Targeted therapy aims to inhibit specific molecular targets involved in cancer cell growth and survival. Chemotherapy treats the whole body but is less specific, while targeted therapy inhibits more specific cancer cell targets like tyrosine kinases, genes, angiogenesis factors, and survival signals. Examples include imatinib for CML and trastuzumab for HER2-positive breast cancer. Resistance can develop but may be overcome through combinations of targeted agents that inhibit multiple cancer cell pathways and processes. New targeted agents continue to be developed that exploit vulnerabilities in cancer signaling networks or stimulate anti-tumor immune responses.

1. Molecular Targeted
Therapies
Dr Ankur shah

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)

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

12. Signaling complexity: The engineering perspective.
Yarden Y The Oncologist 2011;16:23-29
©2011 by AlphaMed Press

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

17. The Origins of CML

18. Imatinib

19. BRAF Mutation in Melanoma

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

21. Response to crizotinib in patients with EML-ALK
NSCLCA

22. Drugs in the Pipeline for ALK

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

25. Herceptin

26. There Are Multiple Agents Already Available

28. Non-Hodgkin Lymphoma

29. Old News Targeted Therapy
(But crucial in breast cancer)

30. Normal Estrogen Effects in Breast Cells

31. Anti-estrogen Therapy in Breast Cancer

32. Antibody-Drug Conjugates

33. A New Agent in Hodgkin's Disease

34. Stimulating an Immune Response

35. New Agent in Melanoma Therapy

36. Pushing Immune Cells to Recognize Cancer Cells

37. Sipuleucel-T in Prostate Cancer

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.