Targeted therapy & Tumor molecular profile. Anton Tikhonov V Bioinformatics Summer School, 2017
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1 Targeted therapy & Tumor molecular profile Anton Tikhonov V Bioinformatics Summer School, 2017
2 What exactly is targeted therapy? It has target It was rationally designed Its target was discovered before therapy was developed
3 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
4 Everybody else s drugs are poisonous, Imatinib is targeted
5 Cancer signaling
6 Cancer signaling
7 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
8 Signaling basics: protein-protein interaction Conformation/activity change through: Interaction Dimerization Covalent modification: phosphorylation, cleavage, acetylation Self-covalent modification
9 Cancer signaling Proliferation Survival Migration Differentiation Immune system interaction Genome stability
10 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
11 Blablablatinib * zu tu Blablablamumab
12 Ras-MAPK pathway in cancer
13 Ras-MAPK pathway in cancer * EGFR overexpression - Cetuximab EGFR activating mutation - Gefitinib * * RAS activation - :( RAF V600E - :( or maybe Vemurafenib * *
14 Associated pathways I-- CRISOTINIB IDELASIB --I EVEROLIMUS --I
15 Resistance mutations EGFR resistance to Gefitinib - Brigatinib EML4-ALK resistance to Crisotinib - Alectinib BRIGATINIB --I * * * I-- ALECTINIB
16 Immune signaling PD-L1 antibody - Pembrolizumab Biomarkers: PD-L1 overexpression and cytotoxic T-cell activity
17 Immune signaling & mutation load Microsatellite instability
18 Immune signaling & mutation load Mismatch repair: MLH1, MSH2, MSH6, PMS2, EPCAM
19
20 Genome as a target - BRCA1/2 => highly sensitive to platinum compounds, mitomycin, PARP inhibitors
21 Genome as a target - BRCA1/2
22 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
23 Inherited cancer syndromes
24 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!!!!!!
25 Genome as a target - BRCA1/2 => highly sensitive to platinum compounds, mitomycin, PARP inhibitors
26
27 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)
28 Inherited cancer syndromes Cause 5-10% of all cancers Incidence ~2.5-5% Cancers: Breast Ovarian Colorectal Gastric Endometrial Pancreatic Thyroid Prostate Renal Neuroendocrine...
29 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
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