Novel Agents. Nelson Chao, MD Duke University

Transcription

1 Novel Agents Nelson Chao, MD Duke University

2 Development of Radiation Injury Initial Physical Interaction Physiochemical Chemical Damage Biomolecular Damage Early Biological Effects Late Biological Effects Excitation, Ionization Free Radical Formation Radical Attack DNA, Proteins, etc. Toxicity, Mutation Cancer, Genetic Effects

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6 Radiation Effects on DNA Chromosome Breaks are DNA Double-Strand Breaks >90% of Low LET-Induced Breaks are Rejoined Restitution; No Repair; Mis repair Misrepair Only broken ends (telomeres?) symmetric/asymmetric interchromosome/intrachromosome Time/dose dependent

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8 Necrosis All Cells Passive Event Mitosis Dependent Giant Cells, Micronuclei, Abortive Colonies, Inflammatory Response Apoptosis Some Cells Active Process Mitosis Independent DNA Degradation, Nuclear Condensation, Apoptotic Bodies, Cell Membrane Alterations, Phagocytosis 3-5 Divisions Minutes to Hours Lethal Event: Mutation Multiple Lethal Events Irreversible Reversible

9 Why Is It Difficult to Find Mitigators? Multiple Pathways Multiple Targets Multiple Modifiers of Response Repair Induced Cell Cycle Signal Transduction Mitotic Death/Apoptosis Cell Cycle Arrest

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11 Best Practice First do no harm Antibiotics/antivirals/antifungals Control of GI symptoms Mitigation of hematopoietic impact Mitigation of skin toxicity

12 Devising Treatment Strategies: Example of Intestinal Radiation Toxicity Pathophysiologic Process ROS-induced injury Enterocyte depletion Intervention ROS scavengers, antioxidants, cytoprotective agents Nutrients, GI peptides, epithelial growth factors Mucosal barrier breakdown Modulators of intraluminal factors Mucositis Secretory diarrhea Bacterial translocation Immunomodulators, cytokines, endothelial-oriented interventions Antidiarrheal interventions Antibiotics, probiotics Adverse tissue remodeling Antifibrotic strategies

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14 Radiation Countermeasure Mission Space ARS Hematopoietic ARS: Neutropenia Thrombocytopenia Anemia Lymphopenia GI ARS Lung Injury Kidney Injury Cutaneous Radiation Syndrome Combined Injury

15 Devising Treatment Strategies: Example of Hematopoietic Toxicity Pathophysiologic Process ROS-induced injury Committed precursor depletion Intervention ROS scavengers, antioxidants, cytoprotective agents Nutrients, Growth factors, anti-apoptotic agents Stem cell depletion/stromal Damage Modulators of cell death [MSCs, EPCs] Cytopenias Immunological compromise Bacteremia, Fungemia, Viremia Immunomodulators, cytokines, endothelial-oriented interventions Reconstitution of immunity Antibiotics, antifungals, antivirals Adverse tissue remodeling Antifibrotic strategies

16 Hematopoietic Syndrome Neutropenia Neupogen/Neulasta Leukine Human Growth Hormone Endothelial Cell Transplantation Myeloid Progenitor Cell Transplantation Thrombocytopenia AMG 531 Eltrombopag AKR 501 Peg-TPOmp TPIAO Licensed Licensed Licensed Preclinical Preclinical Phase III Clinical Trial Phase II Clinical Trial Phase II Clinical Trial Phase III Clinical Trial Licensed in China

17 Neupogen Kuderer, et al. JCO 2007

18 Neupogen

19 TPO Survival Benefit Placebo (n=54) Placebo (n=19) 0.3 ug TPO x 7d (2h; n=30) 0.3 ug TPO (2h; n=10) (8 Gy) Mouthon M-A, et al. Int J Rad Onc Biol Phys 1999;43:

20 TPO Receptor-activating Peptides AMG 531 (Amgen) TPO receptor-activating peptide Attached to IgG Fc Phase III clinical trials Peg-TPOmp (J&J) Pegylated TPO receptor-activating peptide Phase III clinical trials TPIAO (3SBio) Full-length recombinant human TPO Licensed for use in China

21 Oral TPO-receptor Agonists AKR 501 (AkaRx) Full agonist of TPO receptor Efficacy with single dose In phase II clinical trials Eltrombopag (GSK) Partial agonist of TPO receptor Requires repeated dosing for efficacy Positive phase III clinical trial in hepatitic C thrombocytopenia

22 Median Platelet Counts and Percentages of Patients Who Completed the 12-Week Antiviral Treatment Phase McHutchison J et al. N Engl J Med 2007;357:

23 Human Growth Hormone Probability of survival Saline control (n=28) Grow th hormone (n=28) P< Days post irradiation

24 Human Growth Hormone White cells (/ul blood) * Saline control Growth hormone * * * Days post irradiation Platelets (x10 3 /ul blood) Saline control Growth hormone * * * * * * * Days post irradiation

25 Novel Cell Therapy Approaches Myeloid Progenitor Cells Mesenchymal Stem Cells Endothelial Cells Preclinical Phase III Clinical Trial Preclinical

26 Mesenchymal Stem Cells (MSCs) Magic Stem Cells Home to injured tissue (whether radiation, trauma, or burn-induced, with engraftment shown in BM, intestines, kidney, lung, liver, thymus, skin) Have immunomodulatory properties, reducing inflammation Promote tissue regeneration Secrete hematopoietic cytokines, facilitating hematopoietic reconstitution Demonstrated efficacy in combined injury Accelerated healing of full-thickness round incisional wound + 20 Gy local irradiation Facilitate wound healing in general

27 MSCs Radiation Skin Injury Control Treated 30 Gy limb irradiation MSCs infused 24 hours post-irradiation Human MSC-injected NOD/scid mice Francois S, et al. Human mesenchymal stem cells favor healing of the cutaneous radiation syndrome in a xenogenic transplant model. Ann Hematol 2007;86:1-8.

28 MSCs Thermal Injury 32 days after 30% BSA third-degree burns 3 days after topical application of allo MSCs Skin Note grafting extensive performed capillary 33 neoangiogenesis days after injury with additional application of allo MSCs 24 hours after skin graft: pain relief 7-8 days after skin graft: blood chemistries begin to normalize 10 days after skin graft: 99% take observed 28 days after skin graft: patient discharged 50 days after skin graft: patient returns to work Rasulov MF, et al. First experience in the use of bone marrow mesenchymal stem cells for the treatment of a patient with deep skin burns. Bull Exp Biol Med 2005;139:

29 Endothelial Cell Transplantation IV Endothelial Cells IP Endothelial Cells 700 cgy Controls

30 Endothelial Cell Transplantation (n=11) (n=7) P= cgy

31 Gastrointestinal Syndrome Protectan (CLBL 502) R-spondin 1 SOM230 Preclinical Preclinical Preclinical

32 Octreotide 500 GMP Excretion (μg/g feces) Sham XRT + Vehicle XRT + Octreotide 4.2 Gy x 16: Time (days) +7

33 Cutaneous Radiation Syndrome Ulceration/Necrosis Curcumin Esculentoside A (EsA) Celecoxib Mesenchymal Stem Cells Fibrosis Pentoxifylline (+ Vitamin E) MnSOD Phase I/II Clinical Trial Preclinical Licensed Phase III Clinical Trial Licensed Phase I/II Clinical Trial

34 Curcumin Okunieff P, et al. Int J Radiat Oncol Biol Phys 2006;65:

35 Radiation-induced Lung Injury Pneumonitis KGF (palifermin) Pentoxifylline AEOL MnSOD Gene Therapy Fibrosis KGF (palifermin) Pirfenidone AEOL Imatinib Licensed Licensed Phase Ib Clinical Trial Preclinical Licensed Phase III Clinical Trial Phase Ib Clinical Trial Licensed

36 KGF (palifermin) n=6 rats per group 8 Gy/d x 5d KGF given on d5 Chen L, et al. Int J Radiat Oncol Biol Phys 2004;60:

37 AEOL n=16 rats per group 28 Gy to right lung AEOL given by continuous infusion from d1 to 10 weeks Rabbani ZN, et al. Long-term administration of a small molecular weight catalytic metalloporphyrin antioxidant, AEOL 10150, protects lungs from radiation-induced injury. Int J Radiat Oncol Biol Phys 2007;67:

38 One Organism Has Figured It Out Deinococcus Radiodurans Isolated from samples of canned meat thought to be sterilized by radiation as well as radioactive waste pools Ancient, 2 mill years old Non-pathogenic Survives 1.5 x 10e6 rads Grows in 6000 rads/hr conditions Rapid and proper correction of double stranded DNA breaks