"Synthetic Lethality" Emerges as a Prospect in Cancer Treatment
What's Hot in January/February 2011
BY David W. Sharp
When an earlier packet of new Hot Papers reached me from Science Watch headquarters back in August of 2010, I scribbled the following note on the article then at #12: "Wait; difficult to explain." That publication has now jumped to #6, and this rise in citations plus the recent appearance of more clinical evidence means that an attempted explanation can no longer be postponed.
DNA is susceptible to single-strand and then double-strand breaks, and cells, including cancerous ones, normally have the means to repair such damage. Poly (adenosine diphosphate-ribose) polymerases, or PARPs, are key to the repair of single-strand breaks, and if PARP1 is inhibited these breaks accumulate, risking the emergence of double-strand breaks in DNA. The latter in turn can be mended by a pathway involving the tumor-suppression proteins BRCA1 and BRCA2. In patients carrying loss-of-function mutations in BRCA genes (including 5-10% of women with breast or ovarian cancer) inhibiting PARP1 could be clinically effective.
"DNA is susceptible to single-strand and then double-strand breaks, and cells, including cancerous ones, normally have the means to repair such damage."
In vitro support for this "synthetic lethality" (defined in #6 as "a potent and lethal synergy between two otherwise nonlethal events") has emerged since 2005. Now, from Dr. Peter C. Fong and colleagues’ paper in the New England Journal of Medicine (#6) and from two publicationslast July (A. Tutt, et al., Lancet,376[9737]: 235-44, 2010 and M.W. Audeh, et al., Lancet,376[9737]: 245-51, 2010), we have the first clinical evidence.
The PARP inhibitor for which most clinical experience is available is olaparib but at least six such agents are under scrutiny, including iniparib and veliparib (T.D. Penning, Curr. Opin. Drug Discov. Devel.,13[5]: 577-86, 2010).
Fong and colleagues’ was a phase 1 study, looking as much at dose, safety, and pharmacologic indices as at clinical outcome, in 60 patients with various types of cancer attending centers in London and Amsterdam. Anti-tumor activity was observed only in BCRA mutation carriers. In a later paper reporting another phase 1 study, this group found complete or partial responses in 40% of 50 patients with BRCA mutated ovarian cancer (P.C. Fong, et al., J. Clin. Oncol., 28[15]: 2512-9, 2010). The two Lancet papers on olaparib (see above) are described as phase 2 "proof of concept trials." Response rates depended on dose, being 41% and 22%, respectively, in patients with advanced breast cancer who were on 400 mg or 100 mg twice daily (Tutt et al.). In ovarian cancer these rates were 33% and 13% (Audeh et al.).
"Kidney function is routinely explored by the glomerular filtration rate (GFR) but this is not easy to measure directly."
Noting that response rates in this early experience with olaparib might appear lower than those expected from other studies of successful molecule-targeted anti-cancer treatment, Dr. Stephen L. Chan and Dr. Tony Mok (Chinese University of Hong Kong) feel that this "reflects our incomplete understanding of the complexity of DNA repair mechanisms" (Lancet, 376[9737]: 211-3, 2010). Just how incomplete is illustrated by these commentators’ further point—namely, that "the benefits of a PARP inhibitor... might not be restricted only to patients with germline BRCA mutation," and some evidence for this is emerging.
Kidney function is routinely explored by the glomerular filtration rate (GFR) but this is not easy to measure directly. In clinical practice GFR is estimated from formulae based on the serum creatinine concentration. The current front-runner is the Modification of Diet in Renal Disease (MDRD) equation but perhaps this should change. Paper #15 (A.S. Levey, et al., Ann. Intern. Med, 150[9]: 605-12, 2009; total cites 129, latest count 38) reports a possible improvement, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) method. Creatinine remains the main measurement, but the method also takes into account the patient’s broad ethnic group, sex, age, and whether the serum creatinine is above or below a certain figure.
This new approach is said to be more accurate though not perfect, of course. GFR estimates are roughly 8% higher with the CKD-EPI approach. An important consequence of this is a lowering of the estimated prevalence of chronic renal disease in the general adult population by around 12% (about 3 million people in the United States).
A former deputy editor of The Lancet, David W. Sharp, M.A. (Cambridge), is a freelance writer living in Minchinhampton, Gloucestershire, U.K.
What's Hot in Medicine | |||
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Rank | Paper |
Cites This Period Jul-Aug 10 |
Rank Last Period May-Jun 10 |
1 | Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team (F.S. Dawood, et al.), "Emergence of a novel swine-origin influenza A ( H1N1) virus in humans," New Engl. J. Med., 360(25): 2605-15, 18 June 2009. [Writing group: Ctrs. for Disease Control & Prevent., Atlanta, GA] *458WR | 60 | 1 |
2 | F.H. Schröder, et al., "Screening and prostate-cancer mortality in a randomized European study," New Engl. J. Med., 360(13): 1320-8, 26 March 2009. [15 institutions worldwide] *423VP | 53 | 3 |
3 | T.S. Mok, et al., "Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma," New Engl. J. Med., 361(10): 947-57, 3 September 2009. [14 institutions worldwide] *490EI | 51 | 9 |
4 | E. Van Cutsem, et al., "Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer," New Engl. J. Med., 360(14): 1408-17, 2 April 2009. [15 institutions worldwide] *427AL | 49 | † |
5 | C.S. Karapetis, et al., "K-ras mutations and benefit from cetuximab in advanced colorectal cancer," New Engl. J. Med., 359(17): 1757-65, 23 October 2008. [13 institutions worldwide] *363DJ | 45 | 7 |
6 | P.C. Fong, et al., "Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers," New Engl. J. Med., 361(2): 123-34, 9 July 2009. [7 U.K.. and European institutions] *467OS | 43 | † |
7 | Cancer Genome Atlas Research Network (L. Chin, et al.), "Comprehensive genomic characterization defines human glioblastoma genes and core pathways," Nature, 455(7216): 1061-8, 23 October 2008. [60 institutions worldwide] *363FG | 42 | 8 |
8 | J.L. Mega, et al., "Cytochrome P-450 polymorphisms and response to clopidogrel," New Engl. J. Med., 360(4): 354-62, 22 January 2009. [Brigham & Women’s Hosp. and Harvard Med. Sch., Boston, MA; Eli Lilly Res. Lab., Indianapolis, IN; Daiichi Sankyo Pharma Dev., Edison, NJ] *395JH | 42 | † |
9 | R.R. Holman, et al., "10-year follow-up of intensive glucose control in type 2 diabetes," New Engl. J. Med., 359(15): 1577-89, 9 October 2008. [6 U.K. institutions] *358FS | 41 | 4 |
10 | S.J. Connolly, et al., "Dabigatran versus warfarin in patients with atrial fibrillation," New Engl. J. Med., 361(2): 1139-51, 17 September 2009. [12 institutions worldwide] *494QA | 41 | † |
SOURCE: Thomson Reuters Hot Papers Database. Read the Legend. |