economic Treating patients affordably: personalized medicine in India biologic B Moni Abraham Kuriakose MB ChB, MD, FDSRCS, FFDRCS, FRCS Ed., FRCS, Dip AB Professor and Director, Department of Surgical Oncology Chief, Head and Neck Oncology Service Mazumdar-Shaw Cancer Center Narayana Hrudayalaya Health City, Bangalore
Economic impact: Management of laryngeal cancer Diagnostic work up response (80%) Chemo therapy + Radiotherapy (70%) Endoscopy Biopsy CT Hematology PET-CT Induction chemotherapy No response (20%) 10% (PET-CT: 30%) (NGS: 500%)
Issues with personalized medicine Treatment-2 Treatment-1 Patient Treatment -3 Treatment-4 Few validated targeted therapy issue with clinical trials Targeted therapy missing targets issues with tumor heterogeneity
Trial design issue Recurrent or metastatic HNSCC N= 220 Randomize Cisplatin + 5FU Cisplatin + 5FU + Cetuximab Overall survival: 7.4 month Response: 20% Overall survival: 10.1 months (p = 0.04) Response: 36% (P = 0.001)
PATH Trial Pathway based Adaptive Therapy in HNSCC Cisplatin + 5FU Recurrent or metastatic HNSCC N= 120 Randomize EGRF, KRAS/BRAF/COX2, RAR, VEGF/VEGFR/ PGE2, mtor Cisplatin + 5FU + Nimotuximab/S orafenib/bevaxi zumab/atra/m etformin/ Celecoxib Endpoints Overall survival, Disease specific survival, Response
Stratification into the different treatment Arms EGFR WT MUT KRAS PGE 2 EIA WT + pegfr MUT High Low Nimotuzumab Sorafenib Celecoxib Rank I Rank 2 Rank 3 RAR β High mtor High VEGF/VEGFR High ATRA Metformi n Bevacizumab Rank 4 Rank 5 Rank 6 *Ranking in order of available evidence between response to the drug and the biomarker status
In Targeted Therapy are we missing the target? -understanding cancer heterogeneity is the key for success
Tumor heterogeneity Genomic heterogeneity Cellular heterogeneity Stromal heterogeneity
Tumor heterogeneity Genomic heterogeneity Cellular heterogeneity Stromal heterogeneity
Genomic Heterogeneity Stratton et al., Nature, April 2009
Whole genome sequence of HNSCC Invasive Cancer Moderate Dysplasia
Major Pathways/Unique genes Tumor Leukoplakia TGFB EGFR MAPK Apoptosis ErBB AKT Integrins p53 Jak Stat INHB GNA15 GRM7 DKK2 ITGA5 AQP7 SRC ACTN1 ATR COL1A1 Notch TGFB MAPK Wnt PPAR ErBb Jak Stat Integrin AKt NFkB Notch 3 SPHK2 SRC IL12RB1 EDN3 FASN IRS4 Clinically available agents Under trial or used for other indications
Tumor heterogeneity Genomic heterogeneity Cellular heterogeneity Stromal heterogeneity
Cellular heterogeneity Courtesy to Katherine Harmo et al., 2009
A small population in the HEp-2 cell line has cancer stem cell phenotype HEp-2 cell line HEp-2 cells (200 FACS/CD133 cells/ well) 2.3% of CD133+ cells SFM+EGF & b- FGF Spheroids within 2 weeks Sindhu, Oral Oncology April 2012
CSC characterization Monolayer (M) M S Cell lines 18sRNA ABCG2 BMI1 HNSCC tissues OCT4 Nanog Spheroid (S) Sindhu, Oral Oncology April 2012
Drug treatment of the cell line-hep-2 HEp-2 parental cell CDDP, 5-FU & Docetaxel 5 days Drug Treatment IC 25 conc MTT assay CD44, CD133 and ALDH1A1- cancer stem cell markers Nanog, BMI-1, Sox2 and Oct-4 Self renewal markers Notch1 and ABCG2 Chemo resistance
Expression of CSC markers in treated and spheroid cells vs untreated cells Untreated Chemotherapy Spheroids Sindhu, Oral Oncology April 2012
Stem cell marker expression in HNSCC treated with CT/RT Group I: Treatment naive patient patients (n=33) Group II: Patients who received CT/RT followed by salvage surgery (n=31) Normal: mucosal samples from healthy controls (n=3) Sindhu, Oral Oncology April 2012
Stem cell marker in HNSCC All the markers except ALDH1A1 were up regulated in HNSCC. 30% (4/13) treatment naive patients with at least three markers over expression recurred later. 1000 100 Fold expression 10 1 0.1 0.01 CD44 ALDH1A1 ABCG2 Notch-1 0.001 Normal Treatment naive patients CT/RT patients Sindhu, Oral Oncology April 2012
Summary Personalized therapy should make economic sense Essential to develop companion biomarker based clinical trial Time to develop clinical trial based on adoptive design Targeted therapy should address tumor heterogeneity (genomic/cellular/stroma)