HER2 Support Group Forums - View Single Post - Everolimus Plus Herceptin Promising in Metastatic Breast Cancer

Lani · 11-11-2010, 10:32 AM

Last Thanksgiving I posted the following:
11-26-2009, 12:13 PM #1
Lani
Senior Member

Join Date: Mar 2006
Posts: 3,315
a VERY HOPEFUL research result for the HOLIDAY!!!
mTor inhibitors are already in use in clinical trials of several types of cancer and one is FDA approved for use in renal cancer (everolimus, approved just this past March) (http://her2support.org/vbulletin/sho...highlight=mTor){actually several are approved for indications including kidney transplant rejection, kidney cancer, etc} One is already in use in tiny amounts in stents to keep blood vessels open after prying them open with balloon catheters

Clin Cancer Res. 2009 Nov 24. [Epub ahead of print]
Inhibition of Mammalian Target of Rapamycin Is Required for Optimal Antitumor Effect of HER2 Inhibitors against HER2-Overexpressing Cancer Cells.
Miller TW, Forbes JT, Shah C, Wyatt SK, Manning HC, Olivares MG, Sanchez V, Dugger TC, de Matos Granja N, Narasanna A, Cook RS, Kennedy JP, Lindsley CW, Arteaga CL.

Authors' Affiliations: Departments of Medicine, Radiology and Radiological Sciences, Biomedical Engineering, Neurosurgery, Pathology, Cancer Biology, and Chemistry, Program in Chemical and Physical Biology, Vanderbilt University Institute of Imaging Science, and Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, Tennessee.
PURPOSE: A significant fraction of HER2-overexpressing breast cancers exhibit resistance to the HER2 antibody trastuzumab. Hyperactivity of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway confers trastuzumab resistance, and mammalian target of rapamycin (mTOR) is a major downstream effector of PI3K/AKT. Therefore, we examined whether mTOR inhibitors synergize with trastuzumab. EXPERIMENTAL DESIGN: Immunocompetent mice bearing HER2(+) mammary tumors were treated with trastuzumab, the mTOR inhibitor rapamycin, or the combination. Mice were imaged for tumor cell death using an optical Annexin-V probe and with [(18)F]FDG positron emission tomography. The signaling and growth effects of the mTOR inhibitor RAD001 on HER2(+) cells treated with trastuzumab or lapatinib were evaluated. RESULTS: Treatment of mice with trastuzumab plus rapamycin was more effective than single-agent treatments, inducing complete regression of 26 of 26 tumors. The combination induced tumor cell death (Annexin-V binding) and inhibited FDG uptake. Rapamycin inhibited mTOR and tumor cell proliferation as determined by phosphorylated S6 and Ki-67 immunohistochemistry, respectively. In culture, the combination of RAD001 plus trastuzumab inhibited cell growth more effectively than either drug alone. Trastuzumab partially decreased PI3K but not mTOR activity. Knockdown of TSC2 resulted in HER2-independent activation of mTOR and dampened the response to trastuzumab and lapatinib. Treatment with the HER2 inhibitor lapatinib decreased phosphorylated S6 and growth in TSC2-expressing cells but not in TSC2-knockdown cells. CONCLUSIONS: Inhibition of PI3K and mTOR are required for the growth-inhibitory effect of HER2 antagonists. These findings collectively support the combined use of trastuzumab and mTOR inhibitors for the treatment of HER2(+) breast cancer. (Clin Cancer Res 2009;15(23):7266-76).

PMID: 19934303 [PubMed - as supplied by publisher]

11-11-2010, 10:32 AM	#4
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	Re: Everolimus Plus Herceptin Promising in Metastatic Breast Cancer Last Thanksgiving I posted the following: 11-26-2009, 12:13 PM #1 Lani Senior Member Join Date: Mar 2006 Posts: 3,315 a VERY HOPEFUL research result for the HOLIDAY!!! mTor inhibitors are already in use in clinical trials of several types of cancer and one is FDA approved for use in renal cancer (everolimus, approved just this past March) (http://her2support.org/vbulletin/sho...highlight=mTor){actually several are approved for indications including kidney transplant rejection, kidney cancer, etc} One is already in use in tiny amounts in stents to keep blood vessels open after prying them open with balloon catheters Clin Cancer Res. 2009 Nov 24. [Epub ahead of print] Inhibition of Mammalian Target of Rapamycin Is Required for Optimal Antitumor Effect of HER2 Inhibitors against HER2-Overexpressing Cancer Cells. Miller TW, Forbes JT, Shah C, Wyatt SK, Manning HC, Olivares MG, Sanchez V, Dugger TC, de Matos Granja N, Narasanna A, Cook RS, Kennedy JP, Lindsley CW, Arteaga CL. Authors' Affiliations: Departments of Medicine, Radiology and Radiological Sciences, Biomedical Engineering, Neurosurgery, Pathology, Cancer Biology, and Chemistry, Program in Chemical and Physical Biology, Vanderbilt University Institute of Imaging Science, and Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, Tennessee. PURPOSE: A significant fraction of HER2-overexpressing breast cancers exhibit resistance to the HER2 antibody trastuzumab. Hyperactivity of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway confers trastuzumab resistance, and mammalian target of rapamycin (mTOR) is a major downstream effector of PI3K/AKT. Therefore, we examined whether mTOR inhibitors synergize with trastuzumab. EXPERIMENTAL DESIGN: Immunocompetent mice bearing HER2(+) mammary tumors were treated with trastuzumab, the mTOR inhibitor rapamycin, or the combination. Mice were imaged for tumor cell death using an optical Annexin-V probe and with [(18)F]FDG positron emission tomography. The signaling and growth effects of the mTOR inhibitor RAD001 on HER2(+) cells treated with trastuzumab or lapatinib were evaluated. RESULTS: Treatment of mice with trastuzumab plus rapamycin was more effective than single-agent treatments, inducing complete regression of 26 of 26 tumors. The combination induced tumor cell death (Annexin-V binding) and inhibited FDG uptake. Rapamycin inhibited mTOR and tumor cell proliferation as determined by phosphorylated S6 and Ki-67 immunohistochemistry, respectively. In culture, the combination of RAD001 plus trastuzumab inhibited cell growth more effectively than either drug alone. Trastuzumab partially decreased PI3K but not mTOR activity. Knockdown of TSC2 resulted in HER2-independent activation of mTOR and dampened the response to trastuzumab and lapatinib. Treatment with the HER2 inhibitor lapatinib decreased phosphorylated S6 and growth in TSC2-expressing cells but not in TSC2-knockdown cells. CONCLUSIONS: Inhibition of PI3K and mTOR are required for the growth-inhibitory effect of HER2 antagonists. These findings collectively support the combined use of trastuzumab and mTOR inhibitors for the treatment of HER2(+) breast cancer. (Clin Cancer Res 2009;15(23):7266-76). PMID: 19934303 [PubMed - as supplied by publisher]