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.
Highlights
EpidemiologyBladder cancer is the fifth most common type of cancer and the second most frequent urologic malignancy in males after prostate cancer
Long-term rapamycin treatment reduced the incidence of urothelial carcinoma in renal transplant recipients [136], who are at increased risk of malignancy due to a reduced ability to elicit anti-tumor immune responses, the protection against incidence and recurrence was not 100 percent [137]
Heat Shock Protein-90 (Hsp90) blockade by geldanamycin in bladder cancer cells was shown to inhibit signaling by the hepatocyte growth factor and its target oncogene c-Met, which participates in tumor cell migration by disruption of extracellular matrix components [150]
Summary
EpidemiologyBladder cancer is the fifth most common type of cancer and the second most frequent urologic malignancy in males after prostate cancer. Additional chemotherapies under early stage investigation for urothelial carcinoma include the combination of 5-fluoro-2′-deoxycytidine and tetrahydrouridine (antimetabolites), eribulin mesylate (an inhibitor of microtubule dynamics), veliparib (an inhibitor of PARP 1 and 2, which prevents DNA repair within cancer cells to enhance chemoradiosensitivity), and ropidepsin (a histone deacetylase inhibitor). Inhibitors of the mTOR have demonstrated anti-tumor activity alone and in combination with chemotherapy, as mTOR inhibition enhances chemosensitivity of urothelial carcinoma cells [130].
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