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Purpose Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium. Methods Chemo-naive patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. Results Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 μg to 5000 μg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors. Conclusion Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 μg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.

Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation. We also show that the Ser291-phosphorylated form of the multifunctional protein and stem cell marker, CD44, inhibits FBXO21-directed degradation of P-gp. Thus, CD44 increases P-gp mediated drug resistance and represents a potential therapeutic target in P-gp-positive cells.

CD44 is a multifunctional cell receptor that conveys a cancer phenotype, regulates macrophage inflammatory gene expression and vascular gene activation in proatherogenic environments, and is also a marker of many cancer stem cells. CD44 undergoes sequential proteolytic cleavages that produce an intracytoplasmic domain called CD44-ICD. However, the role of CD44-ICD in cell function is unknown. We take a major step toward the elucidation of the CD44-ICD function by using a CD44-ICD-specific antibody, a modification of a ChIP assay to detect small molecules, and extensive computational analysis. We show that CD44-ICD translocates into the nucleus, where it then binds to a novel DNA consensus sequence in the promoter region of the MMP-9 gene to regulate its expression. We also show that the expression of many other genes that contain this novel response element in their promoters is up- or down-regulated by CD44-ICD. Furthermore, hypoxia-inducible factor-1α (Hif1α)-responsive genes also have the CD44-ICD consensus sequence and respond to CD44-ICD induction under normoxic conditions and therefore independent of Hif1α expression. Additionally, CD44-ICD early responsive genes encode for critical enzymes in the glycolytic pathway, revealing how CD44 could be a gatekeeper of the Warburg effect (aerobic glycolysis) in cancer cells and possibly cancer stem cells. The link of CD44 to metabolism is novel and opens a new area of research not previously considered, particularly in the study of obesity and cancer. In summary, our results finally give a function to the CD44-ICD and will accelerate the study of the regulation of many CD44-dependent genes.

PURPOSE: The effectiveness of standard-of-care platinum-taxane chemotherapy in the treatment of patients with advanced gynecologic cancers is limited by the development of chemotherapy resistance in nearly all patients. Based on our preclinical findings that selenium, an essential trace element, inhibits the development of carboplatin drug resistance in an ovarian cancer mouse model, a phase I trial of a combination of selenious acid/carboplatin/paclitaxel was designed to determine the maximum tolerated dose (MTD) and safety of selenium administered with chemotherapy in chemo-naïve women with gynecologic cancers. In addition, the effects of selenium on carboplatin pharmacokinetics were evaluated in this group of patients, and correlative studies were performed to identify potential gene targets of selenium. METHODS: Patients with gynecologic malignancy not previously treated with chemotherapy received 50-5000 µg elemental selenium IV in the form of selenious acid on day 1 followed by carboplatin (cycle 1, AUC 5; subsequent cycles, AUC 6) IV and paclitaxel 175mg/m2 IV on day 3. A standard 3+3 trial design was used in the selenium dose escalation phase. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. RNA expression in tumor specimens and breast and ovarian cancer cell lines were compared before and after treatment with selenium plus chemotherapy using the Human Exon 1.0 ST exon microarray platform. In addition, Western immunoblotting was performed to evaluate protein expression of RAD51AP1, a protein involved in DNA repair, in untreated MCF-7/Adr cells and MCF-7/Adr cells treated with selenium, carboplatin, and the combination of selenium and chemotherapy. RESULTS: Forty-five patients were enrolled and a total of 291 treatment cycles were administered. Grade 3/4 toxicities included neutropenia (66.6%), febrile neutropenia (2.2%), as well as pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The MTD of elemental selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. In the subset of patients with stage III/IV ovarian cancer/fallopian tube/peritoneal cancer, median progression-free survival was 15 months; in those patients within this subset with measurable disease, 30%, 35%, and 23% experienced complete response, partial response, and stable disease, respectively. Correlative studies showed downregulation of RAD51AP1 by selenium plus chemotherapy in cancer cell lines as well as in tumors of patients treated within this clinical trial. CONCLUSION: Selenium in combination with carboplatin and paclitaxel is safe and does not affect carboplatin pharmacokinetics. It is possible that selenium-mediated downregulation of RAD51AP1 plays a role in circumventing the development of resistance to carboplatin/paclitaxel chemotherapy. A phase II study to further investigate these findings is underway. Citation Format: Mihae Song, Muthu N. Kumaran, Murugesan Gounder, Darlene Gibbon, Wilberto Nieves-Neira, Ami Vaidya, Mira Hellman, Michael P. Kane, Brian Buckley, Lorna Rodriguez-Rust. Phase I trial of selenium plus chemotherapy in gynecologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT025.