PMID- 29199023 OWN - NLM STAT- MEDLINE DCOM- 20190204 LR - 20211204 IS - 1938-0682 (Electronic) IS - 1558-7673 (Linking) VI - 16 IP - 2 DP - 2018 Apr TI - The Current Status and Future Role of the Phosphoinositide 3 Kinase/AKT Signaling Pathway in Urothelial Cancer: An Old Pathway in the New Immunotherapy Era. PG - e269-e276 LID - S1558-7673(17)30317-8 [pii] LID - 10.1016/j.clgc.2017.10.011 [doi] AB - The phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a well studied signaling pathway that regulates diverse cellular functions including proliferation, metabolism, and transcription. Aberrant activation of this pathway has been implicated in multiple cancers. Genomic studies have shown that activating mutations in oncogenes as well as inactivating mutations in tumor suppressor genes are present across a variety of malignancies, including urothelial carcinoma. In bladder cancer, up to 40% of tumors exhibit constitutive activation of the PI3K/AKT/mTOR pathway. Current treatments for non-muscle-invasive disease confer a 5-year cancer-specific survival rate as high as 90%. However, patients with muscle-invasive, recurrent, or metastatic disease have a poor prognosis. Although the introduction of immune checkpoint inhibitors is certainly changing the therapeutic landscape and is a great addition to the platinum-based therapy that was the standard of care for the past 3 decades, it is anticipated that a great number of patients would fail to respond or their disease would progress with either chemotherapy or immunotherapy. Therefore, the use of agents that target members of the PI3K/AKT/mTOR pathway represent an attractive, alternative therapeutic strategy for patients with advanced urothelial carcinoma. In this review we describe the pathway, with a focus on the rationale for targeting the PI3K/AKT/mTOR pathway in patients with advanced urothelial carcinoma and considers the challenges that we face from the current clinical trials. Novel agents such as PI3K inhibitors and microRNA inhibitors that target this pathway might lead to durable responses especially when used in combination with chemotherapy or immune checkpoint inhibitors, however, toxicity remains an obstacle. Finally, in this review we discuss the importance of developing biomarkers to help select appropriate patients and identify optimal treatment options. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Liu, Sandy T AU - Liu ST AD - Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA. FAU - Hui, Gavin AU - Hui G AD - David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA. FAU - Mathis, Colleen AU - Mathis C AD - Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA. FAU - Chamie, Karim AU - Chamie K AD - Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA. FAU - Pantuck, Allan J AU - Pantuck AJ AD - Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA. FAU - Drakaki, Alexandra AU - Drakaki A AD - Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA; Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA. Electronic address: adrakaki@mednet.ucla.edu. LA - eng PT - Journal Article PT - Review DEP - 20171103 PL - United States TA - Clin Genitourin Cancer JT - Clinical genitourinary cancer JID - 101260955 RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Antineoplastic Agents/pharmacology/*therapeutic use MH - Carcinoma, Transitional Cell/*drug therapy/metabolism MH - Clinical Trials as Topic MH - Humans MH - Immunotherapy MH - Phosphatidylinositol 3-Kinase/metabolism MH - Prognosis MH - Protein Kinase Inhibitors/pharmacology/therapeutic use MH - Proto-Oncogene Proteins c-akt/metabolism MH - Signal Transduction/*drug effects MH - Standard of Care MH - TOR Serine-Threonine Kinases/metabolism MH - Urinary Bladder Neoplasms/*drug therapy/metabolism OTO - NOTNLM OT - Bladder cancer OT - Inhibitors OT - PI3K OT - Targeted therapy OT - mTOR EDAT- 2017/12/05 06:00 MHDA- 2019/02/05 06:00 CRDT- 2017/12/05 06:00 PHST- 2017/05/26 00:00 [received] PHST- 2017/10/13 00:00 [revised] PHST- 2017/10/14 00:00 [accepted] PHST- 2017/12/05 06:00 [pubmed] PHST- 2019/02/05 06:00 [medline] PHST- 2017/12/05 06:00 [entrez] AID - S1558-7673(17)30317-8 [pii] AID - 10.1016/j.clgc.2017.10.011 [doi] PST - ppublish SO - Clin Genitourin Cancer. 2018 Apr;16(2):e269-e276. doi: 10.1016/j.clgc.2017.10.011. Epub 2017 Nov 3.