Personalized Medicine Approaches in Oncology

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Shiladitya Sengupta, M.D., Assistant Professor of Medicine and Health Sciences and Technology, Harvard Medical School, Brigham & Women's Hospital: Personalized Medicine Approaches in Oncology.

Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

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Personalized Medicine Approaches in Oncology

  1. 1. Nanomedicine‐based  pp gyapproaches in OncologyDr. Shiladitya SenguptaHarvard  Medical SchoolBrigham and Women’s HospitalDana Farber Cancer InstituteHarvard‐MIT Division of Health Sciences and Technology
  2. 2. Someone diagnosed with cancer   Someone diagnosed with cancer 50 during this talk! every second .
  3. 3. 1971
  4. 4. How does How does cancer progress?
  5. 5. DNA binders that induce cell death NH2 Cl Pt Cl NH2 Cisplatin Doxorubicin Bleomycin
  6. 6. Tubulin inhibitors that prevent the cells from dividing Vincristine Taxol
  7. 7. EGFR C‐KIT C‐MET VEGFRMolecular medicine ‐ targeting oncogenic mutations
  8. 8. USD 7000 USD 7000per doseUSD 4500 pper doseUSD 4300 per doseper dose
  9. 9. earlier nowCost of Development       250M       1.5BTime to Market Time to Market 10 Yrs 10 Yrs 15 Yrs 15 YrsNCEs ~40 ~30Most Blockbuster Patents expire in next 2‐5 years Most Blockbuster Patents expire in next 2 5 years
  10. 10. Cancer is more than  3 stories 3 storiesjjust a dividing cell g
  11. 11. 2D or 3D, context matters 2D or 3D context mattersNon‐metastatic Metastatic Weaver and Bissell
  12. 12. Endothelial cells on 2D or 3DEndothelial cells on 2D or 3D
  13. 13. Endothelial cells  Endothelial  Endothelial  in MCF10A in MCF10A cells in MCF7 cells in MCF7 cells in MDA cells in MDA (normal epithelium) (non‐metastatic) (highly‐metastatic)
  14. 14. P*AKT(S473)Green = MDA‐MB‐231Red  P*AKT (S473)Red = P AKT (S473)Blue = DAPI
  15. 15. P*FAK Tyr925 Green = MDA‐MB‐231 Red  P*FAK (Tyr925) Red = P FAK (Tyr925)
  16. 16. OX Uronic Acid O COO‐ OX O O O OH NHY O OX Glucosamine2 O position of uronic acid 2’O position of uronic acid6’O and 3’O position of glucosamineN‐position of glucosamine can either be sulfated, N‐position of glucosamine can either be sulfatedacetylated, or unsubstituted
  17. 17. Post‐synthetic modification of HSGAGs  OH COOH OH COOH O O N‐deacetylase/ O O N sulfotransferase N‐sulfotransferaseOH OH OH OH O O O O NAc OH NSO4 ‐2 OH OH O O COOH OH O OH O O O NSO4‐2 OH OSO4‐2 O O2‐O Sulfotransferase COOH3 O Sulfotransferase3‐O Sulfotransferase OSO4‐2 OH6‐O Sulfotransferase O O NSO4‐2 OSO4‐2
  18. 18. Formation of endothelial cells de novo,  Vasculogenesis PI (Red) vWF (green) Day 3 Day 7 D 7 Day 10
  19. 19. Characterization of HSGAG disaccharides: Sulfation increases  with endothelial differentiation Absorbance units Tri‐sulfate
  20. 20. Knock‐down of NDST1 disrupts neovascularization zNDST1‐Mo  3.5 pmol
  21. 21. IGF2R GRN GRN MDM2 RNA Microarray Analysis TP53 Hsp90 HSPAB MDM2 RRM2 HSPA8 GADD45A IGF2 HSP00AB1 FOXO3A IGF2R IGF2 Hsp90 PPID RRM2B FOXO3A CCNG1 GPI TP73 HSP90AB1 Cav1/3 MDM2 peptidase D GADD45 C2 zgc:76878 SESN1 TP73L wu:fb59a01 HTRA2 zgc:110001 CAV1 TP53 selenoprotein W 2a W, CASP8 CLDN4 PPIA fibrinogen alpha chain BAX 6 somite stage C3 S100A8 wu:fd20g07 Dr_24890_1_S1_at Dr_19402_1_A1_at RP527 SFRP1 PRDX1 Dr_1689_2_A1_a_at zgc:55364 PARP2 FOS fatty acid binding pro MMP2 nuclear receptor subfa S100A9 FOS cytoglobin MIF tubulin, alpha 1 ITGAM CTH proteolipid protein 1a wu:fb55b11 24 hours-po p SFRP4 mesogenin 1 CASP8 PI3K1 FST PTPRN wu:fc19g03 wu:fd50h12 fertilization MBOAT5 Dr_22517_1_S1_at PSMA2 wu:fc49d01 PARP2 FGA PTPRN2 HSPA5 matrix metalloproteina 6‐somites 20‐somites FGG 28‐somites (24 hpf) Dr_19794_1_A1_at membrane protein, palm NR2F1 growth arrest and DNA- CLU A2Minsulin-like growth faangioblasts migrate to midline migrate to midline MMP13 tubes assemble tubes assemble LPA onset of angiogenesis onset of angiogenesis Dr_26003_1_A1_at PSMB4 pleckstrin homology li homology-li CASP8 wu:fc92e10 wu:fi04f09 Dr_15033_1_S1_at MMP2 FOS caspase 8 PARP2 20 somite stage cyclin G1 Dr_7787_1_S1_at poly (ADP-ribose) poly GTP binding protein 1, FST SFRP1 BAX Symbol Legend murine double minute 2 forkhead box O5 zgc:92153 wu:fb96a10 tumor protein p53 TP73L wu:fc84a08 wild‐type FOXO3A NDST1 Mo MDM2 wild‐type Enzyme NDST1 MoNuclear  Receptor zgc:55750 Kinase zgc:56722 wild‐type wu:fj10e08 Acts on TP73 v-fos FBJ murine osteo wu:fj64h06 GADD45A heat shock protein 90- Cytokine shock cognate 70- heat Binds Transcription  Other IGF2R CCNG1 Factor IGF2 Indirect  Transmembrane Phosphorase Peptidase Receptor Interaction -3.00 -2.30 -1.70 -1.00 -0.33 0.33 1.00 1.70 2.30 3.00 24 hpf stage
  22. 22. Cross talk between microenvironment and endothelial  p precursors Foxo3A shRNA * control NDST1 IGF2 IGF1 Foxo3A NDST1 IGFR1 Actin * control shNDST1 picropodophyllin 4 TIE2 LY294002 PI3K              FOXO3 PI3K FOXO3a 3 * AKT Foxo3A Rn 2 rapamycin mTOR 1 * VEGF 0 control l A shFoxo3A Vasculogenesis ro N HIF1 nt R co sh 3A xo Fo
  23. 23. Story 2. The story of Story 2 The story ofJohn CossmanJ h C
  24. 24. Control (30 h) Combretastatin (30 h) Doxorubicin (30 h)
  25. 25. (A) HO O CH3 O CH3 O OH Combretastatin (102 g) O O O n O PLGA 5050 DL 4A (C) Doxorubicin (g) * 1. pNC, pyridine, CH2Cl2 8 * leased * 2. Doxorubicin, DMF, TEA 6 * Total Drug Rel O OH O OH 4 * # OH # # # # O O OH O 2 #H3C O O O CH3 O CH3 H3C NH O O O O OH 0 OH 0 30 60 90 120 125 225 325 Doxorubicin - PLGA conjugate O n O 200 Time (hours) emulsion-solvent nm 200 evaporation Diameter (nm) (B) Ultracentrifugation, sizing and phospholipid membrane 150 coating. Combretastatin encapsulated in lipid layer. 100 D H3CO 50 H3CO na le ll ce c rti no OH pa OCH3 no na OCH3
  26. 26. Normal blood vessels Tumor blood vessels
  27. 27. (A) TUNEL/HIF1a vWF Vehicle L[C] Vehicle L[C] Ve ehicle NC[D] L[CD] L[CD] NC[D] L[ [C] NC[D]+L[C] NC NC[D]+L[C] NC NC (ld) NC C[D]Lewis lung carcinoma B16/F10 melanoma NC[ 5500 Lewis lung carcinoma 10000 B16/F10 melanoma [D]+L[C] 5000 7500 4500 50003 3 olume mm olume mm 4000 2500 3500 2000 3000 Tumor Vo Tumor Vo NC 2500 1500 2000 1500 1000 1000 500 500 L[CD] 0 0 9 11 13 15 17 9 11 13 15 17 Days Days Veh L[C] NC[D] L[CD] NC[D]+L[C] NC NC( ld)
  28. 28. Coming back to JohnComing back to John
  29. 29. Some results from Phase 1, currently Phase 2
  30. 30. Story 3. The future: design of y gnanomedicine based on SAR
  31. 31. Understanding SAR to design a nanomedicine Cl OH Cl Cl aquation q DNA  binding Cisplatin Carboplatin Oxaliplatin
  32. 32. Understanding SAR to design a nanomedicine DMF, H2O Dry DMF,   DBU umber % 30 pH<7 20 Nu 10 0 1             10          100         1000      10000 pH>7 OH Size (d.nm) n n OH OH HO H O O O N O HO O HN O O OH Pt OH Pt H 3N NH3 OH O H 3N NH3 ‐1611.54 ‐2210 ‐ ‐500 ‐1500 ‐2500 ppm
  33. 33. Lung Cancer g PIMA‐GA‐ PIMA‐GA‐ Ovarian Cancer Cisplatin (3mg/kg) CisPt CisPt Cisplatin (1.25 mg/kg) (3mg/kg) (1.25 mg/kg) Vehicle  PIMA GA CisPt PIMA‐GA‐CisPt [1.25mg/kg] PIMA‐GA‐CisPt [1.25mg/kg] PIMA‐GA‐CisPt [3 mg/kg] PIMA‐GA‐CisPt [3 mg/kg] (C) CisPt [1.25 mg/kg] CisPt [1.25 mg/kg] CisPt [3mg/kg] CisPt [3mg/kg] Vehicle Vehicle PIMA-GA-CisPt PIMA-GA-CisPt Vehicle Control CisPt Ci Pt [3 mg/kg] /k ] 225 [1.25 mg/kg] [3 mg/kg] 200 175Kidney 150 mg 125 *** 100 75 50 25Tumor 0 ) ) 5) ) e kg kg (3 cl .2 is hi g/ g/ (1 C ve 5m m is A- (3 C .2 G A- is (1 A- C G M is A- PI C M PI
  34. 34. Translating it to the clinics (a) (b) (a) Cisplatin Cisplatin‐NP Control (3mg/kg) (3mg/kg) tment (a) ( ) LLC 4T1 CP20 Pretreat (b) (c) ent Post treatme (b) ‐1621.5 (f) 10 100 1000
  35. 35. (c) Cisplatin (1 mg/kg) Cisplatin (3 mg/kg) Cisplatin (1 mg/kg) Cisplatin (3 mg/kg) Cisplatin NP (1 mg/kg) Cisplatin NP  (3 mg/kg) Cisplatin NP (1 mg/kg) Cisplatin NP  (3 mg/kg)
  36. 36. MetastasisWhat drives cancer?  SO4
  37. 37. Abhimanyu Paraskar Funding SupportDoD Postdoctoral ScholarCisplatin‐nanoparticle l l NIH DoD Coulter FoundationSudipta basu American Heart AssociationCharles A King Postdoctoral ScholarCharles A King Postdoctoral Scholar Mary Kay Ash Foundation y yNano‐biotechnology CIHR Charles A King TrustRania Harfouche f hCIHR Postdoctoral ScholarVasculogenesisYamicia ConnorNIH‐ MD,PhD ScholarTumor MicroenvironmentStephanie PiecewiczHarvard‐MIT PhDHarvard MIT PhDVasculogenesis
  38. 38. Shape affects outcome

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