المؤلفون: Jeffrey M. Holzbeierlein, Gaurav Kaushik, Eugene K. Lee, Weiya Liu, Ryan Didde, Benjamin L. Woolbright, Karim Pirani, Shrikant Anant, Erika Abbott, John A. Taylor

المصدر: Journal of Clinical Oncology. 37:410-410

مصطلحات موضوعية: Cancer Research, Bladder cancer, Oncology, business.industry, Diabetes mellitus, Bladder cancer cell, Cancer research, Medicine, Cancer, Metabolism, business, medicine.disease, PHOSPHOGLYCERATE MUTASE 2

الوصف: 410 Background: Bladder cancer remains the fourth most common cancer in American males with a higher risk of recurrence and progression for patients with diabetes mellitus. Urothelial bladder cancer is characterized by aerobic glycolysis with upregulation of glycolytic enzymes (known as the Warburg effect) such as phosphoglycerate mutase. Phosphoglycerate mutase 2 (PGAM2), a reversible glycolytic enzyme expressed highly in muscle, represents a target for modulation because of its differential expression from another isoform, phosphoglycerate mutase 1. PGAM2 knockdown may impact bladder cancer growth significantly via its effect on glucose metabolism at different glucose concentrations seen in patients with diabetes mellitus. Methods: UM-UC3 bladder cancer cells were assessed for PGAM2 expression at different glucose concentrations via Western blot and quantitative PCR. One native UM-UC3 line, three PGAM2 knockdown lines, and one vector control cell line were included in the western blot study. Cellular proliferation was analyzed using an enzyme based hexoseaminidase assay and was further supported with an automated cell counter. The effects of cisplatin were also investigated. Results: Increased PGAM2 expression at increased glucose concentrations in UM-UC3 was confirmed by Western blot and quantitative PCR. PGAM2 knockdown cells responded differently to changes in glucose concentration compared to the control cell lines, with a large increase in growth at a low glucose level of 25mg/dL after day 4. Cell proliferation demonstrated similar growth between the knockdown and controls at higher glucose concentrations of 100 and 200mg/dL. Proliferation data using automated cell counter demonstrate the same growth trend. Conclusions: Increased cell growth of PGAM2 knockdowns, most notably at 25mg/dL, suggests that PGAM2 may play a different role in glycolysis than expected, possibly serving as a modulator in cell growth instead of a simple reversible enzyme. We are currently investigating its differential expression compared to PGAM1, an enzyme recently characterized to have an opposite effect to PGAM2.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::c3c55adf2de781eae8c27565e8804b15Test
https://doi.org/10.1200/jco.2019.37.7_suppl.410Test

المؤلفون: Gaurav Singal, Daniel Backenroth, Gerald Li, Vineeta Agarwala, Vincent A. Miller, Claire O'Connell, Garrett Alpha Cobb, Gaurav Kaushik, Kenneth R. Carson, Amy P. Abernethy

المصدر: Journal of Clinical Oncology. 36:e24319-e24319

مصطلحات موضوعية: Cancer Research, Therapy response, Oncology, business.industry, Precision oncology, Interpretation (philosophy), Medicine, Computational biology, business, Genomic databases

الوصف: e24319Background: A central goal of precision oncology is to relate genomic alterations in a patient’s tumor to prognosis and therapy response. Today, variant interpretation is based on functional ...

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::4fde42f411218d492a4c940bc13c2222Test
https://doi.org/10.1200/jco.2018.36.15_suppl.e24319Test

المؤلفون: Garrett Alpha Cobb, Vineeta Agarwala, Vincent A. Miller, Gaurav Singal, Gerald Li, Kenneth R. Carson, Amy P. Abernethy, Chun-Kai Kao, Gaurav Kaushik, Claire O'Connell, Daniel Backenroth

المصدر: Journal of Clinical Oncology. 36:e15072-e15072

مصطلحات موضوعية: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Cancer therapy, Microsatellite instability, Pembrolizumab, medicine.disease, Genomic databases, Internal medicine, Medicine, Microsatellite, In patient, business

الوصف: e15072Background: In May 2017, the FDA approved for the first time a cancer therapy (P) for use in patients based on the presence of a genomic marker (microsatellite instability-high, or MSI-H) ins...

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::c4f85818936118578f884e7d348b1b58Test
https://doi.org/10.1200/jco.2018.36.15_suppl.e15072Test

المؤلفون: Dharmalingam Subramaniam, Scott Weir, Shrikant Anant, Gaurav Kaushik, Eugene K. Lee, Prasad Dandawate, Jeffrey M. Holzbeierlein, Greg Reed

المصدر: Journal of Clinical Oncology. 36:521-521

مصطلحات موضوعية: 0301 basic medicine, 030103 biophysics, Cancer Research, medicine.medical_specialty, Bladder cancer, business.industry, Urinary system, Urology, Cancer, Urine, medicine.disease, Institutional review board, Clinical trial, 03 medical and health sciences, Oncology, Oral administration, Apoptosis, medicine, business

الوصف: 521 Background: Bladder cancer is a common cancer in the US. Approximately seventy-five percent of new cases present as non-muscle invasive bladder cancer (NMIBC) with a high recurrence rate. Our group has demonstrated in well-characterized human NMIBC cell lines that ethacrynic acid (EA) suppresses growth by inhibiting proliferation, clonogenicity, spheroid formation and inducing apoptosis. Additionally, EA affects markers of stemness and may work through the NOTCH signaling pathway. We present a clinical trial characterizing the safety and urinary tract exposure to EA and metabolites following oral administration in patients undergoing transurethral resection of bladder tumor (TURBT). Methods: Institutional review board approval (#3674) was obtained for a Pilot trial in patients with presumed non-muscle invasive bladder cancer undergoing TURBT. All participants were given a single, 50 mg oral dose of EA in the pre-operative bay. Urine was collected at baseline, upon insertion of cystoscope (30-60 minutes post dose), and post-operatively. Urine concentrations of EA and metabolites were determined using a fully-validated UPLC-MS/MS-based analytical method. Participants were monitored for adverse events. Results: Twelve participants participated in the trial between August 2016 and February 2017. Eleven male and one female patient (median age 70.5 years) were enrolled. Final pathology demonstrated urothelial carcinoma in 5/12 (42%) subjects, three with high grade T1 and two with low-grade Ta tumors. Urine concentrations of EA and conjugates observed 30-60 minutes post-dose were as follows: EA 0.1 ug/mL, EA-glutathione 0.2 ug/mL, EA-cysteine 3 ug/mL, and EA-mercapturate 2 ug/mL. No drug-related adverse events were observed following oral EA administration. Conclusions: Despite EA receiving FDA approval over 40 years ago, our pilot trial describes for the first time, urinary tract exposure of EA and its active metabolites in bladder cancer patients after a single oral dose. These data are guiding ongoing preclinical proof of principle studies evaluating EA alone and in combination with standard of care agents in bladder cancer models. These studies warrant further studies of EA in patients with non-muscle invasive bladder cancer. Clinical trial information: NCT02852564.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::4f8c9029f6ba15b4971dbdf533ad7246Test
https://doi.org/10.1200/jco.2018.36.6_suppl.521Test