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

Publication ,  Journal Article
Javle, MM; Shroff, RT; Xiong, H; Varadhachary, GA; Fogelman, D; Reddy, SA; Davis, D; Zhang, Y; Wolff, RA; Abbruzzese, JL
Published in: BMC Cancer
July 14, 2010

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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Published In

BMC Cancer

DOI

EISSN

1471-2407

Publication Date

July 14, 2010

Volume

10

Start / End Page

368

Location

England

Related Subject Headings

  • TOR Serine-Threonine Kinases
  • Survival Rate
  • Sirolimus
  • Signal Transduction
  • Quinazolines
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase Inhibitors
  • Prospective Studies
  • Prognosis
  • Phosphorylation
 

Citation

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Javle, M. M., Shroff, R. T., Xiong, H., Varadhachary, G. A., Fogelman, D., Reddy, S. A., … Abbruzzese, J. L. (2010). Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer, 10, 368. https://doi.org/10.1186/1471-2407-10-368
Javle, Milind M., Rachna T. Shroff, Henry Xiong, Gauri A. Varadhachary, David Fogelman, Shrikanth A. Reddy, Darren Davis, Yujian Zhang, Robert A. Wolff, and James L. Abbruzzese. “Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies.BMC Cancer 10 (July 14, 2010): 368. https://doi.org/10.1186/1471-2407-10-368.
Javle MM, Shroff RT, Xiong H, Varadhachary GA, Fogelman D, Reddy SA, et al. Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer. 2010 Jul 14;10:368.
Javle, Milind M., et al. “Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies.BMC Cancer, vol. 10, July 2010, p. 368. Pubmed, doi:10.1186/1471-2407-10-368.
Javle MM, Shroff RT, Xiong H, Varadhachary GA, Fogelman D, Reddy SA, Davis D, Zhang Y, Wolff RA, Abbruzzese JL. Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer. 2010 Jul 14;10:368.
Journal cover image

Published In

BMC Cancer

DOI

EISSN

1471-2407

Publication Date

July 14, 2010

Volume

10

Start / End Page

368

Location

England

Related Subject Headings

  • TOR Serine-Threonine Kinases
  • Survival Rate
  • Sirolimus
  • Signal Transduction
  • Quinazolines
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase Inhibitors
  • Prospective Studies
  • Prognosis
  • Phosphorylation