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Targeting Hsp90 in urothelial carcinoma.

Chehab M, Caza T, Skotnicki K, Landas S, Bratslavsky G, Mollapour M, Bourboulia D - Oncotarget (2015)

Bottom Line: Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs.The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation.Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

ABSTRACT
Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs. Despite use of current chemotherapies and immunotherapies, long-term remission in patients with muscle-invasive or metastatic disease remains low, and disease recurrence is common. The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation. Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation. Despite promising preclinical data, clinical trials utilizing Hsp90 inhibitors for other malignancies had modest efficacy. Therefore, we propose that Hsp90 inhibition would best serve as an adjuvant treatment in advanced muscle-invasive or metastatic bladder cancers to potentiate other therapies. An overview of bladder cancer biology, current treatments, molecular targeted therapies, and the role for Hsp90 inhibitors in the treatment of urothelial carcinoma is the focus of this review.

No MeSH data available.


Related in: MedlinePlus

Hsp90 is a central hub to bladder cancer signalingHsp90 is a critical signaling hub in the etiopathogenesis of urothelial carcinoma. Hsp90 clients include tumor suppressors, oncogenes, growth factors, cell cycle regulators, histone modifying enzymes, and signal transducers [21, 49–55, 57, 58, 60–62]. All of the listed genes are subject to mutation, gene amplification, or deletion in urothelial carcinoma and are Hsp90 client proteins.
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Figure 3: Hsp90 is a central hub to bladder cancer signalingHsp90 is a critical signaling hub in the etiopathogenesis of urothelial carcinoma. Hsp90 clients include tumor suppressors, oncogenes, growth factors, cell cycle regulators, histone modifying enzymes, and signal transducers [21, 49–55, 57, 58, 60–62]. All of the listed genes are subject to mutation, gene amplification, or deletion in urothelial carcinoma and are Hsp90 client proteins.

Mentions: Several Hsp90 client proteins act as drivers of urothelial carcinoma, and thus inhibitors or modulators of Hsp90 function may impede urothelial carcinoma pathogenesis (Figures 1 and 3). A recent comprehensive study, by the Cancer Genome Atlas Project, identified novel protein determinants involved in urothelial carcinoma including: tumor suppressors (TP53, Rb) [49, 50], oncogenes (ErbB2/HER2, ErbB3, Myc) [49, 51, 52], cell cycle regulatory proteins (by Hsp90 and Cdc37 co-chaperone, cyclins and cyclin-dependent kinases, including Cdk2) [53, 54], Ras-MAPK pathway proteins (HRas and multiple MAP kinases) [55], mTOR pathway components (Akt) [56], growth factor receptors (EGFR, FGFR1/3/4) [57–59] and transcriptional regulators which include proteins involved in histone modification (SWI/SNF complex members), STAT3, MLL/3, SP1 and FOXA2 [60–62] (Figure 3).


Targeting Hsp90 in urothelial carcinoma.

Chehab M, Caza T, Skotnicki K, Landas S, Bratslavsky G, Mollapour M, Bourboulia D - Oncotarget (2015)

Hsp90 is a central hub to bladder cancer signalingHsp90 is a critical signaling hub in the etiopathogenesis of urothelial carcinoma. Hsp90 clients include tumor suppressors, oncogenes, growth factors, cell cycle regulators, histone modifying enzymes, and signal transducers [21, 49–55, 57, 58, 60–62]. All of the listed genes are subject to mutation, gene amplification, or deletion in urothelial carcinoma and are Hsp90 client proteins.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496161&req=5

Figure 3: Hsp90 is a central hub to bladder cancer signalingHsp90 is a critical signaling hub in the etiopathogenesis of urothelial carcinoma. Hsp90 clients include tumor suppressors, oncogenes, growth factors, cell cycle regulators, histone modifying enzymes, and signal transducers [21, 49–55, 57, 58, 60–62]. All of the listed genes are subject to mutation, gene amplification, or deletion in urothelial carcinoma and are Hsp90 client proteins.
Mentions: Several Hsp90 client proteins act as drivers of urothelial carcinoma, and thus inhibitors or modulators of Hsp90 function may impede urothelial carcinoma pathogenesis (Figures 1 and 3). A recent comprehensive study, by the Cancer Genome Atlas Project, identified novel protein determinants involved in urothelial carcinoma including: tumor suppressors (TP53, Rb) [49, 50], oncogenes (ErbB2/HER2, ErbB3, Myc) [49, 51, 52], cell cycle regulatory proteins (by Hsp90 and Cdc37 co-chaperone, cyclins and cyclin-dependent kinases, including Cdk2) [53, 54], Ras-MAPK pathway proteins (HRas and multiple MAP kinases) [55], mTOR pathway components (Akt) [56], growth factor receptors (EGFR, FGFR1/3/4) [57–59] and transcriptional regulators which include proteins involved in histone modification (SWI/SNF complex members), STAT3, MLL/3, SP1 and FOXA2 [60–62] (Figure 3).

Bottom Line: Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs.The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation.Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

ABSTRACT
Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs. Despite use of current chemotherapies and immunotherapies, long-term remission in patients with muscle-invasive or metastatic disease remains low, and disease recurrence is common. The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation. Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation. Despite promising preclinical data, clinical trials utilizing Hsp90 inhibitors for other malignancies had modest efficacy. Therefore, we propose that Hsp90 inhibition would best serve as an adjuvant treatment in advanced muscle-invasive or metastatic bladder cancers to potentiate other therapies. An overview of bladder cancer biology, current treatments, molecular targeted therapies, and the role for Hsp90 inhibitors in the treatment of urothelial carcinoma is the focus of this review.

No MeSH data available.


Related in: MedlinePlus