Targeted therapy & Tumor molecular profile Anton Tikhonov V Bioinformatics Summer School, 2017
What exactly is targeted therapy? It has target It was rationally designed Its target was discovered before therapy was developed
What exactly is targeted therapy? Chemotherapy (non-targeted): Developed first, mechanism (fully) understood later Directly affects cell replication/genome integrity Targeted therapy: Developed for specific molecular target Affects cell signaling (not always) Indirectly affects everything else, including replication/genome integrity
Everybody else s drugs are poisonous, Imatinib is targeted
Cancer signaling
Cancer signaling
Signaling basics Signal transfer mechanisms: Protein-protein interaction (with or without covalent modification) Small molecule-protein interaction Protein-DNA interaction Signal transfer direction: Intra/Intercellular - nucleus Everything else you can imagine
Signaling basics: protein-protein interaction Conformation/activity change through: Interaction Dimerization Covalent modification: phosphorylation, cleavage, acetylation Self-covalent modification
Cancer signaling Proliferation Survival Migration Differentiation Immune system interaction Genome stability
Ras-MAPK pathway EGFR - ligand binding, dimerization, autophosphorylation, recruitment of GRB2 and SOS SOS - RAS activation through GDP exchange RAS - RAF recruitment RAF, MEK, MAPK - phosphorylation MYC - DNA interaction
Blablablatinib * zu tu Blablablamumab
Ras-MAPK pathway in cancer
Ras-MAPK pathway in cancer * EGFR overexpression - Cetuximab EGFR activating mutation - Gefitinib * * RAS activation - :( RAF V600E - :( or maybe Vemurafenib * *
Associated pathways I-- CRISOTINIB IDELASIB --I EVEROLIMUS --I
Resistance mutations EGFR resistance to Gefitinib - Brigatinib EML4-ALK resistance to Crisotinib - Alectinib BRIGATINIB --I * * * I-- ALECTINIB
Immune signaling PD-L1 antibody - Pembrolizumab Biomarkers: PD-L1 overexpression and cytotoxic T-cell activity
Immune signaling & mutation load Microsatellite instability
Immune signaling & mutation load Mismatch repair: MLH1, MSH2, MSH6, PMS2, EPCAM
Genome as a target - BRCA1/2 => highly sensitive to platinum compounds, mitomycin, PARP inhibitors
Genome as a target - BRCA1/2
Other drug-related biomarkers Target expression levels Thymidylate Synthase 5-FU activity Drug-resistance genes expression levels MMR DNA-modifying agents activity MDR1 (multidrug pump) PARP activity PK/Tox Dipyrimidine Dehydrogenase 5-FU TOXIC
Inherited cancer syndromes
Hereditary Breast and Ovarian Cancer Genes: BRCA1/2, PALB2, RAD51, BRIP1, ATM, NBN. - components of homologous recombination system Incidence: 1/300-1/500 Penetrance: BC up to 87% (13% in general population) OC up to 44% (2% in general population) Recommendations: frequent mammography, breast MRI starting early Prophylactic mastectomy and salpingo-oophorectomy!!!!!!
Genome as a target - BRCA1/2 => highly sensitive to platinum compounds, mitomycin, PARP inhibitors
Lynch Syndrome Genes: MLH1, MSH2, MSH6, PMS2, EPCAM - mismatch repair system Incidence: 1/100-1/200 Penetrance: Colorectal up to 82% (6.4 % in general population)
Inherited cancer syndromes Cause 5-10% of all cancers Incidence ~2.5-5% Cancers: Breast Ovarian Colorectal Gastric Endometrial Pancreatic Thyroid Prostate Renal Neuroendocrine...
Inherited cancer syndromes Familial cancers: 15-25% Inherited cancers: 5-10% Syndromes: Lynch syndrome Hereditary breast and ovarian cancer Hereditary diffused gastric cancer Familial Atypical Multiple Mole Melanoma Hereditary mixed polyposis syndrome Polymerase proofreading associated polyposis (PPAP) syndrome PTEN hamartoma tumor syndrome includes Juvenile polyposis Multiple endocrine neoplasia type 2
Why use omics? To find actionable mutations for off-label drug To find actionable mutations for drug in clinical trials To substitute single-biomarker tests (PCR, Sanger, FISH, IHC, Flow-Cytometry, CE-AFLP, Cytogenetics) To find loose resistance/susceptibility associations