Intravesical Delivery of Rapamycin Suppresses Tumorigenesis in a Mouse Model of Progressive Bladder Cancer

Seager, Catherine M.; Puzio-Kuter, Anna M.; Patel, Trushar; Jain, Shalini; Cordon‐Cardo, Carlos; Kiernan, James Mc; Abate‐Shen, Cory

doi:10.1158/1940-6207.capr-09-0169

Cited by 78 publications

(69 citation statements)

References 17 publications

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“…Inhibition of mTOR signaling with rapamycin reduced cell proliferation and migration in vitro and reduced tumor volume in a T24-xenograft model by 55%. 71 These results were supported by a second study that showed mTOR activation in muscle-invasive UCC, 1,72 with mTOR inhibition preventing the progression of CIS to invasive bladder cancer. 72 Another important role of mTOR in tumor biology is the induction of angiogenesis.…”

Section: Role Of Mtor In Bladder Cancermentioning

confidence: 82%

“…71 These results were supported by a second study that showed mTOR activation in muscle-invasive UCC, 1,72 with mTOR inhibition preventing the progression of CIS to invasive bladder cancer. 72 Another important role of mTOR in tumor biology is the induction of angiogenesis. mTOR regulates the expression of hypoxia inducible factor and thus subsequently of vascular endothelial growth factor (VEGF).…”

Section: Role Of Mtor In Bladder Cancermentioning

confidence: 82%

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Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

Ching

Hansel

2010

Laboratory Investigation

139

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Section: Role Of Mtor In Bladder Cancermentioning

confidence: 82%

Section: Role Of Mtor In Bladder Cancermentioning

confidence: 82%

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

Ching

Hansel

2010

Laboratory Investigation

139

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“…In bladder cancer cell lines, mTOR inhibition with rapamycin has been shown to significantly decrease bladder cancer cell proliferation and induce G 0 /G 1 cell-cycle arrest without stimulating apoptosis in vitro and in vivo. [24][25][26] In our panel of cell lines, rapamycin induced heterogeneous and partial growth arrest that plateaued at drug concentrations around 10 nM (Fig. 6).…”

Section: Resultsmentioning

confidence: 81%

Autophagy limits the cytotoxic effects of the AKT inhibitor AZ7328 in human bladder cancer cells

Dickstein¹,

Nitti²,

Dinney³

et al. 2012

Cancer Biology & Therapy

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IntroductionBladder cancer is consistently among the top ten most common cancers and causes of cancer death in both men and women. In the United States, there are greater than 70,000 new cases of bladder cancer reported per year and greater than 14,000 deaths. In the last ten years, the death rate from this disease is essentially unchanged, whereas great strides have been made in other diseases.1 Thus, there is an enormous need to improve current treatment regimens in both the local and advanced setting and to develop novel strategies to prevent or delay progression, which is the main determinant of poor outcome.The phosphatidylinositol 3-kinase (PI3K/AKT/mTOR) pathway is one of the core signal transduction pathways downstream of receptor tyrosine kinases (RTKs) that control cell metabolism, proliferation, protein synthesis, cell size, autophagy, Background: Mutations that activate the pI3K/aKT/mTOR pathway are relatively common in urothelial (bladder) cancers, but how these pathway mutations affect aKT dependency is not known. We characterized the relationship between aKT pathway mutational status and sensitivity to the effects of the selective aKT kinase inhibitor aZ7328 using a panel of 12 well-characterized human bladder cancer cell lines.Results: aZ7328 inhibited proliferation and aKT substrate phosphorylation in a concentration-dependent manner but had minimal effects on apoptosis. proliferative inhibition correlated loosely with the presence of activating pIK3Ca mutations and was strengthened in combination with the mTOR inhibitor rapamycin. aZ7328 induced autophagy in some of the lines and in the cells exposed to a combination of aZ7328 and chemical autophagy inhibitors apoptosis was induced.Methods: sequenome DNa sequencing was performed to identify mutations in a panel of 12 urothelial cancer cell lines. Drug-induced proliferative inhibition and apoptosis were quantified using MTT assays and propidium iodide staining with FaCs analyses. protein activation via phosphorylation was measured by immunoblotting. autophagy was measured by LC3 immunofluorescence and immunoblotting.Conclusions: The cytostatic effects of aZ7328 correlate with pIK3Ca mutations and are greatly enhanced by dual pathway inhibition using an mTOR inhibitor. Furthermore, aZ7328 can interact with autophagy inhibitors to induce apoptosis in some cell lines. Overall, our results support the further evaluation of combinations of pI3K/aKT/mTOR pathway and autophagy inhibitors in pre-clinical in vivo models and ultimately in patients with pIK3Ca mutant bladder cancers.

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“…10). Therefore, and as reported in this issue of the journal, the Abate-Shen group (Seager et al) evaluated local versus systemic delivery of rapamycin, an inhibitor of the TOR complex 1/mTOR complex, for effects on the progression of CIS lesions in their mouse model (11). Their results indicate that mTOR inhibition produces striking inhibitory effects on tumor progression.…”

mentioning

confidence: 99%

The Molecular, the Bad, and the Ugly: Preventing Bladder Cancer via mTOR Inhibition

McConkey

Dinney

2009

Cancer Prevention Research

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This perspective on Seager et al. (beginning on p. 1008) considers an important advance in the effort to control bladder cancer. Frontline therapy for superficial transitional cell carcinoma of the bladder involves instillation of the crude immunomodulatory bacterial extract Bacillus Calmette-Guérin directly into the organ. Seager et al. now show that local administration of a chemical inhibitor of mammalian target of rapamycin strongly suppressed growth in a novel preclinical mouse model that develops carcinoma in situ, a particularly problematic form of transitional cell carcinoma of the bladder. The results not only support the clinical evaluation of mammalian target of rapamycin inhibitors in this setting, they open the door for the evaluation of additional molecular local therapies as well.It is well established that bladder cancer develops along two major molecular tracks (1). The first track is characterized by the development of papillary lesions that rarely become invasive or metastatic but almost always recur (1). These "superficial" tumors are therefore rarely lethal, but their high recurrence rates coupled with patient longevity make them the most expensive solid tumors to treat and therefore a significant public health burden. Superficial tumors are thought to be driven by Ras pathway activation (2), most often (in up to 65% of cases) via the accumulation of activating mutations in the type 3 fibroblast growth factor receptor (3) and less often via mutations in phosphoinositide 3-kinase (4) or Ras itself. The second progression track involves the inactivation of major tumor suppressors [p53, Rb, and phosphatase and tensin homologue (PTEN); refs. 1, 4, 5], and it produces tumors that are highly invasive and metastatic. Although ∼50% of these muscle-invasive tumors respond well to cisplatin-based therapies (6, 7), the other half is highly refractory to all current regimens and leads to rapid mortality.Although superficial and muscle-invasive bladder cancers are considered distinct diseases, there is a form of superficial (non-muscle-invasive) cancer, which is called carcinoma in situ (CIS), that often does appear to progress to muscleinvasive disease (8). This form of bladder cancer is characterized by the presence of flat, dysplastic lesions that can involve the whole bladder mucosa via the "field effect." Current frontline therapy for CIS involves intravesical therapy with the immunomodulator Bacillus Calmette-Guérin (BCG), which produces responses in a majority of patients (9). However, BCG has significant negative side effects, responsive patients recur at a high rate, and there are no effective treatment options for patients who develop BCG-refractory disease. Therefore, it would be of great value to identify less toxic, effective strategies to prevent CIS progression.Abate-Shen's laboratory recently showed that nearly 100% of 6-to 8-week-old animals undergoing conditional inactivation of p53 and PTEN via adenoviral Cre delivery to the urothelium develop muscle-invasive tumors by the time...

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Intravesical Delivery of Rapamycin Suppresses Tumorigenesis in a Mouse Model of Progressive Bladder Cancer

Cited by 78 publications

References 17 publications

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

Autophagy limits the cytotoxic effects of the AKT inhibitor AZ7328 in human bladder cancer cells

The Molecular, the Bad, and the Ugly: Preventing Bladder Cancer via mTOR Inhibition

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