Is mTOR Inhibitor Good Enough for Treatment All Tumors in TSC Patients?

Habib, Samy L.; Al-Obaidi, Noor Y.; Nowacki, Maciej; Pietkun, Katarzyna; Zegarska, Barbara; Kloskowski, Tomasz; Zegarski, Wojciech; Drewa, Tomasz; Medina, Edward A.; Zhao, Zhenze; Liang, Sitai

doi:10.7150/jca.14747

Cited by 25 publications

(25 citation statements)

References 45 publications

(61 reference statements)

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“…Notably, hyperactivated mTORC1, caused by loss-of-function mutations in the TSC1 or TSC2 gene, is considered to be the main reason of tuberous sclerosis complex (TSC), an autosomal dominant disease characterized by formation of benign tumors in multiple organs [6]. Currently, the mTORC1 inhibitors, rapamycin as well as its analogues have been approved for the treatment of several types of human cancer, such as renal cell carcinoma, mantle cell lymphoma, and some TSCrelated tumors, including lymphangioleiomyomatosis, angiomyolipomas, and subependymal giant cell astrocytomas [6,[16][17][18]. Numerous studies indicate that mTORC1 signaling pathway is regulated by miRNAs [10].…”

Section: Discussionmentioning

confidence: 99%

miR-125b-5p/STAT3 Pathway Regulated by mTORC1 Plays a Critical Role in Promoting Cell Proliferation and Tumor Growth

Zhang¹,

Wan²,

Tang³

et al. 2020

J. Cancer

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Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) plays a critical role in tumorigenesis. However, the precise underlying mechanism is still not fully understood. Although accumulating evidence suggests that mTORC1 signaling is regulated by microRNAs (miRNAs), whether miRNAs are involved in the tumorigenesis mediated by mTORC1 dysregulation remains largely unclear. In our study, the comparison between tuberous sclerosis complex 1 (Tsc1) -/-or Tsc2-/-mouse embryonic fibroblasts (MEFs) and the control cells revealed the involvement of microRNA-125b-5p (miR-125b-5p) in the tumorigenesis driven by mTORC1 activation. Our study also showed that loss of TSC1 or TSC2 led to significant downregulation of miR-125b-5p and upregulation of signal transducer and activator of transcription 3 (STAT3) via mTORC1 activation. Overexpression of miR-125b-5p inhibited the proliferation of the cells with hyperactivated mTORC1 both in vitro and in vivo. Furthermore, we demonstrated that STAT3 is a direct target of miR-125b-5p. Depletion of STAT3 mimicked the effect of ectopic expression of miR-125b-5p, and reintroduction of STAT3 rescued the compromised cell proliferation driven by miR-125b-5p overexpression in Tsc1-/-or Tsc2-/-MEFs. We conclude that the miR-125b-5p/STAT3 pathway plays a crucial role in hyperactivated mTORC1-mediated tumorigenesis and miR-125b-5p is a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

miR-125b-5p/STAT3 Pathway Regulated by mTORC1 Plays a Critical Role in Promoting Cell Proliferation and Tumor Growth

Zhang¹,

Wan²,

Tang³

et al. 2020

J. Cancer

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“… 27 , 28 This situation is well observed in specific medical specialties such as oncology and surgery. 29 , 30 On 10 May 2017, two patients underwent PIPAC procedures performed for the first time in the Department of Surgical Oncology, Ludwik Rydygier’s Collegium Medicum, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland. The intensive preparations for this procedure lasted for over 1 year (14 months) and consisted of several important steps.…”

Section: Discussionmentioning

confidence: 99%

The scientific report from the first pressurized intraperitoneal aerosol chemotherapy (PIPAC) procedures performed in the eastern part of Central Europe

Nowacki

Zegarski

2018

J Int Med Res

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ObjectiveTo perform a single-centre, detailed analysis of the preparations for the introduction of the first pressurized intraperitoneal aerosol chemotherapy (PIPAC) programme in the eastern part of Central Europe.MethodsThe study analysed the 14-month preparation period prior to the performance of the first PIPAC procedure with respect to: (i) general preparations; (ii) patient referral and qualification; (iii) the first PIPAC procedure; (iv) the 2 weeks following PIPAC programme establishment; and (v) general problematic issues that arose.ResultsThe length of time needed to prepare our institution for the first PIPAC procedure was extremely long compared with other European Union PIPAC centres: 14 months versus a standard 3–6 months of preparation. The longest amount of time (12 months) was required to prepare the required paperwork.ConclusionsA new PIPAC programme was successfully established in the eastern part of Central Europe. The length of time to implement this method was significantly longer because of lengthy bureaucratic processes. These current findings should help new centres, especially in this part of Europe, to establish a PIPAC programme more quickly.

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“…Targeting mTOR is emerging as an important approach in cancer therapeutics. Early clinical trials show that kidney tumours regress in response to treatment with rapamycin and other mTOR inhibitor including everolimus, a direct-target of inhibition of mTORC1 [ 31 , 32 ]. In addition, activation AMPK by AICAR show significant increase in cell apoptosis and decrease in cell proliferation by targeting Akt/HIF2-α in AML, TSC2 +/− and TSC −/− cells.…”

Section: Discussionmentioning

confidence: 99%

A new drug combination significantly reduces kidney tumor progression in kidney mouse model

et al. 2018

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Tuberous sclerosis complex (TSC) disease is associated with tumors in many organs, particularly angiomyolipoma (AML) in the kidneys. Loss or inactivation of TSC1/2 results in high levels of HIF-α activity and VEGF expression. mTOR inhibitor (rapamycin) and the AMPK activator 5-aminoimidazole-4-carboxamide (AICA)-riboside (AICAR) are currently used separately to treat cancer patients. Here, we investigated the effect of a novel combination of rapamycin and AICAR on tumor progression. Our data show that treatment of AML human cells with drug combinations resulted in 5-7-fold increase in cell apoptosis compared to each drug alone. In addition, drug combinations resulted in 4-5-fold decrease in cell proliferation compared to each drug alone. We found that drug combinations abolished Akt and HIF activity in AML cells. The drug combinations resulted in decrease in cell invasion and cell immigration by 70% and 84%, respectively in AML cells. The combined drugs also significantly decreased the VEGF expression compare to each drug alone in AML cells. Drug combinations effectively abolished binding of HIF-2α to the putative Akt site in the nuclear extracts isolated from AML cells. Treatment TSC mice with drug combinations resulted in 75% decrease in tumor number and 88% decrease in tumor volume compared to control TSC mice. This is first evidence that drug combinations are effective in reducing size and number of kidney tumors without any toxic effect on kidney. These data will provide evidence for initiating a new clinical trial for treatment of TSC patients.

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Is mTOR Inhibitor Good Enough for Treatment All Tumors in TSC Patients?

Cited by 25 publications

References 45 publications

miR-125b-5p/STAT3 Pathway Regulated by mTORC1 Plays a Critical Role in Promoting Cell Proliferation and Tumor Growth

miR-125b-5p/STAT3 Pathway Regulated by mTORC1 Plays a Critical Role in Promoting Cell Proliferation and Tumor Growth

The scientific report from the first pressurized intraperitoneal aerosol chemotherapy (PIPAC) procedures performed in the eastern part of Central Europe

A new drug combination significantly reduces kidney tumor progression in kidney mouse model

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