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AML) Patient’S Response to First Line Therapy? • What Are the Epigenetic Mechanism Regulating OCTN1 Expression?

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AML) Patient’S Response to First Line Therapy? • What Are the Epigenetic Mechanism Regulating OCTN1 Expression? Epigenetic Regulation of OCTN1-mediated Cytarabine Transport in Acute Myeloid Leukemia Jason T. Anderson, PharmD, PhD Advisors: Dr. Sharyn D. Baker and Dr. Alex Sparreboom International Workshop on Clinical Pharmacology of Anticancer Drugs (ICPAD) Friday, November 22, 2019 Outline Research questions: • What role does OCTN1 (SLC22A4) play in Acute Myeloid Leukemia (AML) patient’s response to first line therapy? • What are the epigenetic mechanism regulating OCTN1 expression? Introduction • OCTN1’s role in the cellular disposition of cytarabine Data • Differences of DNA methylation in AML cell lines • Modifying DNA methylation using hypomethylating agents • Impact of OCTN1 (SLC22A4) methylation in AML patients Conclusions 2 Cytarabine (Ara-C) is utilized in AML and is transported via an OCTN1-mediated pathway 1st Line Therapy: “7 + 3” Ara-C (days 1-7) + daunorubicin (days 1-3) • Goal: achieve complete remission (CR) • 2/3 patients respond to 7+3 therapy Consolidation: high or low-dose cytarabine, stem cell transplant • Targets residual leukemic cells Do drug transporters contribute to patient response? OCTN1 (SLC22A4) • Able to transport Ara-C and similar nucleoside analogs • Higher expression of OCTN1 leads to increased survival in both adult and pediatric AML patients Drenberg CD et al., Cancer Res. (2017) 3 One hallmark of AML is genetic and epigenetic dysregulation • Epigenetic disturbances have been involved in the pathogenesis of leukemia • Higher genome methylation leads to worse patient outcomes in both adult and pediatric AML patients 1. What role does this DNA methylation play with OCTN1 expression? 2. Can we modulate this DNA methylation using hypomethylating agents? “Epigenetic Priming” • Using methyltransferase inhibitors before starting first line Hypomethylating Agents therapy • FDA Approved Hypomethylating Agents in AML OFF ON – 5-azacytidine and decitabine Epigenetic Priming Clinical Trials 1. Phase I (2013): 5-Aza x 5 days then cytarabine or Decreased OCTN1 Increased OCTN1 fludarabine treatment (NCT01861002) expression expression 2. Phase II (2017): 5-Aza/decitabine x 5 days then first line SLC22A4 therapy (NCT03164057) (OCTN1) Plass C et al., Seminars in Oncology, (2008). Bullinger L et al., Blood, (2010). 4 Ochs MF et al., Transactions on Computational Biology and Bioinformatics, (2014). “Epigenetic Priming” Without Decitabine Treatment Decitabine Treated Increased OCTN1 Increased mRNA + Decitabine Decreased Expression Increased Expression 5 CpG Islands in close proximity to OCTN1 (SLC22A4) A B Unpublished, manuscript in preparation High Uptake: OCI-AML3 Low Uptake: CHRF 6 Exploring SLC22A4 DNA methylation status and downstream transcription • Constructed CpG-free luciferase (Firefly) plasmid with OCTN1 CpG122 • In vitro methylation • Transfection with methylated and unmethylated constructs • Co-transfected with pTK (constitutively expressed Cypridina luciferase) for normalization A B M e th yla te d Luciferase E m p ty U n m e th yla te d Empty -pCpGfree * (P < 0.001) Luciferase CMV Promoter Luciferase CMV C M V -pCpGfree CMV Promoter Luciferase OCTN1 Promoter Luciferase O C T N 1 1kb OCTN1 * -pCpGfree OCTN1 Promoter Luciferase 0 % 5 0 % 1 0 0 % 1 5 0 % N o rm a liz e d L u c ife ra s e E x p r e s s io n (M e th y la te d /U n m e th y la te d x 1 0 0 ) 7 Unpublished, manuscript in preparation Pretreatment with decitabine is able to decrease DNA methylation within the SLC22A4 promoter region • Decreased SLC22A4 methylation in CHRF after decitabine treatment • Little to no change SLC22A4 methylation in OCI-AML3 (low basal methylation, high Ara-C uptake) Epigenetic Priming 8 Unpublished, manuscript in preparation Impact of 3-day pretreatment with epigenetic modifier, decitabine mRNA [3H]Ara-C Uptake 1 2 0 1 2 0 3 .3 F o ld ) 6 .2 F o ld l ) l o o r t r t n 1 0 0 1 0 0 n o o c c f f o o 8 0 8 0 % % ( ( y y t 72 hr 6 0 t 6 0 i i l l i i b b a a i MTT i 4 0 4 0 V V l l l l e e 2 0 C C 2 0 0 0 0 .0 0 1 0 .0 1 0 .1 1 1 0 1 0 0 0 .0 0 1 0 .0 1 0 .1 1 1 0 1 0 0 A ra -C ( M ) A ra -C ( M ) O C I-A M L 3 O C I-A M L 3 C H R F C H R F (5 0 0 n M D e c ita b in e T re a te d ) (5 0 0 n M D e c ita b in e T re a te d ) High Methylation Cell Line: CHRF Low Methylation Cell Line: OCI-AML3 9 Unpublished, manuscript in preparation Methylation status in SLC22A4 correlates with OCTN1 expression and patient outcomes • Methylation values of 18 probe-sets in SLC22A4 were significantly correlated with the expression values of OCTN1 (R2 = 0.53; p = 0.00020) • Methylation status (P=0.016) and increased OCTN1 expression (P=0.045) was associated with reduced rate of relapse after adjusting for risk group Peds: AML02 HR = 1.52 HR = 1.47 -09 p-value = 0.024 p-value = 8.5e Low High Survival Survival Probability Survival time (years) 10 Unpublished, manuscript in preparation Conclusions Epigenetics of OCTN1 (SLC22A4) • Methylation within the SLC22A4 promoter region has the ability to suppress downstream transcription • Increased SLC22A4 methylation correlates with worse survival in adult and pediatric AML patients • 3-day treatment with hypomethylating agent, decitabine: ➢ Increased mRNA expression of OCTN1 ➢ Increased Ara-C uptake ➢ Increased sensitivity to Ara-C Drug-drug interactions do not always have negative consequences 11 Acknowledgments Experimental Cancer Pharmacology Laboratory St. Jude’s Research Hospital Daelynn Buelow, PhD Stanely Pounds, PhD Mingqing “Sophie” Chen Lei Shi, PhD Eric Eisenmann, PharmD Qiang Fu, PhD University of Florida Jae Yoon “Louis” Jeon, PharmD Jatinder Lamba, PhD, M.Sc Dominique Garrison Alice Gibson Advisors: Emily Goodwin Sharyn Baker, PharmD, PhD Christina Guttke, PhD Alex Sparreboom, PhD Shuiying Hu, PhD Kevin Huang Committee: Alix Leblanc, PhD Sharyn Baker, PharmD, PhD Yang Li, PhD Cynthia Carnes, PharmD, PhD Marissa Pioso Christopher Coss, PhD Erfan Uddin Alex Sparreboom, PhD Megan Zavorka Thomas, PhD Moray Campbell, PhD Supported by: National Cancer Institute OSUCCC Shared Resources.
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