Nibs, Nabs, Mibs & Mabs Heather L. Sloan, BS, RN, OCN

Transcription

1 Puget Sound Oncology Nurses Symposium March 2017 Nibs, Nabs, Mibs & Mabs Heather L. Sloan, BS, RN, OCN Respects Appropriate Growth Signal Responses NORMAL CELLS Recognized by Immune System Fixed Number of Appropriate Apoptosis Respects Boundaries Normal Metabolism Checkpoints Transient Angiogenesis 1 Ignores An@-growth Sustained Prolifera@on Invades and Metastasizes CANCER CELLS Evades Immune System Unlimited Replica@ons Escapes Apopto@c CHEMOTHERAPY TARGETED THERAPY Hyperac@ve Metabolism Broken Replica@on Checkpoints Sustained Angiogenesis 3 1

2 Targeted Therapy vs Chemotherapy Chemotherapy CHEMOTHERAPY Acts on all rapidly dividing normal and cancerous cells Compounds because they kill cells Cytotoxic - they kill tumor cells TARGETED THERAPIES Act on specific molecular targets that are associated with cancer Compounds deliberately chosen or designed to interact with their target Cytosta@c - they block tumor cell prolifera@on Chemotherapy works by stopping or slowing the growth of cells which grow and divide quickly. Chemotherapy is used to: Treat Cancer: cure cancer, lessen the chance it will return, or stop or slow its growth. PalliaOve care: Shrink tumors that are causing pain and other problems. Neoadjuvant chemotherapy: Make a tumor smaller before surgery or radia@on therapy. Adjuvant chemotherapy: Destroy cancer cells that may remain axer treatment with surgery or radia@on therapy. Help other treatments work beyer. 5 6 Targeted Cancer Therapy Targeted drugs zero in on some of the changes that make cancer cells different. They target specific areas of the cancer cell that allow the cell to grow faster and abnormally. There are many different targets on cancer cells and many drugs that have been developed to ayack them. Our understanding of cell biology was at one Ome as simple as this In general targeted drugs work to: Block or turn off chemical signals that tell the cancer cell to grow and divide Change proteins within the cancer cells so the cells die Stop making new blood vessels to feed the cancer cells Trigger your immune system to kill the cancer cells Carry a toxin to the cancer cell to kill it, but not normal cells 7 8 2

3 Our current knowledge now reveals a tangled web of signaling For cells to funcoon normally, complex communicaoon systems govern basic cellular funcoons: Cell division (prolifera@on) Cell migra@on Response to external s@muli Cell death (apoptosis) Goals of targeted therapy Find pathway unique to cancer Develop mechanism to switch pathway off Extra- & Intracellular Signaling EGF Cells communicate with each other by secre@ng signals (ligands) which can be proteins or other molecules. In order to detect a signal (that is, to be a target cell), a neighbor cell must have the right receptor for that signal. When a signaling molecule binds to its receptor, it alters the shape or ac@vity of the receptor, triggering a change inside of the cell Targeted Therapies Discovery: From Bench to Bedside Target iden@fica@on from tumor genomics Target valida@on in cell lines Lead compounds in animal models Proof-ofconcept in small pa@ent sample Clinical trials Phase I, II and III Ø From target discovery through FDA approval, developing a new drug takes at least 10 years on average and costs $2.6 billion. Ø Phases of Clinical Trials Ø Phase I safety and pharmacology of a compound. 15 to 30 pa@ents globally. Ø Phase II effec@veness and side effects profile. Less than 100 pa@ents globally Ø Phase III compare to standard treatment. From 100 to thousands of pa@ents Ini@al FDA approval and further studies Nibs: Small Molecule Kinase Inhibitors A kinase is an enzyme that transfers a phosphate group from ATP to a specific molecule (phosphoryla@on) Kinases are cri@cal in metabolism, cell signaling, protein regula@on, cellular transport, secretory processes, and many other cellular pathways. Many different kinds of kinases: Protein kinases, lipid kinases, carbohydrate kinases, nucleoside plus many more

4 Nibs: Small Molecule Kinase Inhibitors GREEN Epidermal Growth Factor RED ATP binding site ATP ErloOnib Nabs: NanoparOcle, Albumin-bound Allows for non-toxic delivery of hydrophobic compounds. Exploits the natural of albumin. Albumin reversibly binds to and transports a wide range of molecules from the blood stream to cells. Once the Nab-drug combo enter the inters@@al space, the drug payload is released from the albumin. The cytotoxic drug then diffuses into the tumor cells where it induces apoptosis Mibs: Proteosome Inhibitors The proteosome is responsible for the diges@on of proteins inside the cell If proteasome func@on is blocked, the build-up of these proteins triggers apoptosis. A. Direct signaling induced death of cancer cells (e.g. hercep@n and rituximab). B. Inhibit angiogenesis (e.g. bevacizumab) C. Block inhibitory signals thereby resul@ng in a stronger an@-tumor T cell response (e.g. ipilimumab and nivolumab) D. Deliver radioisotopes (e.g. 131 I tositumomab) E. Deliver highly potent toxic drugs directly to cancer cells (trastuzumab emtansine) F. Retarget immune cells towards cancer cells with special mab that connects the two (e.g. blinatumomab) G. CAR T-cells

5 Immune checkpoint inhibitors are a hot area of clinical research. AnObody Origin Naming Substem Examples Chimeric - xi - Rituximab; cetuximab; infliximab Humanized - zu - Trastuzumab; bevacizumab; pembrolizumab Human - u - Ipilumumab; nivolumab Humanized Chimeric Bispecific (BiTEs) - o - Blinatumomab QuesOons? Comments? THANK YOU!! 5