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Fanconi Anemia: Diagnosis and Treatment Markus Grompp,E, MD Oregon Health & Science University What This Talk Will Cover

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Fanconi Anemia: Diagnosis and Treatment Markus Grompp,E, MD Oregon Health & Science University What This Talk Will Cover Fanconi Anemia: Diagnosis and Treatment Markus Grompp,e, MD Oregon Health & Science University What this talk will cover History (brief) Clinical presentation Cellular phenotype Gi/BihilfiGenetics/Biochemical function Pathogenesis Treatment Search for new therapies Fanconi anemia history NdftthSiNamed after the Swiss Pediatrician Guido Fanconi (18921892--19791979) Guido Fanconi attended the University of Zürich. Before graduating in 1918 he trained in Lausanne, Munich, Zürich, and Bern. His ma in fie ld o f in teres t was in paediatrics, and in 1929 he became director of the Children ’s Hosp ita l an d professor of paediatrics at the University of Zurich His name is attached to 17 conditions. Fanconi Anemia Two major initial presentations Birth defects Anemia Typical birth defects Diagnosis early in life, often before anemia Anemia Patients usually have no/minor birth defects Later presentation Percentage of birth defects Abnormality Percent in all FA patients Radial ray defect 49 Other skeletal 22 Renal and urinary tract 34 Male genital 20 Gastrointestinal 14 Heart defect 13 Hearing loss 11 CNS defo rmity 8 Image courtesy Dr Blanche Alter FA face Image courtesy Dr Blanche Alter Anemia Pancytopenia/progressive bone marrow failure Empty marrow on biopsy Initial presentation can be any blood lineage Age of onset: 2 --1212 years RlifRarely, if ever, present tis in newb orn peri idod Red blood cell anemia macrocytic Neutropenia Thrombocytopenia Fanconi Anemia: Cellular ppyphenotype Hypersensitivity to interstrand DNA crosscross--linkinglinking agents Chromosome breakage, radial formation, apoptosis Mitomyc in C, diepoxy bu tane, cy toxan, psoral en + UVA Abnormal "G2/M" phase of the cell cycle sppypgontaneously prolonged "G2/M" "G2/M" accumulation after crosslinker treatment ? Oxygen sensitivity ? Sensit ivi ty to i nhibi tory cytoki nes ( --IFN,IFN, TNF-TNF-) FA karyyypotype Chromosome breakage read--outout Tot al # of Cells with th e Following Breaks per ML# Ref L ab Clastogen Conc # % Total Cell # ng/ml 0 1 2 3 4 5 6 7 >8 Radials Radials # of Cells 8823 GM0236 1 None 0 40 8 1 1 0 0 0 0 0 0 0% 50 p.13 MMC 15 4 1 2 6 5 0 0 0 3 29 58% 50 DEB 150 7 1 0 5 2 1 1 0 3 30 60% 50 The Fifteen Fanconi Anemia Genes Gene FA pp,atients, Chromosome Protein pp,roduct, estimated, % location kD A 60% 16q24.3 163 B 2% Xp22.31 95 C 10% 9q22.3 63 D1/BRCA2 4% 13q12.3 380 D2 4% 3p25.3 155 E 10% 6p21-22 60 F rare 11p15 42 G 10% 9p13 68 I rare 15q26 150 J/BRIP1 rare 17q 23. 2 130 L rare 2p16.1 52 N\ M rare 14q21.2 250 N/PALB2 rare 16p12 130 O/RAD51C rare 17q25.1 42 P/SLX4 rare 16p13.3 200 The Fifteen Fanconi Anemia Genes Gene FA pp,atients, Chromosome Protein pp,roduct, estimated, % location kD A 60% 16q24.3 163 B 2% Xp22.31 95 C 10% 9q22.3 63 D1/BRCA2 4% 13q12.3 380 D2 4% 3p25.3 155 E 10% 6p21-22 60 F rare 11p15 42 G 10% 9p13 68 I rare 15q26 150 J/BRIP1 rare 17q 23. 2 130 L rare 2p16.1 52 N\ M rare 14q21.2 250 N/PALB2 rare 16p12 130 O/RAD51C rare 17q25.1 42 P/SLX4 rare 16p13.3 200 (monoubiquitinated) IF-anti-FANCD2 Blot FANCD2 Monoubiquitination is aCritical FANCD2 - FANCD2-S FANCD2 anti - FANCD2 Event in the FA pathway Event intheFA - L 123456 7 89 wt (mutant) (corrected) FA-A FA-A+FANCA FA-C FA-C+FANCC FA-G FA-G+FANCG FA-F FA-F+FANCF The Fifteen FA proteins regulate DNA crosslink repair during S phase E3 Ligase DNA Damage with crosslink P I I/D2 Dissociates in S phase FhtiFrom chromatin P D2 Ub DNA Repair Ub D2 USP1 Ub I UAF1 Ub D2 I/D2 Associates with chromatin Ub I BRCA2 J ? USP1/UAF1 activity is N O required for Fanconi MldMoldovan an dD’Add D’Andrea, Anemia pathway Ann Rev Genetics, 2009 The Fanconi Anemia DNA Repair Pathway E3 Ligase DNA Damage P I I/D2 Dissociates FhtiFrom chromatin P D2 Ub DNA Repair Ub D2 USP1 Ub I UAF1 Ub D2 I/D2 Associates with chromatin Ub I BRCA2 J ? USP1/UAF1 activity is N O required for Fanconi MldMoldovan an dD’Add D’Andrea, Anemia pathway Ann Rev Genetics, 2009 BRCA2 is a Fanconi Anemia Gene (D1) Breast Cancer Breast Cancer FA 7691 insAT + - + + - - 9900 insA - + + - + + Howlett, N. et al, Science 297: 606, 2002 This Fanconi Anemia (D1) patient has two mutant BRCA2 alleles 1 3418aa 1 2 3 4 5 6 7 8 LKRR Transcriptional KKRR activation domain Paternal Allele NLS s 1 3418aa 1 2 3 4 5 6 7 8 LKRR Transcriptional KKRR activation domain NLS s Maternal Allele Conclusion: The Breast Cancer Susceptibility Gene, BRCA2, is the Fanconi D1 Gene (> 15 D1 families identified to date) Paradox In BRCA2 kin dre ds: BRCA2 (+/ -) Heterozygous Adult Carriers Develop Breast, Ovarian, Pancreatic Cancer (()Not AML) BRCA2(-/-) Children have Fanconi Anemia and Deve lop AMLMdllblAML, Medulloblastoma, an dWild Wilms Tumor Fanconi anemia and somatic mosaicism Mosaicism Not all the cells in the patient have the same genetic makeup. In FA,,p ~ 20% of all patients are mosaic in their peripheral blood. In addition to mutant cells they also have a population of healthy cells Natural history of FA Birth defects Pancytopenia Leukemia Solid tumors B. P. Alter et al Cancer in Fanconi anemia. Blood 101 (5):2072 , 2003. Pathoppyhysiology DNA repair Bone marrow failure: damaged stem cells die Cancer: unrepaired mutations cause cancer Birth defects: damaged cell die Signaling defects Bone marrow fa ilure: cy to kine hypersens itivit y Cancer: Clonal evasion from cytokine hypersensitivity Birth defects: aberrant signaling during development NonNon--canonicalcanonical functions of FA proteins Treatment of Fanconi Anemia Androgens Rationale: males have higher hematocrits than females GG--CSFCSF Transfusions/supportive care RdblRed bloo d ce lls, p ltltlatelets Bone marrow transplantation Most slides are the courtesy of John Wagner, University of Minnesota HSCT for FA: Standard Guidelines HGB <8 g/dL Pancytopenia ANC <1000/uL PLT <40,000/uL Matched Androgens Sibling Cytokines HCT Rx failure/toxicity or MDS/AML Alternate Donor HCT Unrelated Donor BMT for FA 100% Survival 19871987--19951995 100% 90% 90% 80% 80% S 70% 70% u r 60% 60% v 50% 50% i v 40% 40% a 18% ± 9% l 30% 30% 20% 20% 10% 10% 0% 0% 0123 Years After Transplant NMDP 100%Survival 100% 90% Effect of Fl udarabine 90% 80% 80% S u 70% 70% r 60% 60% v 50% 50% i Fludarabine (n = 16) v 40% 40% a 30% 30% l 20% No Fludarabine (n = 68) 20% 10% 10% P=0.00 0% 7 0% 0123 YAfTYears After Transp lant November 2001 New treatments are badly needed Gene Therapy Cell transplantation Small molecule intervention TtTreatment Prevention CtiCancer prevention Prevention of bone marrow failure Is there a small molecule that can be beneficial to bbthhoth hema topoi esi s and cancer preventi ti?on? Cancer prevention Enhance apoptosis of cells with damaged genomes Concern: this could lead to loss of hematopoietic stem cells Anemia prevention Enhance survival and growth of HSC Concern: this could stimulate tumor growth BtBest sol ltiution Prevent DNA damage or enhance DNA repair Alan D’Andrea John Postlethwait Markus Grompe Grover Bagby Heterozygosity for Trp53 accelerates tumors in Fancd2 KO *p<.05 **p<.01 mammary AC ovarian AC 10 mo 13 mo mammary AC lung AC 15 mo 13 mo malignant fibrous osterosarcoma histiocytoma 10 mo 10 mo First small molecule to be tested in Fancd2 mutant mice Proppperties of tempol Superoxide dismutase (SOD) mimetic Hyyydroxyradical scaveng er Effective in animal models of ischemiaischemia--reperfusionreperfusion injury Myocardial infarction Renal ischemia Effective in reducing tumor incidence in animal models of cancer In vivo competitive repopulation assay: 3 mo. NAC Bone 1200 Rad treatment marrow KSL cells Fancc-/- (2K) -/- Bone Fancd2 marrow ROSA26Tg/+ KSL cells (2K) 6 months blood cells Genotyping PCR Conclusions The SOD mimetic tempol significantly delays tumors in an FA animal model. This effect is not specific for FA , but also has been seen in 3 other tumortumor--proneprone mouse models. Oxidative damage may be the main source of DNA damage in FA, bu t a lso o ther tumor mod el s i n mi ce. Tempol does not adversely affect the repopulating ability of FA mutant stem cells. Should we have a clinical trial with a) tempol, b) another SODSOD-- mimetic? Other compounds that have been tested Chloroquine N-Acetylcysteine From: Maclean KH, Dorsey FC, Cleveland JL, Kastan MB. J Clin Invest. 2008 Jan 2;118(1):79-88. ATM ATM chloroquine P P ATM P oxidative stress Mean tumor-free survival: Placebo: 11.5 mon Chloroquine: 12 mon P=0.64 Models for hematopoietic defects in Fanconi Anemia Is it really true that FA knockout mice are not a model for the anemia? Reduced numbers of stem cells Reduced colonyygy forming ability Changgyes in cell cycle status of stem cells Hematopoietic defects in Fancd2Fancd2--//-- mice Reduced numbers of KLS stem cells Reduced repopulation ability Reduced CFU-CFU-SS Re duce d co lony f ormi ng abili ty ( cobbl estone assay) Decreased pool of quiescent (G0) stem cells SRT3025 (“SirT Diet”) treatment increased the frequencies of KSL cells in both D2 mutant and wildtype mice P < 0.01 P < 0.01 SL % SL KK Placebo SRT3025 Placebo SRT3025 Fancd2-/- Fancd2-/- Fancd2+/+ Fancd2+/+ Conclusions Fancd2 mutant mice have several hematopoietic defects, which can be used to test drugs for their potential to ameliorate the defect The FA defects affects the stem cells themselves as well as the stroma The Sirt1 mimetic resveratrol ameliorates some ofhf these hematopo iet ic d dfefects Srt3025 significantly increases the number of stem cells in both wild--ttype and FA mutant mice Cancer Cells are often defective in one DNA Repair Pathway Normal cells Cancer cells Predicts PARPi sensitivity of ++++++ B − +++++ breast cancer BRCA1 mutation Six normal DNA The specific pathway lost repair pathways may determine the best course of chemotherapy and radiation (personalized medicine) Kennedy and D’Andrea, J.C.O.
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