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Fishing for treatment biomarkers from genomic profiling Cancer Hub, Feb 2013 Lynch syndrome -­‐ HNPCC (Hereditary Nonpolyposis Colorectal Cancer) Lynch syndrome – a defecTve mismatch repair phenotype (dMMR) •  Autosomal dominant disease, to be disTnguished from sporadic dMMR -­‐ associated with BRAF(V600E) and CpG island methylator phenotype (CIMP) •  Frequencies in CRC: Lynch ~3%, sporadic ~15% •  Diagnosis through Microsatellite Instability and IHC for DNA mismatch repair proteins OMIM name Genes implicated in HNPCC Frequency of muta<ons in Locus HNPCC families HNPCC1 MSH2 60% 2p22 HNPCC2 MLH1 20-­‐30% 3p21 HNPCC5 MSH6 7-­‐10% 2p16 HNPCC4 PMS2 <5% 7p22 HNPCC3 PMS1 2q31-­‐q33 HNPCC6 TGFBR2 3p22 HNPCC7 MLH3 14q24.3 Pathway variaTon between pMMR and dMMR CRC: BRAF mutaTon & TGFβ/AcTvin LOF in dMMR Non-­‐Hypermutated (pMMR) Hypermutated (MSI-­‐H/dMMR) • 
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WNT signaling 92% TGF-­‐β signaling 27% RTK-­‐RAS signaling 59% PI3K signaling 50% P53 signaling 64% • 
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WNT signaling 97% TGF-­‐β signaling 87% RTK/RAS/BRAF signaling 80% PI3K signaling 53% P53 signaling 47% No targeted therapies for the main mutated pathways in CRC The Wnt/β-­‐catenin acTvaTon pathway Common MLH1 downregulaTon in sporadic dMMR CRC: hazard of the CpG island methylator phenotype (CIMP) OpTonal treatment: 5-­‐AzacyTdine treatment or HDAC inhibitor CKIα DownregulaTon correlates with growth arrest: A beneficial CIMP phenotype? CKIα
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Pribluda, Elyada et al. Cancer Cell, 2013 Polyp
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Pathway variaTon between pMMR and dMMR CRC: BRAF mutaTon & TGFβ/AcTvin LOF in dMMR GeneTc AlteraTons in the PI3K Pathway in CRC PI3K Pathway Inhibitors in Clinical Trials for Cancer Treatment (Oct 2011) •  Aher five years of daily aspirin, death due to gastrointesTnal cancers decreased by 54 percent. •  Aher 20 years, death due to prostate cancer decreased by 10 percent. •  Aher 20 years, death due to lung cancer decreased by 30 percent (among those with cancers typically seen in nonsmokers). •  Aher 20 years, death due to colorectal cancer decreased by 40 percent. •  Aher 20 years, death due to esophageal cancer decreased by 60 percent. The key take home message from this analysis is that taking 2 aspirins daily for at least 2 years results in a reducTon of around 63% in colorectal cancer in people with a hereditary predisposiTon, but this effect does not become apparent unTl about 5 years from the beginning of the intervenTon. ‫‪A Tny aspirin a day keeps cancer away ‬‬
‫אספירין קטן כל יום ולסרטן אין כלל‬
‫מקום‪ ‬‬
Liao et al, NEJM 367:17, 2012 Mutant PIK3CA as an aspirin-­‐response biomarker? Outstanding issues: 1.  17% acTvaTng PIK3CA mutaTons in CRC vs. 40-­‐45% in Ras 2.  PTEN deficiency unaccounted 3.  Cancer mortality rate reduced up to 59% vs. 17% mutant frequency How does aspirin work? Is COX-­‐2 the target of aspirin? In paTents with wild-­‐type PIK3CA tumors, aspirin use aher diagnosis, even among those with PTGS2-­‐posiTve tumors, did not appear to be significantly associated with survival. However, the effect of aspirin appeared to be stronger among paTents with both mutated-­‐PIK3CA and PTGS2-­‐posiTve tumors, although the number of events in paTents with mutated-­‐PIK3CA tumors was too small to perform a robust staTsTcal analysis. Liao et al, NEJM 367:17, 20 Acosta & Gil, 2009 The CKIα-­‐p53 double knockout mouse: a model for InvesTgaTng malignant conversion Villin
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p53 CKIα+/fl;p53fl/fl;Villin-­‐Cre-­‐ERT2 mice + Tamoxifen Stage IV CRC following CKIα LOH H&E
Elyada, Pribluda et al., Nature 2011 CKIα
Extensive DNA damage response and senescence in
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SA-­‐β-­‐gal 50µm 53BP1 TUNEL 20µm Het Het 50µm KO Elyada, Pribluda et al., Nature 2011 20µm KO NSAID pre-­‐treatment abolishes the senescence inflammatory response and carcinogenesis
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0.2 0 DKO Pribluda, Elyada et al. Cancer Cell, 2013 DKO Sul