we will first review three types of drugs that can be used as targeted therapies—small molecules, antibodies, and vaccines.
The best target for therapy is a molecule or pathway that is present in cancer cells and absent in normal cells.
The Philadelphia chromosome was first discovered and described in 1960 by Peter Nowell from University of Pennsylvania School of Medicine and David Hungerford from the Fox Chase Cancer CenterThe exact chromosomal defect in Philadelphia chromosome is a translocation, in which parts of two chromosomes, 9 and 22, swap places. The result is that a fusion gene is created by juxtapositioning the Abl1 gene on chromosome 9 (region q34) to a part of the BCR ("breakpoint cluster region") gene on chromosome 22 (region q11)
The BRAF mutation causes cells to proliferate without any control or normal programmed cell death (apoptosis). Approximately 50% of melanoma cells have the mutated BRAF gene. It is more common in the young and more likely present in metastatic disease compared with primary melanoma.
The EML4-ALK fusion gene is responsible for approximately 3-5% of non-small-cell lung cancer(NSCLC). The vast majority of cases are adenocarcinomas. Through an unknown mechanism, cells with this mutation can no longer control their growth cycle, leading to uncontrolled proliferation and the potential for cancer.
The next best target for therapy is a molecule that is present more frequently in cancer cells compared to normal cells. In this case, it may be possible to adjust the dose of a drug so that cancer cells are killed more often than nearby normal cells.
Other possible targets for therapy include molecules that are present on both cancer cells and normal cells, but the patient's body can replace the normal cells that get destroyed.
Second, they can also be used as delivery vehicles, guiding radioactive molecules or toxins to the cancer cells.
an antibody-drug conjugate that works by binding to CD30 proteins on the surface of Hodgkin lymphoma cells. The ADC then forms a complex with CD30 and enters the cell. Inside the cell, the ADC’s chemotherapy component is released and kills the cancer cell. [
Third, antibodies attached to a cell can trigger an immune response that destroys the cell.
Ipilimumab or Yervoy is a monoclonal antibody against the CTLA-4 receptor on T cells (white blood cells that fight cancer). By blocking this receptor the T cell remains activated against cancer cells such as melanoma.Two phase III trials have shown a survival benefit over traditional melanoma treatment in the form of Dacarbazine or a peptide vaccine. The most recent presented at ASCO in June 2011 showed higher survival rates at 1 year (47.3% v’s 36.3%), 2 years (28.5% v’s 17.9%) and at 3 years (20.8% v’s 11.6%).
Unlike other targeted therapies, therapeutic cancer vaccines do not act specifically on pathways in cancer cells. Instead, they act broadly by trying to activate the body's immune system to make it recognize and attack cancer cells.Eg: interleukin 2
Developed based on concept of antigen-presenting cells (APCs), which include dendritic cells, macrophages and B lymphocytesAPCs from patients blood are harvested by leukapheresis, sent to drug company (Dendreon), where they are incubated with recombinant fusion protein antigen containing PAP (prostatic acid phosphatase) and GM-CSF (granulocyte-macrophage colony-stimulating factor) ● These antigen-loaded APCs are infused into patient, and may prime a T-cell mediated immune response against prostatic cancer cells (J Clin Oncol 2006;24:3089)
Chemotherapy vs. Targeted Therapy James J Lechner, MD Medical DirectorProvidence Regional Cancer System
The Role of Systemic Therapy• Treatment of the whole body• Intent? – Induction therapy – Adjuvant therapy – Palliative
Chemotherapy vs Targeted Therapy• Chemotherapy: – Drugs that effect cells that are doubling – Not very specific – Mostly intravenous, some oral agents – Cytotoxic• Targeted therapy: – Drugs that inhibit a more specific target in cells – Many are oral agents – Mixture of cytostatic and cytotoxic
Class Example Method of Action Cycle SpecficAlkylating agents Cytoxan Effects DNA chemically AllAntimetabolites 5-FU Substitutes for normal cell S Gemzar building blocksAnthracyclines Adriamycin DNA damage or inhibit All topoisomeraseAnti-tumor Bleomycin DNA damage AllAntibioticsTopoisomerase Irinotecan Complex DNA and SInhibitors topoisomerase together G-2Vinca Alkaloids Vincristine Binds to tubulin, interferes M with mitosisTaxanes Taxol Prevents microtubules from M Taxotere disassociating
Targeted Therapy Attempts to take advantage of agenetic change in the malignant cells
EML4-ALK Mutation in Lung Cancer• Present in 3-5% of non-small cell lung cancer, usually adenocarcinoma• Mutation leads to formation of a fusion gene that codes for an abnormal tyrosine kinase receptor
Response to crizotinib in patients with EML- ALK NSCLCA
Her-2/neu• About 25% of breast cancer cases are associated with a amplification of the genes coding for a cell surface receptor called Her-2/neu• These cells may a 1000 fold increase in the number of these receptors over normal breast cells• Associated with rapid growth