Early Drug Development: Making it Happen Gabriel Lopez-Berestein, M.D., Professor of Gabriel Lopez-Berestein, M.D., Professor of Medicine and Cancer Biology, Department of Medicine and Cancer Biology, Department of Experimental Therapeutics, M D Anderson Cancer Experimental Therapeutics, M D Anderson Cancer Center Center Professor, Department of NanoMedicine and Professor, Department of NanoMedicine and Bioengineering, UTHealth Bioengineering, UTHealth Fundacion Areces Symposium Madrid October 15, 2014
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Dr. Gabriel López-Berestein- Simposio Internacional 'Terapias oncológicas avanzadas'
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
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Early Drug Development: Making it HappenEarly Drug Development: Making it Happen
Gabriel Lopez-Berestein, M.D., Professor of Medicine and Cancer Gabriel Lopez-Berestein, M.D., Professor of Medicine and Cancer Biology, Department of Experimental Therapeutics, M D Anderson Biology, Department of Experimental Therapeutics, M D Anderson Cancer CenterCancer Center
Professor, Department of NanoMedicine and Bioengineering, Professor, Department of NanoMedicine and Bioengineering, UTHealthUTHealth
Gabriel Lopez-Berestein, M.D., Professor of Medicine and Cancer Gabriel Lopez-Berestein, M.D., Professor of Medicine and Cancer Biology, Department of Experimental Therapeutics, M D Anderson Biology, Department of Experimental Therapeutics, M D Anderson Cancer CenterCancer Center
Professor, Department of NanoMedicine and Bioengineering, Professor, Department of NanoMedicine and Bioengineering, UTHealthUTHealth
Fundacion Areces Symposium
Madrid October 15, 2014
The New Drug Development Process:The New Drug Development Process:Steps from Test Tube to New Drug Application ReviewSteps from Test Tube to New Drug Application Review
http: www.fda.gov.cder.handbook.develop.htm
Nucleus
siRNA
dsRNA
Liposomal siRNAViral vectors
Translation
miRNA
mRNA cleavage
Dicer RISC
Translational inhibition
miRNP
**
Chemically-modified siRNA
RNA InterferenceRNA Interference
OBJECTIVEOBJECTIVE OBJECTIVEOBJECTIVE
Develop a systemic nanoliposomal
delivery system for siRNA
HYPOTHESISHYPOTHESISHYPOTHESISHYPOTHESIS
Tumoral in vivo siRNA delivery can be improved by using neutral liposomal delivery
Downregulation of an ovarian cancer relevant target protein with siRNA reduces tumor growth in an orthotopic mouse model of ovarian cancer
Tumoral in vivo siRNA delivery can be improved by using neutral liposomal delivery
Downregulation of an ovarian cancer relevant target protein with siRNA reduces tumor growth in an orthotopic mouse model of ovarian cancer
IN VIVO IN VIVO SIRNA DELIVERYSIRNA DELIVERYIN VIVO IN VIVO SIRNA DELIVERYSIRNA DELIVERY
Successful siRNA delivery in vivo requires methods that are clinically limitedIntratumoral
Intrathecal
Intraocular
Viral vectors
Nanoliposomes as an alternative
Successful siRNA delivery in vivo requires methods that are clinically limitedIntratumoral
Intrathecal
Intraocular
Viral vectors
Nanoliposomes as an alternative
Phospholipid structurePhospholipid structure
Effect of temperature on the Effect of temperature on the packing of the phospholipidspacking of the phospholipids
Unsaturated and Saturated Unsaturated and Saturated PhospholipidsPhospholipids
1,2-Dioleyl-sn-Glycero-3-Phosphocholine (DOPC)
Lamellar vs Hexagonal PhaseLamellar vs Hexagonal Phase
•In Life: Hematology, clinical chemistry, urinalysis, coagulation, bone marrow evaluation revealed no test-article effects
•Anatomic Pathology: Necropsy – no test article effects; Histopathology: mild immunologic effects observed in both controls and test animals – ascribed as unrelated to test article
•In Life: Hematology, clinical chemistry, urinalysis, coagulation, bone marrow evaluation revealed no test-article effects
•Anatomic Pathology: Necropsy – no test article effects; Histopathology: mild immunologic effects observed in both controls and test animals – ascribed as unrelated to test article
Effects on immune parameters
Dicer and Drosha – Validation StudiesDicer and Drosha – Validation StudiesDicer and Drosha – Validation StudiesDicer and Drosha – Validation Studies
Ovarian cancer
New Engl J Med, 2008
Functional Impact of Low DicerFunctional Impact of Low Dicer
New Engl J Med, 2008
Clinical Trial DesignClinical Trial Design IND 072924Clinical Trial DesignClinical Trial Design IND 072924
Clinical ProtocolClinical ProtocolIND IND 072924
Clinical ProtocolClinical ProtocolIND IND 072924
Title: Therapeutic EphA2 Gene Targeting using Neutral Liposomal Small Interfering RNA Delivery: A Phase I Clinical Trial
Investigators:
PI: Robert L. Coleman, M.D.
Radiology: Vikas Kundra, M.D., Ph.D.
.
Title: Therapeutic EphA2 Gene Targeting using Neutral Liposomal Small Interfering RNA Delivery: A Phase I Clinical Trial
Investigators:
PI: Robert L. Coleman, M.D.
Radiology: Vikas Kundra, M.D., Ph.D.
.
SiRNA EphA2: Phase I StudySiRNA EphA2: Phase I StudySiRNA EphA2: Phase I StudySiRNA EphA2: Phase I Study
Primary Objectives: To determine the safety and tolerability of IV
siRNA-DOPC-EphA2 in patients with advanced solid tumors
To determine the maximum tolerated dose or optimal biological dose
To determine the target efficacy in escalating doses
Primary Objectives: To determine the safety and tolerability of IV
siRNA-DOPC-EphA2 in patients with advanced solid tumors
To determine the maximum tolerated dose or optimal biological dose
To determine the target efficacy in escalating doses
Bridge Study OCT 2014 Bridge Study OCT 2014
Secondary Objectives:
To determine the pharmacokinetic profile of IV siRNA-DOPC-EphA2 (twice weekly)
To evaluate the impact of therapy on by non-invasive imaging (DCE-MRI, DW-MRI FDG-PET)
To evaluate the impact of therapy on surrogate biomarkers (CF-DNA, CTCs, VEGFplasma)
SiRNA EphA2: Phase I StudySiRNA EphA2: Phase I StudySiRNA EphA2: Phase I StudySiRNA EphA2: Phase I Study
Eligibility: Solid tumors - recurrent or
considered incurable with standard therapy
Bi-dimensionally measurable disease (>2 cm)
Amenable to biopsy EphA2 overexpression
(IHC)
Eligibility: Solid tumors - recurrent or
considered incurable with standard therapy
Bi-dimensionally measurable disease (>2 cm)
Amenable to biopsy EphA2 overexpression
(IHC)
DoseDose MulMult.t.
FrequencyFrequency
450 µg/m450 µg/m22 -- 2/weekly2/weekly
900 µg/m900 µg/m22 100100%%
2/weekly2/weekly
1800 µg/m1800 µg/m22 100100%%
2/weekly2/weekly
3600 µg/m3600 µg/m22 100100%%
2/weekly2/weekly
7200 µg/m7200 µg/m22 100100%%
2/weekly2/weekly
SIRNA EPHA2 Murine Bridge StudySIRNA EPHA2 Murine Bridge Study