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Cited by 171PI3K/AKT/mTOR signaling in cancerPancreatic and Hepatic Oncology ResearchAdvanced Breast Cancer Therapies

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Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies

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Javle, Milind M, Shroff, Rachna T, Xiong, Henry, Varadhachary, Gauri A, Fogelman, David, Reddy, Shrikanth A, Davis, Darren, Zhang, Yujian, Wolff, Robert A, Abbruzzese, James L·2010·BMC Cancer
DOI 10.1186/1471-2407-10-368PMC PMC2910694
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Abstract

BACKGROUND: The phosphoinositide 3-kinase (PI3K)/Akt pathway is constitutively activated in pancreatic cancer and the mammalian target of rapamycin (mTOR) kinase is an important mediator for its signaling. Our recent in vitro studies suggest that prolonged exposure of pancreatic cancer cells to mTOR inhibitors can promote insulin receptor substrate-PI3K interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells (negative feedback loop). The addition of erlotinib to rapamycin can down-regulate rapamycin-stimulated Akt and results in synergistic antitumor activity with erlotinib in preclinical tumor models. METHODS: Two studies prospectively enrolled adult patients with advanced pancreatic cancer, Eastern Cooperative Oncology Group performance status 0-1, adequate hematologic, hepatic and renal parameters and measurable disease. In Study A, temsirolimus was administered intravenously at 25 mg weekly. In Study B, everolimus was administered orally at 30 mg weekly and erlotinib was administered at 150 mg daily. The primary endpoint in both studies was overall survival at 6 months. Secondary endpoints included time to progression, progression-free survival, overall survival, response rate, safety and toxicity. Pretreatment tumor biopsies were analyzed by immunofluorescence and laser scanning cytometry for the expression of pmTOR/mTOR, pAkt/Akt, pErk/Erk, pS6, p4EBP-1 and PTEN. RESULTS: Five patients enrolled in Study A; Two patients died within a month (rapid disease progression and hemorrhagic stroke, respectively). One patient developed dehydration and another developed asthenia. Sixteen patients enrolled in Study B.: 12 males, all ECOG PS = 1. Median cycles = 1 (range 1-2). Grade 4 toxicity: hyponatremia (n = 1), Grade 3: diarrhea (n = 1), cholangitis (n = 3), hyperglycemia (n = 1), fatigue (n = 1). Grade 2: pneumonia (n = 2), dehydration (n = 2), nausea (n = 2), neutropenia (n = 1), mucositis (n = 2) & rash (n = 2). Four patients were hospitalized. Progressive disease occurred in 15 and 1 was non-evaluable. Pretreatment biopsies revealed a higher pAkt/Akt ratio in tumor specimens that in nonmalignant pancreatic tissue. No such trends were noted for the other biomarkers. CONCLUSIONS: Neither study with mTOR inhibitors demonstrated objective responses or disease stability. The negative feedback loop resulting from mTOR inhibition may account for the disease progression and toxicity noted in these studies. Future strategies should aim for a broader targeting of the PI3K pathway in pancreatic cancer. STUDY A: NCT 0075647. STUDY B: NCT00640978.

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Figure 1 Protein Expression by Immunofluorescence. Pretreatment biopsies revealed increased pAkt/Akt ratio in tumor specimens as compared with non malignant pancreatic tissue. No such trends were noted for pErk/Erk or pmTOR/mTOR. Immunofluorescence results depicted above.
Figure 1 Protein Expression by Immunofluorescence. Pretreatment biopsies revealed increased pAkt/Akt ratio in tumor specimens as compared with non malignant pancreatic tissue. No such trends were noted for pErk/Erk or pmTOR/mTOR. Immunofluorescence results depicted above.CC BY · PubMed Central
Figure 2 Mean fluorescence intensity (MFI) of the biomarkers by laser scanning cytometry (LSC). For each biomarker, the box represents the middle half of the distribution of the data points stretching from the 25th to the 75th percentile. The line across the box represents the median. The lengths of the lines above and below the box are defined by the maximum and minimum data point values, respectively.
Figure 2 Mean fluorescence intensity (MFI) of the biomarkers by laser scanning cytometry (LSC). For each biomarker, the box represents the middle half of the distribution of the data points stretching from the 25th to the 75th percentile. The line across the box represents the median. The lengths of the lines above and below the box are defined by the maximum and minimum data point values, respectively.CC BY · PubMed Central
Figure 3 Ratio of phosphorylated/total Akt and phosphorylated/total mTOR. For each set of values, the box represents the middle half of the distribution of the data points stretching from the 25th to the 75th percentile. The line across the box represents the median. The lengths of the lines above and below the box are defined by the maximum and minimum data point values, respectively.
Figure 3 Ratio of phosphorylated/total Akt and phosphorylated/total mTOR. For each set of values, the box represents the middle half of the distribution of the data points stretching from the 25th to the 75th percentile. The line across the box represents the median. The lengths of the lines above and below the box are defined by the maximum and minimum data point values, respectively.CC BY · PubMed Central

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Authors
Javle, M. M., Shroff, R. T., Xiong, H., Varadhachary, G. A., Fogelman, D., Reddy, S. A., Davis, D., Zhang, Y., Wolff, R. A., & Abbruzzese, J. L.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Center for Cancer and Blood Disorders (US)
Corresponding author
Javle, Milind M
ORCID
Venue
BMC Cancer
Publisher
Springer Science and Business Media LLC
Published
2010-07-14
Volume
10
Issue
1
Pages
368-368
ISSN
1471-2407 (ISSN-L)
DOI
10.1186/1471-2407-10-368
PMC
PMC2910694
OpenAlex
W2026890779
Cited by
170
References
21
Citations by year
2026: 3 · 2025: 2 · 2024: 5 · 2023: 7 · 2022: 19 · 2021: 13 · 2020: 12 · 2019: 9 · 2018: 11 · 2017: 10 · 2016: 5 · 2015: 28 · 2014: 12 · 2013: 11 · 2012: 11
FWCI
4.56
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
Keywords
mTOR inhibition, advanced pancreatic cancer, temsirolimus, everolimus, erlotinib, PI3K/Akt signaling, insulin receptor substrate, cyclin D1, drug toxicity, anticancer activity, combination therapy, overall survival, PTEN, rapamycin, EGFR tyrosine kinase
MeSH terms
Everolimus, Erlotinib Hydrochloride, Adenocarcinoma, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Female, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Immunosuppressive Agents, Male, Middle Aged, Neoplasm Staging, Pancreatic Neoplasms, Phosphorylation, Prognosis, Prospective Studies, Quinazolines, Biomarkers, Tumor, Signal Transduction, Survival Rate, Sirolimus, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases, ErbB Receptors

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