng/ml threshold. With a normal genotype, he as considered non-deficient as targeted genotype was normal and the standard dose was administered. These two cases underscore the need to pair DPD phenotyping with whole DPYD gene sequencing, due to the frequent discrepancies between these pharmacogenetic tools, the burden of rare variants and ethnic differences in variant frequencies.

Background: Polygala tenuifolia and its active components have been revealed to possess anti-tumor activities. However, the role of Tenuigenin (TEN), a bioactive ingredient from Polygala tenuifolia, in tumors such as osteosarcoma (OS) remains unclear. The present research intended to explore the efficacy and underlying mechanism of TEN on OS.

Methods: OS cells were administrated with different concentrations of TEN. Cell viability, proliferation, invasion, and migration were assessed with CCK-8 assay, colony formation assay, transwell assay, and wound healing assay, respectively. Protein and mRNA levels were determined with western blot and qRT-PCR, while protein phosphatase 2A (PP2A) activity was tested with PP2A phosphatase assay kit. The interaction between PP2A and cancerous inhibitor of protein phosphatase 2A (CIP2A) or nuclear factor kappaB (NF-κB) signaling was detected using co-immunoprecipitation. p-p65 expression in the nucleus was determined with immunofluorescence. The efficacy of TEN in vivo was also explored in a xenograft tumor model. Immunohistochemistry was performed to detect CIP2A and Ki67 in mice.

Results: TEN treatment or CIP2A depletion repressed cell viability, proliferation, invasion, and migration in OS cells. Additionally, TEN reduced CIP2A, increased PP2A activity, and inactivated NF-κB signaling. PP2A directly interacted with CIP2A or NF-κB signaling, and PP2A inhibition reversed CIP2A knockdown-induced repression of NF-κB signaling. CIP2A overexpression overturned the efficacy of TEN, which was reversed by NF-κB inhibition. TEN decreased CIP2A, elevated PP2A activity, inactivated NF-κB signaling, and inhibited tumor growth in vivo, which was antagonized by CIP2A overexpression.

Conclusion: TEN suppressed OS growth via CIP2A/PP2A/NF-κB axis, indicating that it would be a novel drug for treating OS.

Purpose: The blood concentrations of some tyrosine kinase inhibitors are known to decrease with long-term administration. We evaluated the variability in the serum concentrations of sunitinib and its metabolites in patients receiving long-term sunitinib treatment.

Methods: This study prospectively recruited patients who received sunitinib for metastatic renal cell carcinoma at the Showa University Hospital between March 2020 and January 2022. Bivariate correlations between the serum concentration/dose (C/D) ratios of sunitinib and its metabolites (i.e., N-desethyl sunitinib and sunitinib N-oxide) and treatment duration were evaluated using Pearson's correlation coefficient.

Results: Seven patients were enrolled, and 79 blood samples were collected. Among six patients who received sunitinib for > 1 year, three showed a decreasing trend in the C/D ratio of sunitinib (Pt1: r = -0.608, p = 0.047; Pt2: r = -0.555, p = 0.077; Pt6: r = -0.590, p = 0.073). In these patients, the median annual decrease in the C/D ratio of sunitinib was 55.8% (26.5-63.2%). Additionally, two of the three patients also showed a decrease in the C/D ratio of N-desethyl sunitinib. The ratio of N-desethyl sunitinib/sunitinib concentration at baseline and the end of follow-up was similar between the C/D-decreased and C/D-non-decreased groups.

Conclusion: This study showed that the C/D ratio of sunitinib decreased by half over time in half of the patients who received long-term sunitinib treatment despite continuing the same dose. Therefore, serum concentrations of sunitinib and its metabolites should be monitored periodically in patients receiving long-term treatment to prevent decrease in serum sunitinib concentrations.