How to Make the Choice? Translational Approach for Cancer Treatment 闻丹忆 Danyi.wen@lidebiotech.com 181 9229 52 Nov 23, 214 1
Tumor volume (mm 3 ) Tumor growth (Efficacy study in LIX4-FP1+2) 15 Vehiclel, qd 14, p.o. 1 5 sorafenib,15 mg/kg, qd 14, p.o. sorafenib,3 mg/kg, qd 14, p.o. 5 1 15 Days post administration (Day) Market Pain PDX: Patient Derived Xenograft Pre-Clinic Xenograft Lack of efficient drug screening model PDX ATCC Cell Lines Correlation with clinic: Tumor Nude mice very poor Nude mice Correlation with clinic: 89-9% Reported by Multi-national big pharmaceutical companies Clinic Difficulty on drug selection Standard treatment (1 st line, 2 line of Chemo or targeted therapy) Surgery PDX Genetic analysis Biomarker Drug sensitivity Individualized Treatment Plan 2
Outline Pre-Clinical Application of PDX ---Four Stages of Translational Medicine in Oncology Clinical Application of PDX Case Study Shanghai LIDE: One Stop Shop Solution for Personalized Medicine of Oncology Patients 3
Oncology Translational Medicine Stage I Human Primary Tumor Model Platform (Patient Derived Xenograft, PDX) Stage II Molecular Characterization of PDX (Consortium Effort) Stage III Reverse Correlation (Clinical endpoint vs in vivo efficacy on PDX) Stage IV Biomarker Identification and Validation 4
Stage I: PDX Model Platform Cancer type Success Pancreatic Cancer 152 Gastric Cancer 143 HCC 64 Cholangiocarcinoma 25 NSCLC 18 SCLC 1 Rectal Cancer 21 Colon Cancer 25 Duodenal Cancer 2 Esophagus Cancer 11 Glioblastoma 2 Breast Cancer 8 Ovarian Cancer 11 Endometrial Cancer 2 Cervical Cancer 1 Total 486 5
Tumor volume (mm 3 ) Tumor volume (mm 3 ) Tumor volume (mm 3 ) Tumor volume (mm 3 ) PDX Efficacy Correlate Well with Clinic PD Tumor growth (Efficacy study of Gemcitabine in PAPF6-FP1+3 model) 1 Vehicle PR Tumor growth (Efficacy study of Gemcitabine in PAPF63-FP1+3 model) 8 Vehicle 8 Gemcitabine 6mg/kg IP Q4D*7 6 Gemcitabine 6mg/kg IP Q4D*7 6 4 4 2 2 SD 1 2 3 Days post administration Tumor growth (Efficacy study of Gemcitabine in PAPF65-FP1+3 model) CR 1 2 3 Days post administration Tumor growth (Efficacy study of Gemcitabine in PAPF4-P3 model) 15 Vehicle 1 Gemcitabine 6mg/kg IP Q4D*7 15 Vehicle 1 Gemcitabine 6mg/kg IP Q4D*7 5 5 2 4 6 8 1 12 14 16 18 2 22 24 26 28 3 Days post administration 1 2 3 Days post administration 6
% Inhibition Rate In vitro Chemosensitivity Assay (TCA) + compound Sorafenib 1 8 6 4 2-2.1 1 1 Log CPD concentration (μm) 7
PDX Matching Cell Line Establishment Cancer Type Model ID Banked passage In culture status STR* LIPF39 P7+11 Matched LIPF143 P19+9 HCC LIPF159 P3+1 Matched LIPF181 P7+8 Matched LIPF28 P3+7 LIPF295 P4+5 LIPF6 P2+9 Matched LIPF155 P7+9 Matched Cholangio cancer LIPF157 P3+5 LIPF178 P4+6 Matched LIPF296 P3 LIPF161 P5 PAPF38 P3+8 Matched PAPF75 P8+8 PAPF94 P2 PAPF98 P3 Pancreatic cancer PAPF99 P8 PAPF179 P3+6 Matched PAPF21 P4+11 Matched PAPF27 P2 PAPF268 P1+7 Lung cancer LUPF23 p3+13 P16+2 Matched LUPF38 P9 P9+3 Esophageal ESPF26 P2+12 Gastric cancer GAPF161 P4 Glioblastoma GLPF2 P1+4 8
Tumor volume (mm 3 ) Identification of Established Cell Lines Immunohistochemistry Chromosome Analysis STR Analysis IgG1 AFP Cytokeratin AFP, hepatocyte biomarker Cytokeratin, epithelial cell biomarker Cell Cycle Efficacy H&E Staining 25 Vehicle control 2 Sorafenib 3mg/kg po qd 15 1 5 5 1 15 2 25 Days post administration 9
Stage II: PDX Characterization Goal Through consortium effort to systemically characterize established and to be established PDX models in the world Consortium Effort Whole Exon Sequencing RNAseq SNP 1
Tumor volume (mm 3 ) % Inhibition Rate Stage III:Reverse Correlation Studies Surgery PDX Gemcitabine Chemo Follow up 1 8 6 4 2-2.1 1 Log CPD concentraton (μm) Tumor growth (Efficacy study of 5-FU and cisplatin in GAPF3-FP1+3 xenograft model) 6 Vehicle 5-FU 25 mg/kg IP 5 days/week*3 Cisplatin 5 mg/kg IP Q7D*3 4 2 5 1 15 2 25 Days post administration Drug Sensitivity test Genetic Analysis CORRELATION 相关性研究 11
Stage IV: Companion Diagnostic Marker In July 211, the FDA issued a new draft guidance to facilitate the development and review of companion diagnostics. The guidance, currently available for public comment, is intended to provide companies with guidance on the agency s policy for reviewing a companion diagnostic and the corresponding drug therapy. Zelboraf (Vemurafenib) for Melanoma (17 Aug 211 FDA approved) cobas 48 BRAF V6 Mutation Test (first-of-a-kind ) Xalkori (Crizotinib) for NSCLC (26 Aug 211 FDA approved) Vysis ALK Break Apart FISH Probe Kit (first-of-a-kind ) EMK4-ALK fusion protein 12
Outline Pre-Clinical Application of PDX ---Four Stages of Translational Medicine in Oncology Clinical Application of PDX Case Study Shanghai LIDE: One Stop Shop Solution for Personalized Medicine of Oncology Patients 13
Clinic Application of PDX Pancreatic PDX PDX efficacy highly correlation with clinic 引自美国 Champions oncology 的数据,http://championsoncology.com/. 患者情况 : 61 岁, 男, 诊断为低分化胰腺腺癌, 术后两个月后出现淋巴结转移,CA19-9 血清水平升至 1,132U/mL( 图 B) 治疗史 : 初期化疗方案为 Gemcitabine, 无疗效, 疾病快速进展, CA19-9 血清水平升至 98,45U/mL( 图 B) 肿瘤个体化动物模型及药敏测试 : 将手术切除的肿瘤组织移植到免疫缺陷小鼠上建成了肿瘤个体化动物模型, 利用该模型测试的药敏结果表明 Mitomycin C 和 Cisplatin 有非常好的效果 ( 图 A) 调整方案后的治疗结果 : 根据体内药敏测试结果, 患者选用 Mitomycin C 单药化疗方案, 疗效保持长达 22 个月之久 ( 图 B), 术后 5 年后的随访结果表明患者一直未出现临床症状 引自文献 -Villarroel et al. Personalizing Cancer Treatment in the Age of Global Genomic Analyses: PALB2 Gene Mutations and the Response to DNA Damaging Agents in Pancreatic Cancer. Mol Cancer Ther, 211: 1: 3-8. 14
妇产科案例研究 History 45 year old female -Married - No histology of uterine fibroids and endometriosis; - 4 years ago: Lung Carcinoids, 3x4cm; OP, part of lung was removed; without chemotherapy - 23 months ago: Endometrial Carcinomas, 3x4cm, mixed clear cells, Stage IIA First Treatment: After surgery, Carboplatin + Palitaxel treatment for 9 weeks, plus radiotherapy for 8 times, CA125 reduced to 8 Second Treatment: Recurrent 1 year later. CA125=85 cisplatin + Palitaxel treatment for 1.5 months, CA125 increase from 85 to 1 15
Inhibition (%) Tumor volume (mm 3 ) Inhibition (%) Personalized Medicine Genetic mutation detected by Miseq: PTEN: Two mutation sites cause D331A mutation and frame shift P53: A161T mutation 1 Establish PDX model, and test few drugs in in vivo and in vitro 8 6 4 2 5 1 15 2 25 Days post administration Vehicle Control 5-FU 25 mpk CPT-11 1 mpk Epirubicin 1 mpk Bleomycin 15 mpk DDP 3.5 mpk + CPT-11 1mpk Paclitaxel 15mpk + DDP 3.5mpk Mitomycin C 3.25mpk + CPT-11 1mpk 16
Outline Pre-Clinical Application of PDX ---Four Stages of Translational Medicine in Oncology Clinical Application of PDX Case Study Shanghai LIDE: One Stop Shop Solution for Personalized Medicine of Oncology Patients 17
LIDE Biotech Lab for Innovated Diagnosis and Experimental Therapeutics A company for translational medicine Shanghai LIDE Xian LIDE Shanghai LIIWEN 4+ Employees Sept 213 Shanghai LIWEN Biotech Registered April 213 TigerMed (public listed company) invests in LIDE Nov 211 Shanghai LIDE Registered Jan. 212 June 212 USD 3M P.O. ~1 Scientists April 212 Xian LIDE registered March 212 Affiliated with National Biobank Project through Xiehe Hospital (PUMC/CAMS) Sign official collaborating agreement with ZhongShan, HuaShan, XiJing Hospital http://www.lidebiotech.com/ 18
Market Position and Business Model Clinical Application of Translational Medicine Pre-Clinic Drug Discovery Translation Application of PDX (mouse trial) Biomarker Molecular Diagnosis Mouse Trial PD/PK correlation Patient stratification marker live Biobank PDX Clinical Application Personalized Medicine Pre-Clinic Clinic Market Position Pharma Hospital Patients CRO service Medical License
Tumor volume (mm 3 ) % Inhibition Rate One Stop Shop Solution for Cancer Patients cancer diagnosis In vitro drug sensitivity Biomarker 8 ml whole blood 循环肿瘤细胞 CTC Biomarker 初诊 Plasma ALK 免疫组化 FISH Sorafenib Molecular Diagnosis 1 8 6 4 2-2.1 1 1 Log CPD concentration (μm) Personalized Medicine NGS & gene expression Cloud database Tumor growth (Efficacy study of 5-FU and cisplatin in GAPF3-FP1+3 xenograft model) 6 Vehicle 4 2 5-FU 25 mg/kg IP 5 days/week*3 Cisplatin 5 mg/kg IP Q7D*3 5 1 15 2 25 Days post administration In vitro drug sensitivity testing PDX In vivo PDX Efficacy Testing Surgery 2
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