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Rich66 · 06-14-2009, 10:22 PM

Interview with Dr. Wicha:
http://jco.ascopubs.org/cgi/content/full/26/17/2795
"It is also likely that treatment of patients with CSC-targeted therapeutics will require new clinical end points for monitoring therapeutic efficacy. This is the case because one is targeting only a small fraction of cells within the tumor, not the bulk of the tumor. In addition, responses may take a much longer time than is typically seen with agents that are cytotoxic to the rapidly dividing cells that constitute the bulk of the tumor. Rational approaches might also include using cytotoxic chemotherapies to target the proliferating bulk of the tumor in addition to a CSC-directed therapy directed at eliminating this critical cell population. An important end point will likely involve assessing changes in the size of the CSC population in response to treatment. One way to do this might be by monitoring the burden of CSCs in the circulation. Of course patient survival remains the ultimate clinical end point, which will involve appropriate clinical trials."

From St. Gallen 2009

http://ex2.excerptamedica.com/ciw-09...tRowDetail=218

Combined ER and HER-targeted therapy in breast cancer treatment

Citation: THE BREAST, Volume 18, Supplement 1, March 2009, Page S8

K. Osborne1, R. Schiff1

1Breast Center, Baylor College of Medicine, Houston, USA

The estrogen receptor (ER) and HER signaling networks are complex, redundant, evolvable and robust pathways, each with several regulatory controls. Several levels of crosstalk between these two networks act as modulatory circuits that when altered can contribute to resistance to therapies targeting them. Nuclear ER when bound by estrogen increases the expression of ligands binding to HER receptors while at the same time reducing the expression of the receptors themselves. At the same time, the HER signaling pathway reduces expression of ER and progesterone receptor (PR) while it can activate ER functionally through phosphorylation of the receptor and its coactivators. Therefore, blockade of ER signaling by endocrine therapy can increase the cellular content of HER1 and HER2, while blockade of HER signaling can increase the expression of ER and PR. Non-nuclear ER can also activate the HER signaling pathway by several mechanisms at the level of the cell membrane. Although there are several potential mechanisms for resistance to ER and HER-targeted therapy, preclinical data from our group and others, as well as supporting data from recent clinical trials, indicate that upregulation at the HER signaling pathway can cause resistance to ER-targeted therapy and that upregulation of ER signaling can cause resistance to HER-targeted therapy.
These data suggest that optimal treatment in some patients using therapies targeting these two pathways might necessitate simultaneous blockade of both pathways. In preclinical models and, now, data from clinical trials, simultaneous use of endocrine therapy to target ER and therapy targeting the HER receptor network can overcome resistance to endocrine therapy and delay the time to tumor progression. Using a combination of HER inhibitors to completely block the HER pathway together with ER blockade is very potent therapy in preclinical xenograft models of ER+/HER2+ tumors and is able to eradicate tumors even after short term therapy. In ER+ tumors that express initially low levels of HER receptors, the addition of HER receptor blockade to endocrine therapy anticipating upregulation of HER receptors during endocrine therapy delays the emergence of resistance and prolongs time to progression. Combined HER-targeted therapy in this situation does not eradicate these xenograft tumors indicating that other survival pathways still function and that these tumors have not yet become “oncogene addicted” to the HER pathway. There is an urgent need to biopsy patients immediately before embarking on targeted therapy to profile the tumor and to select the optimal patient for this new approach.

C. Kent Osborne
Director, Breast Center at Baylor College of Medicine
Director, Baylor Cancer Center
Professor of Medicine and Cellular and Structural Biology
Phone: 713-798-1641
Fax: 713-798-1642
Email: kosborne@breastcenter.tmc.edu
Funding
Publications
Research

More discussion here:
http://her2support.org/vbulletin/showthread.php?t=38998

06-14-2009, 10:22 PM	#9
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Interview with Dr. Wicha: http://jco.ascopubs.org/cgi/content/full/26/17/2795 "It is also likely that treatment of patients with CSC-targeted therapeutics will require new clinical end points for monitoring therapeutic efficacy. This is the case because one is targeting only a small fraction of cells within the tumor, not the bulk of the tumor. In addition, responses may take a much longer time than is typically seen with agents that are cytotoxic to the rapidly dividing cells that constitute the bulk of the tumor. Rational approaches might also include using cytotoxic chemotherapies to target the proliferating bulk of the tumor in addition to a CSC-directed therapy directed at eliminating this critical cell population. An important end point will likely involve assessing changes in the size of the CSC population in response to treatment. One way to do this might be by monitoring the burden of CSCs in the circulation. Of course patient survival remains the ultimate clinical end point, which will involve appropriate clinical trials." From St. Gallen 2009 http://ex2.excerptamedica.com/ciw-09...tRowDetail=218 Combined ER and HER-targeted therapy in breast cancer treatment Citation: THE BREAST, Volume 18, Supplement 1, March 2009, Page S8 K. Osborne1, R. Schiff1 1Breast Center, Baylor College of Medicine, Houston, USA The estrogen receptor (ER) and HER signaling networks are complex, redundant, evolvable and robust pathways, each with several regulatory controls. Several levels of crosstalk between these two networks act as modulatory circuits that when altered can contribute to resistance to therapies targeting them. Nuclear ER when bound by estrogen increases the expression of ligands binding to HER receptors while at the same time reducing the expression of the receptors themselves. At the same time, the HER signaling pathway reduces expression of ER and progesterone receptor (PR) while it can activate ER functionally through phosphorylation of the receptor and its coactivators. Therefore, blockade of ER signaling by endocrine therapy can increase the cellular content of HER1 and HER2, while blockade of HER signaling can increase the expression of ER and PR. Non-nuclear ER can also activate the HER signaling pathway by several mechanisms at the level of the cell membrane. Although there are several potential mechanisms for resistance to ER and HER-targeted therapy, preclinical data from our group and others, as well as supporting data from recent clinical trials, indicate that upregulation at the HER signaling pathway can cause resistance to ER-targeted therapy and that upregulation of ER signaling can cause resistance to HER-targeted therapy. These data suggest that optimal treatment in some patients using therapies targeting these two pathways might necessitate simultaneous blockade of both pathways. In preclinical models and, now, data from clinical trials, simultaneous use of endocrine therapy to target ER and therapy targeting the HER receptor network can overcome resistance to endocrine therapy and delay the time to tumor progression. Using a combination of HER inhibitors to completely block the HER pathway together with ER blockade is very potent therapy in preclinical xenograft models of ER+/HER2+ tumors and is able to eradicate tumors even after short term therapy. In ER+ tumors that express initially low levels of HER receptors, the addition of HER receptor blockade to endocrine therapy anticipating upregulation of HER receptors during endocrine therapy delays the emergence of resistance and prolongs time to progression. Combined HER-targeted therapy in this situation does not eradicate these xenograft tumors indicating that other survival pathways still function and that these tumors have not yet become “oncogene addicted” to the HER pathway. There is an urgent need to biopsy patients immediately before embarking on targeted therapy to profile the tumor and to select the optimal patient for this new approach. C. Kent Osborne Director, Breast Center at Baylor College of Medicine Director, Baylor Cancer Center Professor of Medicine and Cellular and Structural Biology Phone: 713-798-1641 Fax: 713-798-1642 Email: kosborne@breastcenter.tmc.edu Funding Publications Research More discussion here: http://her2support.org/vbulletin/showthread.php?t=38998