Why has the prognosis for muscle-invasive bladder cancer not significantly improved after decades of therapeutic advancements?

Goto, T.; Miyamoto, Hiroshi

doi:10.1080/14737140.2020.1744437

Cited by 9 publications

(7 citation statements)

References 14 publications

(14 reference statements)

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“…The treatment outcomes of radical cystectomy for muscle invasive bladder cancer (MIBC) combined with chemotherapy are insufficient (24), and the five-year survival rate is only ~5% in patients with metastatic bladder cancers (25). As there have been no significant improvements in the treatment outcome over the last three decades (26), new treatment strategies for MIBC and metastatic bladder cancers are necessary. PDK4 expression has been shown to be markedly higher in high-grade than in low-grade bladder cancers without the overexpression of PDK1, 2 or 3 (27).…”

Section: Introductionmentioning

confidence: 99%

Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis

et al. 2021

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The phosphorylation of pyruvate dehydrogenase (PDH) by pyruvate dehydrogenase kinase (PDK) 4 inhibits its ability to induce a glycolytic shift. PDK4 expression is upregulated in various types of human cancer. Because PDK4 regulation is critical for metabolic changes in cancer cells, it is an attractive target for cancer therapy given its ability to shift glucose metabolism. It was previously shown that a novel PDK4 inhibitor, cryptotanshinone (CPT), suppressed the three-dimensional (3D)-spheroid formation of pancreatic and colorectal cancer cells. In the present study, the effects of CPT on the invasiveness of bladder cancer cells were investigated. CPT significantly suppressed the invasiveness and 3D-spheroid formation of T24 and J82 bladder cancer cells. CPT also suppressed the phosphorylation of PDH and β-catenin, as well as the expression of N-cadherin, which are all critical for inducing epithelial-mesenchymal transition (EMT). The knockdown of β-catenin or PDK4 using specific small interfering RNAs suppressed N-cadherin expression and invasiveness in T24 cells. An mTOR inhibitor also suppressed the phosphorylation of β-catenin and N-cadherin expression. Furthermore, CPT injection significantly suppressed pancreatic tumor growth and peritoneal dissemination of highly metastatic SUIT-2 pancreatic cancer cells in a mouse orthotopic pancreatic cancer model, without evident toxicity. Moreover, immunohistochemistry analyses demonstrated decreased β-catenin expression in CPT-treated pancreatic tumors compared with control tumors. Taken together, these results indicate that CPT reduced the invasiveness and metastasis of bladder cancer cells by suppressing EMT via the mTOR/β-catenin/N-cadherin pathway.

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Section: Introductionmentioning

confidence: 99%

Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis

et al. 2021

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“…Conventional non-surgical therapy against bladder cancer includes systemic chemotherapy, intravesical pharmacotherapy with anti-cancer agents or BCG, radiotherapy, and immunotherapy with immune checkpoint inhibitors. Although these are quite effective in some patients, bladder cancer, especially MI disease, remains lethal [ 65 ]. The development of strategies for not only overcoming therapeutic resistance where underlying mechanisms are poorly understood, but also predicting its sensitivity, is thus urgently required.…”

Section: Sex Hormone Receptor Signaling and Sensitivity To Conventional Non-surgical Treatment For Bladder Cancermentioning

confidence: 99%

“…In selected patients with MI bladder cancer, radiotherapy combined with chemotherapy led to survival rates comparable to those undergoing radical cystectomy [ 4 ]. Specifically, in these patients, trimodal therapy consisting of either transurethral resection or partial cystectomy followed by radiotherapy with concurrent chemotherapy is currently considered to yield the best oncologic outcomes [ 4 , 65 ]. Although the trimodal therapy may increase quality-adjusted life years, current data on overall survival or disease-specific survival are still in favor of radical cystectomy [ 82 ].…”

Section: Sex Hormone Receptor Signaling and Sensitivity To Conventional Non-surgical Treatment For Bladder Cancermentioning

confidence: 99%

“…In this study, either genistein supplement or placebo is given to the patients with NMI bladder tumor for 10 weeks (i.e., during BCG therapy and one-month post-therapy). Several antibodies against programmed cell death-1 (PD-1) or its ligand (PD-L1) have recently been approved by the U.S. Food and Drug Administration, and there are a number of PD-1/PD-L1 inhibitors entering clinical trials [ 65 ]. These drugs, as immune checkpoint inhibitors that attack tumor cells via enhancing the host immune response, are expected to considerably improve the prognosis of various types of malignancies, including bladder cancer.…”

Section: Sex Hormone Receptor Signaling and Sensitivity To Conventional Non-surgical Treatment For Bladder Cancermentioning

confidence: 99%

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Sex Hormone Receptor Signaling in Bladder Cancer: A Potential Target for Enhancing the Efficacy of Conventional Non-Surgical Therapy

Ide

Miyamoto

2021

Cells

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There have been critical problems in the non-surgical treatment for bladder cancer, especially residence to intravesical pharmacotherapy, including BCG immunotherapy, cisplatin-based chemotherapy, and radiotherapy. Recent preclinical and clinical evidence has suggested a vital role of sex steroid hormone-mediated signaling in the progression of urothelial cancer. Moreover, activation of the androgen receptor and estrogen receptor pathways has been implicated in modulating sensitivity to conventional non-surgical therapy for bladder cancer. This may indicate the possibility of anti-androgenic and anti-estrogenic drugs, apart from their direct anti-tumor activity, to function as sensitizers of such conventional treatment. This article summarizes available data suggesting the involvement of sex hormone receptors, such as androgen receptor, estrogen receptor-α, and estrogen receptor-β, in the progression of urothelial cancer, focusing on their modulation for the efficacy of conventional therapy, and discusses their potential of overcoming therapeutic resistance.

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“…Since the late 1980s, cisplatin (CDDP)‐based combination chemotherapy has been the standard of care in patients with muscle‐invasive bladder cancer in a neoadjuvant or adjuvant setting, and in those with metastatic disease 1 . Importantly, the mortality rate of bladder cancer patients has not significantly improved in the past several decades 2 . Consequently, the development of chemosensitization strategies constitutes a goal with critical clinical implications.…”

Section: Figurementioning

confidence: 99%

FOXO1 inactivation induces cisplatin resistance in bladder cancer

et al. 2020

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We found that FOXO1‐shRNA sublines or FOXO1‐positive cells co–treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p‐FOXO1) in cisplatin‐resistant sublines established by long‐term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle‐invasive bladder cancer undergoing cisplatin‐based neoadjuvant therapy further showed a strong trend to associate between p‐FOXO1 positivity and unfavorable response to chemotherapy.

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Why has the prognosis for muscle-invasive bladder cancer not significantly improved after decades of therapeutic advancements?

Cited by 9 publications

References 14 publications

Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis

Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis

Sex Hormone Receptor Signaling in Bladder Cancer: A Potential Target for Enhancing the Efficacy of Conventional Non-Surgical Therapy

FOXO1 inactivation induces cisplatin resistance in bladder cancer

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