Germline and sporadic mTOR pathway mutations in low-grade oncocytic tumor of the kidney

Among alternative therapeutic strategies in clinically aggressive neuroendocrine tumors (NETs) of the lung, promising results have been obtained in experimental clinical trials with mammalian target of rapamycin (mTOR) inhibitors, though in the absence of a proven mTOR signaling activation status. This study analyzed the expression of phosphorylated mTOR (p-mTOR) and its major targets, the ribosomal p70S6-kinase (S6K) and the eukaryotic initiation factor 4E-binding protein 1 (4EBP1) in a large series of 218 surgically resected, malignant lung NETs, including 24 metastasizing typical carcinoids, 73 atypical carcinoids, 60 large cell neuroendocrine carcinomas (LCNECs), and 61 small cell carcinomas (SCLCs). By immunohistochemistry, low-to-intermediate-grade tumors as compared with high-grade tumors showed higher levels of p-mTOR and phosphorylated S6K (p-S6K) (P<0.001), at variance with phosphorylated 4EBP1 (p-4EBP1), which was mainly expressed in LCNECs and SCLCs (P<0.001). The activated status of mTOR pathway was proved by the strong correlation of p-mTOR with p-S6K and somatostatin receptor(s). Western blot analysis of NET tumor samples confirmed such findings, and differential sensitivity to mTOR inhibition according to mTOR pathway activation characteristics was determined in two lung carcinoid cell lines in vitro. None of the investigated molecules had an impact on survival. However, in low-grade tumors, low p-mTOR expression correlated with lymph node metastases (P=0.016), recurrent disease, and survival (P=0.005). In conclusion, these data demonstrate a differential mTOR activation status in the spectrum of pulmonary NETs, possibly suggesting that mTOR pathway profiling might play a predictive role in candidate patients for mTOR-targeted therapies.

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Low-grade oncocytic renal tumor (LOT): mutations in mTOR pathway genes and low expression of FOXI1

Modern Pathology ◽

10.1038/s41379-021-00906-7 ◽

2021 ◽

Author(s):

Aurélien Morini ◽

Tom Drossart ◽

Marc-Olivier Timsit ◽

Mathilde Sibony ◽

Viorel Vasiliu ◽

...

Keyword(s):

Renal Tumor ◽

Mtor Pathway ◽

Low Grade ◽

Low Expression

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A phase II study of continuous oral mTOR inhibitor everolimus for recurrent, radiographic-progressive neurofibromatosis type 1–associated pediatric low-grade glioma: a Neurofibromatosis Clinical Trials Consortium study

Neuro-Oncology ◽

10.1093/neuonc/noaa071 ◽

2020 ◽

Vol 22 (10) ◽

pp. 1527-1535 ◽

Cited By ~ 7

Author(s):

Nicole J Ullrich ◽

Sanjay P Prabhu ◽

Alyssa T Reddy ◽

Michael J Fisher ◽

Roger Packer ◽

...

Keyword(s):

Phase Ii ◽

Neurofibromatosis Type 1 ◽

Mtor Inhibitor ◽

Neurofibromatosis Type ◽

Mtor Pathway ◽

Pharmacokinetic Parameters ◽

Low Grade ◽

Nerve Sheath Tumor ◽

Pathway Inhibition

Abstract Background Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs. Methods Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks. Results Twenty-three participants (median age, 9.4 y; range, 3.2–21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants. Conclusion Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.

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Reversion of Hormone Treatment Resistance with the Addition of an mTOR Inhibitor in Endometrial Stromal Sarcoma

Case Reports in Medicine ◽

10.1155/2014/612496 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

J. Martin-Liberal ◽

C. Benson ◽

C. Messiou ◽

C. Fisher ◽

I. Judson

Keyword(s):

Hormone Receptors ◽

Mtor Inhibitor ◽

Acquired Resistance ◽

Mammalian Target Of Rapamycin ◽

Treatment Resistance ◽

Endometrial Stromal Sarcoma ◽

Hormone Treatment ◽

Mtor Pathway ◽

Low Grade ◽

Stromal Sarcoma

Background. Endometrial stromal sarcomas (ESS) are a subtype of gynaecological sarcomas characterized by the overexpression of hormone receptors. Hormone treatment is widely used in ESS but primary or acquired resistance is common. The mammalian target of rapamycin (mTOR) pathway has been suggested to play a key role in the mechanisms of hormone resistance. Recent studies in breast and prostate cancer demonstrate that this resistance can be reversed with the addition of an mTOR inhibitor. This phenomenon has never been reported in ESS.Methods. We report the outcome of one patient with pretreated, progressing low grade metastatic ESS treated with medroxyprogesterone acetate in combination with the mTOR inhibitor sirolimus.Results. Partial response was achieved following the addition of sirolimus to the hormone treatment. Response has been maintained for more than 2 years with minimal toxicity and treatment is ongoing.Conclusion. This case suggests that the resistance to the hormone manipulation in ESS can be reversed by the addition of an mTOR pathway inhibitor. This observation is highly encouraging and deserves further investigation.

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Morphologic Overlap Between Low Grade Oncocytic Tumor (LOT) & Eosinophilic Variant of Chromophobe Renal Cell Carcinoma

Human Pathology ◽

10.1016/j.humpath.2021.09.010 ◽

2021 ◽

Author(s):

Sounak Gupta ◽

Ross A. Rowsey ◽

John C. Cheville ◽

Rafael E. Jimenez

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Chromophobe Renal Cell Carcinoma ◽

Low Grade ◽

Oncocytic Tumor

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A Case of Low-Grade Oncocytic Tumor/Chromophobe Renal Cell Carcinoma (Oncocytic Variant) of the Kidney

Case Reports in Pathology ◽

10.1155/2021/6684777 ◽

2021 ◽

Vol 2021 ◽

pp. 1-4

Author(s):

Noriyoshi Ishikawa ◽

Nao Kimura ◽

Toshio Yoshida ◽

Ichiro Yoshimura ◽

Ken Nakahara ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Chromophobe Renal Cell Carcinoma ◽

Low Grade ◽

Diagnostic Challenge ◽

Eosinophilic Cytoplasm ◽

Oncocytic Tumor ◽

Oncocytic Variant ◽

Disease Entities

The oncocytic variant of chromophobe renal cell carcinoma (oChRCC) and low-grade oncocytic tumor (LOT) is introduced as new renal disease entity. Both of these tumors are low-grade malignancies consisting of cells with eosinophilic cytoplasm. Distinguishing between eosinophilic variant of chromophobe renal cell carcinoma (eCRCC) and oncocytoma is often a diagnostic challenge in routine surgical pathology. However, oChRCC and LOT might be independent disease entities that might not fit completely into any of these categories. Histologically, these tumors have greater morphological similarity with oncocytoma than with ChRCC. However, immunohistochemically, they exhibit diffuse and dense positivity for CK7 and are negative for CD117. In the present case, we initially had difficulty distinguishing among oncocytoma, eCRCC, and type 2 papillary renal cell carcinoma (2-pRCC). However, after learning about new disease entities such as oChRCC and LOT, we were able to diagnose this tumor.

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Low-grade oncocytic tumor: report of two cases of an emerging entity in the spectrum of oncocytic renal neoplasms

Turkish Journal of Pathology ◽

10.5146/tjpath.2021.01549 ◽

2021 ◽

Author(s):

Divakar Sharma ◽

Trupti Pai ◽

Gagan Prakash ◽

Sangeeta Desai ◽

Santosh Menon

Keyword(s):

Low Grade ◽

Renal Neoplasms ◽

Oncocytic Tumor

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ACTR-42. PI3K/mTOR PATHWAY ACTIVATION SELECTED PHASE II STUDY OF EVEROLIMUS (RAD001) WITH AND WITHOUT TEMOZOLOMIDE IN THE TREATMENT OF ADULT PATIENTS WITH SUPRATENTORIAL LOW-GRADE GLIOMA [NCT NCT02023905]

Neuro-Oncology ◽

10.1093/neuonc/noz175.084 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi22-vi23

Author(s):

Jennie Taylor ◽

Annette Molinaro ◽

Eduardo Rodriguez Almaraz ◽

Ciara Downey ◽

Joanna Phillips ◽

...

Keyword(s):

Survival Data ◽

Primary Outcome ◽

Pi3k Pathway ◽

Mtor Pathway ◽

Low Grade ◽

Diffuse Glioma ◽

Eligibility Criteria ◽

Low Grade Gliomas ◽

Pathway Activation ◽

Central Pathology

Abstract Functional activation of the PI3K/AKT/mTOR pathway is seen in ~50% of low-grade gliomas and correlates with worse survival. Everolimus is a selective inhibitor of mTOR that targets mTOR-raptor signaling, halting proliferation and indirectly inhibiting angiogenesis. This phase 2 study evaluated the efficacy of everolimus in untreated grade II diffuse glioma. Patients were stratified by 1p19q status and PI3K pathway activation (via phosphorylation of PRAS-40) into three arms: 1) 1p19q intact, PRAS-40 phosphorylated received everolimus monotherapy; 2) 1p19q intact, PRAS-40 not phosphorylated received everolimus with temozolomide; and 3) 1p19q co-deleted received everolimus monotherapy. Primary outcome was landmark PFS-33 months for Arms 1 and 2; and PFS-38 months for Arm 3 (null hypothesis 50% for all arms individually). Key eligibility criteria included central pathology confirmation, no prior treatment, and initiation of everolimus within 120 days of most recent tissue sampling. From 05/2014 to 07/2018, 27 patients were enrolled – 16 into Arm 1; 2 into Arm 2; and 9 into Arm 3. Median age at enrollment was 38 years (range 21 – 65); median KPS 90 (range 70 – 100) and a majority were male (74%). Although follow-up is not complete, as of 05/2019 11 of 16 patients had progressed prior to 33 months in Arm 1, and 5 of 9 patients had progressed prior to 38 months in Arm 3. Toxicity was as expected with frequent grade 1/2 AEs of diarrhea, rash, and mucositis. Headache was the most common grade 3 AE and was seen in three cases. The study was closed prematurely secondary to slow accrual and loss of drug support. Updated survival data as well as results of secondary and exploratory analyses will be reported. In summary, everolimus was well tolerated in previously untreated low-grade gliomas. However, it failed to meet primary outcome of extending PFS in this population.

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