Early Studies of New Drug for Chronic Myeloid Leukemia Encouraging

Early Studies of New Drug for Chronic Myeloid Leukemia Encouraging

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Sep-Oct 01	Rank Last Period Jul-Aug 01
1	M.A. Cobleigh, et al., "Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpression metastatic breast cancer that has progressed after chemotherapy for metastatic disease," J. Clin. Oncol., 17(9):2639-48, September 1999. [8 U.S. and French institutions] *232QG	28	†
2	B. Pitt, et al., "The effect of spironolactone on morbidity and mortality in patients with severe heart failure," New Engl. J. Med., 341(10):709-17, 2 September 1999. [6 institutions worldwide] *231DB	25	†
3	S. Singhal, et al., "Antitumor activity of thalidomide in refractory multiple myeloma," New Engl. J. Med., 341(21):1565-71, 18 November 1999. [U. Arkansas Med. Sch., Little Rock; U. South Carolina, Columbia; Rockefeller U., New York, NY] *256GF	22	†
4	B. Thurner, et al., "Vaccination with Mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma," J. Exp. Med., 190(11):1669-78, 6 December 1999. [U. Erlangen-Nuremberg, Germany; U. Wurzburg, Germany; U. Mainz, Germany; Rockefeller U., New York, NY] *263QY	22	†
5	A. Kugler, et al., "Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids," Nature Medicine, 6(3):332-6, March 2000. [U. Gottingen, Germany; U. Tubingen, Germany; Humboldt U., Berlin, Germany] *288TL	22	†
6	S. Yusuf, et al., "Effects of angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients," New Eng. J. Med., 342(3):145-53, 20 January 2000. [Hamilton Gen. Hosp., Ont., Canada] *275ZT	21	2
7	A.M.J. Shapiro, et al., "Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen," New Engl. J. Med., 343(4):230-8, 27 July 2000. [U. Alberta, Edmonton, Canada] 337QC	21	†
8	B.J. Druker, et al. "Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia," New Engl. J. Med., 344(14):5 April 2001. [Oregon Hlth. Sci. U., Portland; U. Texas M.D. Anderson Canc. Ctr., Houston; Nova Pharmaceut. Corp., E. Hanover, NJ; U. Calif., Los Angeles] *417XH	21	†
9	A.E. Buxton, et al., "A randomized study of the prevention of sudden death in patients with coronary artery disease," New Engl. J. Med., 341(25):1882-90, 16 December 1999. [7 U.S. institutions] *264XZ	20	†
10	P.M. Ridker, et al., "C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women," New Engl. J. Med., 342(12):836-43, 23 March 2000. [Brigham & Women's Hosp., Boston, MA; Harvard U. Sch. Med., Boston; Children's Hosp., Boston] *296FU	19	3
SOURCE: ISI’s Hot Papers Database. the Legend.

t a molecular level, we now know a lot about chronic myeloid leukemia (CML). Almost all patients with CML, and one-fifth of those with acute lymphoblastic leukemia, have a characteristic switch of parts of two chromosomes, generating two unnatural fusion genes called ABL-BCR and BCR-ABL, which lie on chromosomes 9 and 22, respectively. The abnormal 22 is known as the Philadelphia chromosome. BCR-ABL codes for a deregulated form of a tyrosine kinase, and tyrosine kinases involved in cell signalling have long been a focus of interest in the study of malignant disease.

Prof. John M. Goldman and Dr. Junia V. Melo, in an editorial on two papers from lead author Dr. Brian J. Druker and colleagues (one paper currently at #8 and the other, with 19 citations this period, just below the list at #12), say that we now have "final proof" that the oncoprotein that BCR-ABL encodes for is the unique cause of chronic-phase CML. The papers and editorial are in the April 5, 2001, issue of the New England Journal of Medicine. So, what have Druker, who's based at Oregon Health Sciences University, Portland, and his collaborators done?

About 10 years ago the pharmaceutical company Ciba-Geigy (now Novartis) took up Druker’s proposal that pharmacological inhibition of BCR-ABL tyrosine kinase might be useful. Signal transduction inhibitor 571, now called imatinib (Glivec), was the result, and these papers record the first clinical experience with this drug in CML patients who had not responded to interferon-alfa (#8), which is currently the lead therapy apart from bone-marrow transplantation, and also in patients in CML blast-cell crisis (#12). The second paper extends clinical experience to Philadelphia chromosome-positive acute lymphoblastic leukemia, and elsewhere imatinib is also being tried in brain, lung, and prostate cancers. At the time of writing, the most recent published clinical experience was from a European collaborative group treating patients with gastrointestinal stromal tumors (see Lancet, 358:1421-3, 2001). Here too the aberrant molecular signal activates a tyrosine kinase that promotes tumor growth or prevents programmed cell death. Here the target is a tyrosine kinase known as KIT; imatinib also inhibits platelet-derived growth-factor receptors.

For a paper published in April to reach the Top Ten by September/October of the same year is very unusual, in my years of writing for Science Watch. Imatinib may prove to be a breakthrough for patients with this type of leukemia, but even if the early optimism is not confirmed this research will have vindicated the strategy of developing attacks on targets derived from molecular medicine. Druker tells Science Watch: "This strategy has been the driving force behind cancer research for decades, and we have been waiting for a success story like imatinib. We can now display this as a paradigm for future therapies but recognize that there is still much work to be done."

Mr. David W. Sharp, M.A. (Cambridge), was deputy editor of The Lancet,
London, U.K., from 1976 to May, 2001; he is currently a contributing editor to that journal.

Science Watch^®, January/February 2002, Vol. 13, No. 1
Citing URL: http://www.sciencewatch.com/jan-feb2002/sw_jan-feb2002_page7.htm