Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although formation of urothelial carcinoma of the bladder (UCB) requires multiple steps and proceeds along divergent pathways, the underlying genetic and molecular determinants for each step and pathway remain undefined. By developing transgenic mice expressing single or combinatorial genetic alterations in urothelium, we demonstrated here that overcoming oncogene-induced compensatory tumor barriers was critical for urothelial tumor initiation. Constitutively active Ha-ras (Ras*) elicited urothelial hyperplasia that was persistent and did not progress to tumors over a 10 months period. This resistance to tumorigenesis coincided with increased expression of p53 and all pRb family proteins. Expression of a Simian virus 40 T antigen (SV40T), which disables p53 and pRb family proteins, in urothelial cells expressing Ras* triggered early-onset, rapidly-growing and high-grade papillary UCB that strongly resembled the human counterpart (pTaG3). Urothelial cells expressing both Ras* and SV40T had defective G(1)/S checkpoint, elevated Ras-GTPase and hyperactivated AKT-mTOR signaling. Inhibition of the AKT-mTOR pathway with rapamycin significantly reduced the size of high-grade papillary UCB but hyperactivated mitogen-activated protein kinase (MAPK). Inhibition of AKT-mTOR, MAPK and STAT3 altogether resulted in much greater tumor reduction and longer survival than did inhibition of AKT-mTOR pathway alone. Our studies provide the first experimental evidence delineating the combinatorial genetic events required for initiating high-grade papillary UCB, a poorly defined and highly challenging clinical entity. Furthermore, they suggest that targeted therapy using a single agent such as rapamycin may not be highly effective in controlling high-grade UCB and that combination therapy employing inhibitors against multiple targets are more likely to achieve desirable therapeutic outcomes.
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PMID:Urothelial tumor initiation requires deregulation of multiple signaling pathways: implications in target-based therapies. 2228 62

The treatment of genitourinary malignancies has dramatically evolved over recent years. Renal cell carcinoma, urothelial carcinoma of the bladder, and prostate adenocarcinoma are the most commonly encountered genitourinary malignancies and represent a heterogeneous population of cancers, in both histology and approach to treatment. However, all three cancers have undergone paradigm shifts in their respective therapeutic landscapes due to a greater understanding of their underlying molecular mechanisms and oncogenic drivers. The advance that has gained the most recent traction has been the advent of immunotherapies, particularly immune checkpoint inhibitors. Immunotherapy has increased overall survival and even provided durable responses in the metastatic setting in some patients. The early success of immune checkpoint inhibitors has led to further drug development with the emergence of novel agents which modulate the immune system within the tumor microenvironment. Notwithstanding immunotherapy, investigators are also developing novel agents tailored to a variety of targets including small-molecule tyrosine kinase inhibitors, mTOR inhibitors, and novel fusion proteins to name a few. Erdafitinib has become the first targeted therapy approved for metastatic bladder cancer. Moreover, the combination therapy of immune checkpoint inhibitors with targeted agents such as pembrolizumab or avelumab with axitinib has demonstrated both safety and efficacy and just received FDA approval for their use. We are in an era of rapid progression in drug development with multiple exciting trials and ongoing pre-clinical studies. We highlight many of the promising new emerging therapies that will likely continue to improve outcomes in patients with genitourinary malignancies.
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PMID:Emerging therapeutic agents for genitourinary cancers. 3148 60