2. The Role of Systemic Therapy
• Treatment of the whole body
• Intent?
– Induction therapy
– Adjuvant therapy
– Palliative
3. 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
4. Six Essential Alterations
in Cell Physiology in Malignancy
Limitless replicative
potential
Tissue invasion
& metastasis
Sustained
angiogenesis
Insensitivity to
anti-growth signals
Self-sufficiency in
growth signals
Evading
apoptosis
Targets for classical drugs?
Targets for novel drugs?
Hanahan & Weinberg,
Cell 100:57 (2000)
5.
6. What is Targeted Therapy?
A “smart” bomb versus a “cluster” bomb.
Dr. Nevin Murray
7. Targeted Therapy: A definition
• Drugs targeted at pathways, processes and physiology which are
uniquely disrupted in cancer cells:
– Receptors
– Genes
– Angiogenesis
– Tumor pH
• Examples:
– tyrosine kinase pathway (bcr-abl, PDGF)
– proteosomal pathways
– survival signals (MCL1, BCL2)
– heat shock proteins
– immunological activation/tolerance
8. Attempts to take advantage of a genetic change
in the malignant cells
9. The revolution of molecular targeted cancer therapy.
and the journey still continues…
Yarden Y The Oncologist 2011;16:23-29
13. How to hit the target
• If you know the target, and there is only one
target you can be very specific.
• If you don’t really know or it’s a really big target, a
larger weapon may be needed.
14. But all is not lost…
• Return to the fundamental assumption.
• Targeted therapy works when you can identify
and validate the target.
– Need to enrich the population for the target:
Herceptin
– May need to hit more than one target
15. Leveraging your opponents weight, or how targeted
therapy can work with other treatments and toss
the opponent out of the ring
20. 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
24. 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
38. CONCLUSIONS
• Targeted therapy can exploit fragile aspects of
oncogenic networks
• Drug resistance reflects system plasticity, and
may be overcome by drug combinations.
• System controls, such as receptor endocytosis
and transcriptional feedback loops, are often
defective in cancer, and may be another source of
exploitations with future therapies.
39. Targeted Therapy: The Future
• Modern biology has identified a host of new
potential targets for cancer therapy
• Drugs interacting with these targets are available.
• The benefit of these agents is dependent upon the
criticality of the target. More than one target may
need to be inhibited.
• New agents may “tip the balance” when combined
with chemotherapy, radiation.
Editor's Notes
we will first review three types of drugs that can be used as targeted therapies—small molecules, antibodies, and vaccines.
Signaling complexity: The engineering perspective. Abbreviations: EGFR, epidermal growth factor receptor; GPCR, G protein-coupled receptor; HER-2, human epidermal growth factor receptor; MAPK, mitogen-activated protein kinase; PIP, phosphatidylinositol-bisphosphate. Adapted by permission from Macmillan Publishers Ltd: Molecular Systems Biology. Oda K, Matsuoka Y, Funahashi A et al. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol 2005;1:8–24, copyright 2005.
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[8] and David Hungerford from the Fox Chase Cancer Center
The 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 lymphocytes
APCs 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)