FDX2, an iron-sulfur cluster assembly factor, is essential to prevent cellular senescence, apoptosis or ferroptosis of ovarian cancer cells.

Recent studies reveal that biosynthesis of iron-sulfur clusters (Fe-Ss) is essential for cell proliferation, including that of cancer cells. Nonetheless, it remains unclear how Fe-S biosynthesis functions in cell proliferation/survival. Here, we report that proper Fe-S biosynthesis is essential to prevent cellular senescence, apoptosis or ferroptosis, depending on cell context. To assess these outcomes in cancer, we developed an ovarian cancer line with conditional KO of FDX2, a component of the core Fe-S assembly complex. FDX2 loss induced global down-regulation of Fe-S-containing proteins and Fe2+ overload, resulting in DNA damage and p53 pathway activation, and driving the senescence program. p53-deficiency augmented DNA damage responses upon FDX2 loss, resulting in apoptosis rather than senescence. FDX2 loss also sensitized cells to ferroptosis, as evidenced by compromised redox homeostasis of membrane phospholipids (PLs). Our results suggest that p53 status and PL homeostatic activity are critical determinants of diverse biological outcomes of Fe-S deficiency in cancer cells.

Lenvatinib plus Pembrolizumab Combination Therapy for Advanced or Recurrent Endometrial Cancer: A Single-Center, Retrospective Analysis.

A multi-kinase inhibitor, lenvatinib, plus an immune checkpoint inhibitor, pembrolizumab, became a viable therapeutic option for advanced or recurrent endometrial cancer in Japan by the end of 2021. The Japanese population has a relatively unique genetic background. Hence, the safety profile and effectiveness of lenvatinib plus pembrolizumab may differ between the Japanese and other populations. This single-center, retrospective study aimed to evaluate the treatment efficacy of lenvatinib plus pembrolizumab and the safety profile of the associated adverse events. The clinical records of 15 patients, who received lenvatinib plus pembrolizumab for advanced or recurrent endometrial cancer at the Tohoku University Hospital, were reviewed. Best overall response and disease control rates were 40.0% and 73.3%, respectively. Treatment was discontinued owing to disease progression and adverse events in six patients, respectively. As of the end of July 2023, treatment was ongoing in the remaining three patients. The median treatment and progression-free survival durations were 118 and 258 days, respectively. Relative dose intensity of lenvatinib was not positively associated with progression-free survival, neither during the first 4 weeks after treatment initiation nor during the entire treatment period. All patients experienced one or more adverse events, the most common of which were hypothyroidism (90%) and hypertension (83.3%). Among the 15 patients, 13 required lenvatinib dose reduction owing to adverse events. One patient developed grade 4 interstitial pneumonia requiring intensive care. Our results validate the short-term efficacy of lenvatinib plus pembrolizumab, and indicate that dose optimization of lenvatinib could be individualized without impairing efficacy.

Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma.

Nicotinamide phosphoribosyltransferase (NAMPT) plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells is associated with down-regulation of genes relevant to quinolinate phosphoribosyltransferase-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also report that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but nicotinamide riboside kinase 1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations is synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma.

Precautions during Direct Oral Anticoagulant Introduction in Gynecologic Malignancies: A Single-Center Retrospective Cohort Study.

The risk factors for venous thromboembolism (VTE) recurrence/exacerbation or a change from a direct oral anticoagulant (DOAC) to another anticoagulant in patients with gynecologic cancer using DOACs have not been thoroughly elucidated. Here, we aimed to investigate the risk factors for a composite primary outcome, including VTE recurrence/exacerbation, or a change from a DOAC to another anticoagulant, in this population. A total of 63 patients were analyzed. Risk factors for a primary outcome within 2 years after DOAC initiation were investigated using multiple logistic regression analysis. Among the 63 patients, 10 developed a primary outcome. Clear cell carcinoma of the ovary (adjusted odds ratio (aOR), 18.9; 95% confidence interval (CI), 2.25-350.74), pulmonary embolism (PE) or proximal deep vein thrombosis without PE (aOR, 55.6; 95% CI, 3.29-11,774.66), and D-dimer levels in the third tertile (≥7.6 µg/dL) when VTE was first diagnosed (aOR, 6.37; 95% CI, 1.17-66.61) were associated with increased odds of a primary outcome in patients with gynecologic cancer using DOACs. Patients with one or more risk factors for a primary outcome require careful follow-up after DOAC initiation for the early recognition of treatment failure.

The Impact of Histological Subtype on Survival Outcome of Patients with Stage IIB-IVA Cervical Cancer Who Received Definitive Radiotherapy.

The impact of histologic subtype on definitive radiotherapy for patients with locally advanced cervical cancer remains unclear. The aim of this retrospective analysis was to assess clinicopathological findings and clinical outcome by histological type in patients with stage IIB-IVA cervical cancer. Ninety-two patients with stage IIB-IVA [International Federation of Gynecology and Obstetrics (FIGO) 2008] cervical cancer, who underwent definitive radiotherapy between 2013 to 2018, were identified as eligible for this study. The clinical information of the eligible patients was obtained from medical records of our hospital. Seventy-eight patients underwent concurrent chemoradiotherapy, and the remaining 14 patients received radiotherapy alone. Of 92 patients, 83 had squamous cell carcinoma (SCC) and 9 had non-SCC histology. Progression-free survival (PFS) rate of patients with non-SCC was significantly worse than of those with SCC (2-year PFS: 62.0% vs. 12.5%, p = 0.0020), but overall survival (OS) rate did not statistically differ between the two subtypes (2-year OS: 82.4% vs. 62.5%, p = 0.2157). Pelvic failure-free (PFF) rate of patients with non-SCC histology was significantly worse than of those with non-SCC (2-year PFF; 88.2% vs. 25.0%, p < 0.0001). In univariate analysis, non-SCC histology was associated with PFS rate, although there was no association with OS rate. In multivariate analysis, non-SCC histology and lymph node metastasis were independent prognostic factors for shorter PFS. In patients with stage IIB-IVA cervical cancer who underwent definitive radiotherapy, patients with non-SCC showed significantly worse PFS rate than those with SCC.