HER2 Support Group Forums - View Single Post - Any info on HKI-272?

mymom's BC · 03-16-2007, 12:25 PM

HKI-272 was suggested as a possible next step when/If my mom's cancer became resisant to Herceptin when we visited Dana Farber 2 weeks ago. I researchedit when we got back.

Here is some info from a paper:

Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase.

Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A.

Department of Oncology, Wyeth Research, Pearl River, New York, USA. Rabinds@wyeth.com

HER-2 belongs to the ErbB family of receptor tyrosine kinases, which has been implicated in a variety of cancers. Overexpression of HER-2 is seen in 25-30% of breast cancer patients and predicts a poor outcome in patients with primary disease. Trastuzumab (Herceptin), a monoclonal antibody to HER-2, is specifically approved for HER-2-positive breast cancer but is active only in a subset of these tumors. Blocking HER-2 function by a small molecule kinase inhibitor, therefore, represents an attractive alternate strategy to inhibit the growth of HER-2-positive tumors. HKI-272 is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G(1)-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation. In vivo, HKI-272 is active in HER-2- and EGFR-dependent tumor xenograft models when dosed orally on a once daily schedule. On the basis of its favorable preclinical pharmacological profile, HKI-272 has been selected as a candidate for additional development as an antitumor agent in breast and other HER-2-dependent cancers.

************************

There is a climical trial at Dana Farber at this link as well:

http://www.dana-farber.org/res/clinical/trials/adult/default.html?n-state=http://www.emergingmed.com/pub_search_trial_detail.asp?i_trial_sys_id%3d22032 %26i_site_sys_id%3d0~~~G!0A1237295D04!LYOMwg4%252b 3NNzpuUVR3A%3d~emed-trials~~~@http://syndicator.www.emergingmed.com/dfci/my-emergingmed-trials-7

Hope this helps.

03-16-2007, 12:25 PM	#3
mymom's BC Member Join Date: Mar 2007 Posts: 5	Hki-272 HKI-272 was suggested as a possible next step when/If my mom's cancer became resisant to Herceptin when we visited Dana Farber 2 weeks ago. I researchedit when we got back. Here is some info from a paper: Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A. Department of Oncology, Wyeth Research, Pearl River, New York, USA. Rabinds@wyeth.com HER-2 belongs to the ErbB family of receptor tyrosine kinases, which has been implicated in a variety of cancers. Overexpression of HER-2 is seen in 25-30% of breast cancer patients and predicts a poor outcome in patients with primary disease. Trastuzumab (Herceptin), a monoclonal antibody to HER-2, is specifically approved for HER-2-positive breast cancer but is active only in a subset of these tumors. Blocking HER-2 function by a small molecule kinase inhibitor, therefore, represents an attractive alternate strategy to inhibit the growth of HER-2-positive tumors. HKI-272 is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G(1)-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation. In vivo, HKI-272 is active in HER-2- and EGFR-dependent tumor xenograft models when dosed orally on a once daily schedule. On the basis of its favorable preclinical pharmacological profile, HKI-272 has been selected as a candidate for additional development as an antitumor agent in breast and other HER-2-dependent cancers. ************************ There is a climical trial at Dana Farber at this link as well: http://www.dana-farber.org/res/clinical/trials/adult/default.html?n-state=http://www.emergingmed.com/pub_search_trial_detail.asp?i_trial_sys_id%3d22032 %26i_site_sys_id%3d0~~~G!0A1237295D04!LYOMwg4%252b 3NNzpuUVR3A%3d~emed-trials~~~@http://syndicator.www.emergingmed.com/dfci/my-emergingmed-trials-7 Hope this helps.