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History of Patupilone: From Bench to Clinic

Explore the history, mechanism, and clinical potential of Patupilone, a potent anti-cancer drug targeting microtubules, with effective results against various human tumor cell lines and resistant tumors. Discover its in vitro and in vivo activities, selective cytotoxicity, and anti-metastatic and anti-vascular properties. Learn about its implications for cancer treatment.

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History of Patupilone: From Bench to Clinic

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  1. History of Patupilone:From Bench to Clinic Paul M.J. McSheehy, PhD Novartis Pharma AG Basel, Switzerland

  2. Epothilones A and B16-membered macrolide-lactones from myxobacteria R = H: Epothilone A R = CH3:Epothilone B(Patupilone) Sorangium cellulosum So ce90 • Identified by Reichenbach et al as anti-fungal agent, 1993 • Paclitaxel-like mechanism shown by Bollag et al, 1995 • More soluble and more lipophilic than taxanes

  3. Tubulin / microtubules:Effective targets for anticancer therapy • Tubulin: • heterodimerof55kDaα-andβ-tubulin • Microtubules: • hollow fibers with 22-24 nm diameter • 12-13 protofilaments / microtubule • Polymerization inhibitors • Colchicine • Vincristine, Vinblastine • Many others (+) end Microtubule Dynamics • 2 GTP: • hydrolysis required for tubulin addition • Polymerization enhancers • Taxol, Taxotere • Epothilones • Discodermolide • Eleutherobine, Sarcodyctin (-) end

  4. Tubulin: The binding site β-tubulin β-tubulin 274 α-tubulin • Paclitaxelbindingsite(β-tubulin)similar;overlappingbutnotidentical • Patupilonehasahigheraffinity(Bueyetal,2004)

  5. Consequences of interference with microtubule function • Disruption of cell cycle • reduced proliferation, • increased cell death (apoptosis / mitotic catastrophe) • Disruption of protein movement and therefore function • affects gene expression • affects enzyme function (e.g. HIF-1), • Disruption of cell movement and shape • affects metastasis, endothelial cell permeability

  6. Effect of in vitro incubation time on anti-proliferativeactivity of Patupilone vs. Paclitaxel In contrast to paclitaxel, short exposure times of patupilone suffice to produce potent anti-proliferative effects

  7. Comparison of activity on Paclitaxel-sensitivehuman tumour cell lines in vitro Patupilone shows increased potency in vitro (median of 14-fold) against a broad panel of human cancer cell lines

  8. Patupilone is selectively cytotoxic towardsproliferating cells YO-PRO-1 fluorescent dye: detects apoptosed (permeable) cells yielding an EC25 Proliferating human PBLs Resting human PBLs Drug concentration [nM] Drug concentration [nM] Similar observations made on human tumour cells: a) leukaemia: MTT assay, b) colon: 3H-Thd

  9. Comparison of activity on Paclitaxel-resistant human cell lines in vitro Patupilone retains activity in paclitaxel-resistant cell lines over-expressing either P-gp or harbouring ß-tubulin mutations

  10. Prolonged retention of Patupilone in rodentsincluding brain & tumours after a single iv dose 4 mg/kg in nude mouse 1.5 mg/kg in Lewis rat Time Post-Administration (h) Time Post-Administration (h) Patupilone crosses the BBB (P-gpRes) and shows high retention

  11. Tissue half-lives of Patupilone vs. Taxanes following single-dose administration to mice aEstimates based on Blum et al., Novartis Release Ready Report 1999, RD-1999-03642 bData from: Fujita et al., Jpn J Cancer Chemother 1994, 21: 659-664 cData from Bissery et al., Anticancer Drugs, 1995, 6: 339-355

  12. Patupilone access and activity is unalteredin large poorly vascularised tumours 2.5 mg/kg i.v. weekly Tumour volume (mm3) Days post treatment

  13. Comparison of activity on Taxol-sensitivehuman tumour xenografts in vivo Patupilone shows equivalent activity in Taxol-sensitive tumours at comparable tolerability

  14. Patupilone retains activity against Taxol-resistanthuman tumour xenografts in vivo Patupilone is active in Taxol - resistant tumours at tolerated doses

  15. Overview of in vivo activity of Patupilone:human tumour s.c. xenograft models in nude mice • Drug-sensitive tumour models: • Breast:MDA-MB468 (regr) • Prostate:PC-3M (regr), Du-145 (regr) • Lung:NCI-H596 (regr), NCI-H460 • Colon:HCT-116, HT-29 • Ovarian:SKOV-3, 1A9 • Glioma:U-373, U87MG • Cervical:HeLa, KB31 • Lung coloniesHT1080 • Drug-resistant tumour models: • Lung:A549 • Ovarian1A9PTX10 • Colon:HCT-15 • Cervical/Oral:KB-8511 (regr, cures) Patupilone activitycomparableto standard drugs Patupilone activitysuperior to Taxol

  16. Patupilone activity against a human lung tumour(H460-Luc) growing in mouse brain Days post cell injection(treatment on day 5) Days post cell injection (treatment on day 7) %T/C (Patupilone) = 25.1 (D14) %T/C (Patupilone) = 10.0 (D16) Significantly less body-weight loss and increased survival

  17. Anti-metastatic activity in orthotopic models Patupilone showed strong activity in these models – whether this involves prevention of formation is not yet clear: • Human H460 lung mets from mouse lung to brain • Murine B16/BL6 melanoma to mouse lymph-nodes • Rat BN472 mammary to rat lymph-nodes • Rat MTLn3 mammary to rat lymph-nodes • Human HT1080 fibrosarcoma colonising nude mouse lung • Human H460 lung cells injected into mouse brain

  18. Anti-vascular activity detectable after 2 daysbefore a change in rat breast tumour size DCE-MRI: blood volume maps Vehicle: Day 0 Day 2 Patupilone: Day 0 Day 2

  19. Drug transporters: Patupilone • Weak/no substrate for 7 different drug transporters: • P-gp • BCRP • MRP-1, -2, -3, -4, -5 • Patupilone did not influence activity of 6 different drug transporters (MRP-4 not tested) This implies • Reduced basal and acquired drug resistance(rationale for activity in colon, hepatoma, brain where Taxol little activity) • Good combination partner with other drugs

  20. Simultaneous administration of Patupilone withcarboplatin provides synergistic tumour cell kill in vitro Lung (A549) cell line Colon (HCT116) cell line Simultaneous Simultaneous Patupilone first Patupilone first Carboplatin first Carboplatin first

  21. Human H460-Luc cells injected in lung day 0 and treatment begins day-5: Patupilone (3 mg/kg q2W), RAD001 (10 mg/kg q1D) Untreated mice: brain tumors detectable day 10, culled day 17 Patupilone shows strong activity in an orthotopic human lung tumour model and synergises with RAD001

  22. Combination with ionising radiation (IR) in humanSW480 tumour xenografts Patupilone 2 mg/kg, day 0; IR (4 x 3 Gy) on days 1-4 • A positive interaction in vitro • Positive interaction in vivo(P=0.0004) • BW loss unchanged • Effect independent of scheduling Hofstetter et al, Clin Cancer Res,11:1558, 2005

  23. In vitro Scheduling important…Why? Positive interactions where Patupilone precedes cytotoxic: Carboplatin Oxaliplatin Gemcitabine Negative in simultaneous for: All of above 5FU Gemetecan (a camptothecin) Doxorubicin Many others Positive in simultaneous for: Vincristine, Cladribine, RAD001 In vivo Scheduling important for the cytotoxics Gemcitabine, Alimta Scheduling NOT important for IR, PTK787, STI571, RAD001 Positive interactions for Ionising Radiation PTK787 STI571 (imatinib) RAD001 Gemcitabine (Patupilonefirst) Alimta (Alimta first) Carboplatin Doxil Patupilone combinations:Conclusions to date (Aug-2006)

  24. Patupilone: Summary(a potent microtubule stabiliser) • MoresolublethanTaxanes • Bindsβ-tubulinwithaveryhighaffinity • Weaksubstrateforalldrug-transporters(P-gpetc) • Largevolumeofdistribution;retainedbytumours • CrossesBBB;retainedinbrain • PotentinhibitoroftumourcellproliferationinvitroandinvivoincludingthoseexpressingP-gpandsomewithβ-tubulinmutations • Caninhibittumourgrowthinbrain • Inhibitsmetastaticgrowth • Goodcombinationpotential–schedulingmaybeimportantwithothercytotoxics • Early-responsebiomarkers:MRI;FDG/FLT-PET;IFP

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