This document discusses cancer genetics, tumor markers, and targeted cancer therapy. It begins by explaining how cancer results from gene mutations that disrupt cell cycle control. It then describes different types of genetic alterations like gene amplifications and chromosome translocations. It also discusses proto-oncogenes, oncogenes, and tumor suppressor genes. The document next covers tumor markers and their use in cancer detection and monitoring. Finally, it examines targeted cancer therapies, how they differ from chemotherapy, examples of targeted drugs, their side effects and limitations, and specific targets like BCR-ABL in CML and HER-2 in breast cancer.

1. CANCER GENETICS, TUMOUR MARKERS
AND TARGETED THERAPY IN CANCER
GUIDE : Dr. K. Mujalda
CANDIDATE: Dr. Naresh Patel

3. • It is now widely accepted that cancer results from the accumulation
of mutations in the genes that directly control cell cycle.
• Mutations of gene are unstable & instability exists at two distinct
levels:
1. Nucleotide level.
2. Chromosome level.

4. GENETIC ALTERATION:
1. Subtle sequence changes : These changes involve base substitutions
or deletions or insertions of a few nucleotides.

5. 2. Gene amplifications:
Gene amplifications are seen at the
cytogenetic level as homogeneously
stained regions or double minutes.
e.g. Amplification of NMYC gene in
neuronalstoma on chromosome 2p.

6. 3. Chromosome translocations.
Movement of a proto-
oncogene on chromosome 8
to the vicinity of a highly
active gene on chromosome
14 causes Burkitt’s lymphoma.

7. Genetic Mutations
• Proto-oncogenes: normal cellular genes whose products promote
regulated cell proliferation, e.g. RAS, ABL.
• Oncogenes: mutated or overexpressed versions of proto-oncogenes
that function autonomously, having lost dependence on normal
growth promoting signals.
• Tumour suppressor genes : products of most tumor suppressor genes
apply brakes to cell proliferation, and abnormalities in these genes
lead to failure of growth inhibition.e.g. RB, P53.

8. Proto-Oncogene - RAS
In response to growth factor
binding at receptor, the Ras gene
product combines with GTP to
promote cell division
In cancer cells, the RAS
gene product is locked into
its GTP-binding shape and
does not require a signal at
the receptor in order to
stimulate cell division

9. Proto-Oncogene - ABL

10. Tumor Suppressor Genes
• RB gene : Governor of the cell
cycle.
• p53 gene : Gurdian of genome.
ROBBIN'S 9th Ed.

11. In Normal Cells, the Rb Gene Product
Controls the G1 S Transition
Rb = product of
Retinoblastoma gene,
inhibits action of E2F
until chemically
modified
E2F = transcription factor
required to activate genes for
DNA synthesis
CDK-cyclin (intracellular signal)
modifies Rb so the E2F can
mediate the G1S transition

12. In Normal Cells, the p53 Gene Product
Acts at the G1 S Checkpoint Preventing Entry
Into S Phase If DNA Is Damaged
p21 inhibits intracellular signals
that would activate EF2
p53 = transcription factor that
causes p21 to be produced
Cells with
damaged DNA do
not pass the
G1S checkpoint
In cancer cells the mutated p53 gene product no
longer stimulates p21 production. Cells will pass
the G1 S checkpoint even when chromosomal
damage exists.

13. In Normal Cells, the p53 Gene Product Stimulates
Apoptosis If DNA Damage Cannot Be Repaired.
p53 gives an internal
signal for apoptosis
In cancer cells, a mutated p53 gene
product no longer initiates self-
destruction. Cells with damaged
DNA can divide and more DNA
damage can be accumulated.
p53 is the most frequently mutated
of all known cancer-causing genes,
contributing to many types of cancer.

14. THE CLONAL ORIGIN AND MULTISTEP NATURE OF
CANCER
HARRISON 19th ed.

15. Progressive somatic mutational steps in the
development of colon carcinoma.
HARRISON 19th ed.

16. Tumour Markers
Substances present in, or produced by, a tumour itself or produced by
host in response to a tumour that can be used to differentiate a tumour
from normal tissue or to determine the presence of a tumour based on
measurements in blood or secretions.

17. Characteristics of an ideal tumor marker

18. Methods of detection of tumor markers

19. Recommendations for ordering tumour marker tests
BMJ | 10 October 2009 | Volume 339

20. Some benign conditions associated
with rise in tumor markers

21. Targeted Therapy in Cancer
What are targeted cancer therapies?
• Targeted cancer therapies are drugs or other substances that block
the growth and spread of cancer by interfering with specific
molecules that are involved in the growth, progression, and spread of
cancer.
• Targeted cancer therapies are sometimes called "molecularly targeted
drugs," "molecularly targeted therapies," "precision medicines“.
www.cancer.gov

22. How Targeted therapies differ from standard
chemotherapy :
• Targeted therapies act on specific molecular targets that are
associated with cancer, whereas most standard chemotherapies act
on all rapidly dividing normal and cancerous cells.
• Targeted therapies are deliberately chosen or designed to interact
with their target, whereas many standard chemotherapies were
identified because they kill cells.
• Targeted therapies are often cytostatic (that is, they block tumor cell
proliferation), whereas standard chemotherapy agents are cytotoxic.
www.cancer.gov

23. Classification and Naming
Targeted cancer agents are broadly classified as:
1. Therapeutic monoclonal antibodies target specific antigens found
on the cell surface, such as transmembrane receptors or
extracellular growth factors.
2. Small molecules can penetrate the cell membrane to interact with
targets inside a cell. Small molecules are usually designed to
interfere with the enzymatic activity of the target protein.

24. Naming Formula
Variable

25. FDA approved small molecule inhibitors for the
treatment of various cancers
Current Drug Discovery Technologies, 2015, Vol. 12, No. 1

26. FDA approved monoclonal antibodies for the
treatment of various cancers
Current Drug Discovery Technologies, 2015, Vol. 12, No. 1

27. Side effects of targeted cancer therapies
• Diarrhea
• Liver problems,
- such as hepatitis and elevated liver enzymes
• Skin problems (acneiform rash, dry skin, nail changes, hair
depigmentation)
• Problems with blood clotting and wound healing
• High blood pressure
• Gastrointestinal perforation (a rare side effect of some targeted
therapies)
Most Common

28. Certain side effects have been linked to better
patient outcomes
For example,
• Patients who develop acneiform rash, while being treated with the
signal transduction inhibitors erlotinib or gefitinib, both of which
target the epidermal growth factor receptor, have tended to respond
better to these drugs than patients who do not develop the rash.
• Similarly, patients who develop high blood pressure while being
treated with the angiogenesis inhibitor bevacizumab generally have
had better outcomes.

29. Limitations of targeted cancer therapies
1. Cancer cells can become resistant to them. Resistance can occur in
two ways:
- the target itself changes through mutation so that the targeted
therapy no longer interacts well with it, and/or
- the tumor finds a new pathway to achieve tumor growth that
does not depend on the target.
2. Some identified targets are difficult to develop because of the
target’s structure and/or the way its function is regulated in the cell,
e.g. Ras

30. BCR-ABL as a Therapeutic Target for CML
• BCR-ABL translocation is detected in all
patients with CML.
• BCR-ABL tyrosine kinase is constitutively
activated in CML cells, and activation is
necessary for growth.
• Inhibitors of BCR-ABL Imatinib mesylate
specifically blocks the function of BCR-
ABL.

31. Mechanism of Action of Imatinib Mesylate
Goldman JM, Melo JV. N Engl J Med. 344:1084-1086.

32. HER-2 - A Target for Breast Cancer
• Human epidermal growth
factor receptor – 2.
• Overexpressed in 25% of breast
cancers.
• Historically associated with
more aggressive course.