Drug-targeted therapies and Predictive Prognosis: Changing Role for the Pathologist

Transcription

1 Drug-targeted therapies and Predictive Prognosis: Changing Role for the Pathologist Moderator: S. Terence Dunn, Ph.D. Associate Professor, Pathology Director, Molecular Pathology Laboratory University of Oklahoma Health Sciences Center

2 What is Targeted Therapy? Drugs which target specific molecules involved in a disease process In context of targeted cancer therapies, these are specific molecules involved in growth and spread of tumor cells Could argue that all drug therapies are targeted therapies molecular basis to them all Targeted therapy should be measurable clinically

3 Approaches to Drug Development Traditional approach Identify drug to test against specific disease Targeted approach Identify key pathway in disease Evaluate its laboratory and clinical effects Develop drug to targeted molecule Identify the target molecule Evaluate its laboratory and clinical effects

4 Molecules for Targeted Therapy 4 types of molecules used Small molecule inhibitors e.g., Gleevec - brand name Imatinib generic name STI571 lab development name Monoclonal antibodies Human Murine Chimeric Humanized -umab -momab -ximab -zumab Fusion proteins Antisense oligonucleotides and PNAs

5 Current Use of Targeted Therapies Monotherapy In combination with radiation In combination with chemotherapy In combination with other targeted therapies

6 Signal transduction inhibitors -target protein kinases (esp. tyrosine kinases), their ligands or signal transducers Protein kinases Catalyze transfer of phosphate from ATP to protein substrate Regulate variety of cellular processes Receptor kinases extracellular receptor and intracellular portion Non-receptor kinases interact with receptor kinases, other proteins, lipids and DNA

7 Signal transduction inhibitors Small molecule inhibitors e.g., Gleevec (imatinib mesylate) - binds to ATP-binding site of ABL, PDGF, SCF and c-kit tyrosine kinases; GIST and CML e.g., Iressa (gefitinib) and Tarceva (erlotinib) targets EGFR; advanced NSCLC Monoclonal antibodies e.g., Herceptin (trastuzumab) targets HER2; breast cancer e.g., Erbitux (cetuximab) targets EGFR; advanced colorectal cancer with Irinotecan Antisense oligonucleotides e.g., Affinitak (ISIS3521) targets PKCα; in clinical trials for treatment of breast and NSCLC

8 Proteasome inhibitors Proteins Proteasome Amino acids Normal cellular activity Apoptosis Proteasome inhibition Proteins Proteasome

9 Proteasome inhibitors Small molecule inhibitors e.g., Velcade (PS-341 or bortexomib) multiple myeloma that has failed other treatments

10 Apoptosis-inducing drugs Antisense oligonucleotides e.g., Genesense (oblimersen) targets BCL-2 mrna; in clinical trials for treatment of leukemia, NHL and solid tumors

11 Angiogenesis inhibitors target angiogenic factors, angiogenic factor receptors, endothelial cell growth factors, or tissue metalloproteinases Small molecule inhibitors e.g., Neovastat - in clinical trials for kidney cancer and others Monoclonal antibodies e.g., Avastin (bevacizumab; anti-vegf) first-line metastatic colorectal cancer in combination with 5FU Antisense oligonucleotides e.g., Angiozyme (anti-angiogenesis ribozyme) in clinical trials for colorectal and breast cancer

12 Immunotherapy Directed immunotargeting of tumor cells e.g., Rituxan (rituximab) targets CD20; relapsed or refractory NHL e.g., Campath (alemtuzumab) targets CD52; CLL Radioimmunotherapy agents e.g., Bexxar (tositumomab; I 131 -radiolabeled anti- CD20) and Zevalin (ibritumomab; Y 90 -radiolabeled anti-cd20) CD20-expressing relapsed or refractory NHL

13 Immunotherapy Cytotoxin-complexed immunotherapy agents e.g., IL13-PE38 - fusion protein of Pseudomonas toxin conjugated to IL13; in clinical trials for gliomas e.g., Ontak - fusion protein of IL2 and diphtheria toxin; advanced or refractory CTCL e.g., Gemtuzumab (mylotarg) - calicheamicin conjugated anti-cd33; refractory AML Chemotherapy-complexed immunotherapy agents

14 Others e.g., HLA class II molecules (e.g., anti-lym-1 and apolixumab) G-proteins (Ras) Histone deacetylase complex CD markers (e.g., CD19, CD22, CD25)

15 Challenges for Targeted Therapy Multiple redundant pathways Alternative ligands for receptors Alternative signaling pathways Design of effective drugs Side-effects Defining appropriate patient groups Resistance through mutations

16 Changing Role for the Pathologist Patients eligibility Immunohistochemistry Flow cytometry FISH Mutation analysis Microarray analysis Response to treatment Quantitative measurement methods as above Monitoring for resistance to treatment Mutation analysis