The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax.

Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer.

Multiple drug resistant (MDR) malignancy remains a predictable and often terminal event in cancer therapy, and affects individuals with many cancer types, regardless of the stage at which they were originally diagnosed or the interval from last treatment. Protein biomarkers of MDR are not globally used for clinical decision-making, but include the overexpression of drug-efflux pumps (ABC transporter family) such as MDR-1 and BCRP, as well as HIF1α, a stress responsive transcription factor found elevated within many MDR tumors. Here, we present the important in vitro discovery that the development of MDR (in breast cancer cells) can be prevented, and that established MDR could be resensitized to therapy, by adjunct treatment with metformin. Metformin is prescribed globally to improve insulin sensitivity, including in those individuals with Type 2 Diabetes Mellitus (DM2). We demonstrate the effectiveness of metformin in resensitizing MDR breast cancer cell lines to their original treatment, and provide evidence that metformin may function through a mechanism involving post-translational histone modifications via an indirect histone deacetylase inhibitor (HDACi) activity. We find that metformin, at low physiological concentrations, reduces the expression of multiple classic protein markers of MDR in vitro and in preliminary in vivo models. Our demonstration that metformin can prevent MDR development and resensitize MDR cells to chemotherapy in vitro, provides important medical relevance towards metformin's potential clinical use against MDR cancers.

Diagnostic and interventional sialendoscopy: a preliminary experience.

OBJECTIVES/HYPOTHESIS: To review our preliminary experience with diagnostic and therapeutic sialendoscopy for the management of non-neoplastic disorders of the salivary gland. STUDY DESIGN: Retrospective chart review. METHODS: Thirty-three consecutive patients undergoing 36 sialendoscopy procedures performed at a tertiary medical center from July 2008 to July 2010 were included. RESULTS: The mean age of presentation was 43 years (range, 7-74 years), and 61% of patients were male. Indications included sialolithiasis (47%; 17 of 36), recurrent sialadenitis (44%, 16 of 36), and Sjögren's syndrome (8%; three of 36). Successful endoscopy was performed in 97% (35 of 36). A papillotomy for access was necessary in 25% (nine of 36). In patients with sialolithiasis (n = 17), the mean size of the stones was 7.3 mm (range, 1-20 mm). Complete stone removal was achieved in 76% (13 of 17) of cases. Endoscopic stone removal was possible in 29% (five of 17), and a combined approach technique was required in 47% (eight of 17). Seventy-two percent (26 of 36) of patients had complete resolution of symptoms after sialendoscopy, with 19% (seven of 36) having partial resolution of symptoms. Patients with partial improvement of symptoms had a mean duration of improvement of 4.7 months. The overall complication rate was 22% (eight of 36). The major and minor complication rates were 3% (one of 36) and 19% (seven of 36), respectively. CONCLUSIONS: Sialendoscopy is safe and effective in managing non-neoplastic salivary gland disorders with low rates of major complications. Knowledge of options to navigate the rate-limiting steps, like dilation of the papilla and careful case selection, are key to successful outcomes.

Hepatic resection for recurrent metastatic ovarian cancer.

BACKGROUND: The role for liver resection in metastatic ovarian cancer has not been defined. The aim of the current study was to investigate the validity of hepatic resection as a treatment option in metastatic ovarian cancer. METHODS: Retrospective review of a single institution's experience of patients undergoing hepatic resection for metastatic ovarian cancer from 1998-2006. RESULTS: Ten patients underwent resection for metastatic ovarian cancer. Primary tumor type included serous cystadenocarcinoma (n = 8), granulosa cell (n = 1), and yolk sac (n = 1). Median disease-free interval was 48 months. Liver resections included trisegmentectomy (n = 4), lobectomy (n = 4), and bisegmentectomy(n = 1). Additional surgeries included diaphragm resection (n = 60), bowel resection, (n = 30), and adrenalectomy (n = 10). The median overall survival following liver resection was 33 months. CONCLUSION: Liver resection for metastatic ovarian cancer is safe and is associated with long-term survival in some patients. Larger analysis may lead to the identification of prognostic factors associated with improved outcomes.