A review on targeted therapies in Cancer.

1. HIMADRI NATH
ROLL- BGC/ZOOL NO- 14101
REG NO: 002558-2013 OF 2013
P.G . DEPT. OF ZOOLOGY
BARASAT GOVT. COLLEGE

2. Drugs or other substances that block the growth and
spread of cancer by interfering with specific molecules
("molecular targets") involved in the growth,
progression, and spread of cancer.
“Molecularly targeted drugs," "molecularly targeted
therapies," "precision medicines,”
The major modalities of medical treatment
(pharmacotherapy) for cancer.
Interfere with specific targeted molecules needed for
carcinogenesis and tumor growth rather than by simply
interfering with all rapidly dividing cells (e.g. with
traditional chemotherapy).

3. Targeted Therapies Chemotherapy
Act on specific molecular
targets that are associated with
cancer
Act on all rapidly dividing
normal and cancerous cells.
Deliberately chosen or designed
to interact with their target
Identified because they kill
cells.
Often cytostatic Cytotoxic

4. Ref: Gibbs JB.(2000) Anticancer drug targets: growth factors and growth factor signaling.

5. 1.Proteins present in cancer cells but
not normal cells or more abundant in
cancer cells especially if they are
known to be involved in cell growth
or survival.
Example:
i. human epidermal growth factor
receptor 2 protein (HER-2) is
expressed at high levels on the
surface of some cancer cells.
ii. Neu growth factor receptor
present at high number in breast
cancer cells.

6. Target identification cont’d….
2. To determine whether cancer cells produce mutant
(altered) proteins that drive cancer progression.
Example:
The cell growth signaling protein BRAF is present in an
altered form (known as BRAF V600E) in many
melanomas.
 Vemurafenib (Zelboraf®) targets this mutant form of
the BRAF protein and is approved to treat patients with
metastatic melanoma that contains this altered BRAF
protein.

7. 3. Abnormalities in chromosomes present in cancer cells but not in
normal cells. Sometimes these result in the creation of a fusion gene
whose product, called a fusion protein, may drive cancer development.
Such fusion proteins are potential targets for targeted cancer therapies.
Example
Imatinib mesylate
(Gleevec®) targets the
BCR-ABL fusion
protein, which is made
from pieces of two
genes that get joined
together in some
leukemia cells and
promotes the growth
of leukemic cells.
Ref: Press MF, Lenz HJ (2007)
Target identification cont’d….

8. The main categories of targeted therapy are currently small
molecules and monoclonal antibodies.
A. Small-molecule compounds are typically developed for targets
that are located inside the cell because such agents are able to
enter cells relatively easily.
B. Monoclonal antibodies are relatively large and generally
cannot enter cells, so they are used only for targets that are
outside cells or on the cell surface.

9. GENERIC NAMES OF TARGETED DRUGS

10. Identified in what are known as "high-throughput screens,”
in which the effects of thousands of test compounds on a
specific target protein are examined.
Compounds that affect the target (sometimes called "lead
compounds") are then chemically modified to produce
numerous closely related versions of the lead compound.
These related compounds are then tested to determine
which are most effective and have the fewest effects on
nontarget molecules.

11. Targeted most intensively
for drug development are
plasma membrane-
associated protein tyrosine
kinases
The first kinase inhibitors
were described nearly and
developed in the early 1980s
by Hiroyoshi Hidaka.
Eight are FDA-approved,
numerous others are in
development
Most widely used are
Gleevec and Gefitinib
Generic
Name
Brand Name Cancer
Imatinib Gleevec CML,
GIST,
others
Dasatinib Sprycel CML, ALL
Nilotinib Tasigna CML
Gefitinib Iressa Lung
Erlotinib Tarceva Lung,
Pancreas
Lapatinib Tykerb Breast
Sorafenib Nexavar Kidney,
Liver
Sunitinib Sutent Kidney
FDA – Approved TKIs list

12. TK TK
ATP ATP
Cell Proliferation Antiapoptosis
Angiogenesis
Gene Transcription
Cell Cycle Progression
+
MetastasesSurvival
Tumor Cell Stimulation

13. MONOCLONAL ANTIBODIES AS TARGETED THERAPY
Developed by injecting animals (usually mice) with purified target proteins,
causing the animals to make many different types of antibodies against the target.
Antibodies are then tested to find the ones that bind best to the target without
binding to non target proteins.
Before monoclonal antibodies are used in humans, they are "humanized" by
replacing as much of the mouse antibody molecule as possible with
corresponding portions of human antibodies.

14. Ref: Drebin JA, Link VC, Weinberg RA, Greene MI (1986)

15. Generic
Name
Brand
Name
Target Cancer(s
)
Alemtuzumab Campath CD52 CLL
Bevacizumab Avastin VEGF Multiple
Cetuximab Erbitux EGFR1 Colon,
H&N
Panitumumab Vectibix EGFR1 Colon
Rituximab Rituxan CD20 Lympho
mas
Trastuzumab Herceptin HER-2 Breast
MONOCLONAL ANTIBODIES AS TARGETED THERAPY
In 1997 the first therapeutic antibody,
rituximab (Rituxan; Genentech/Biogen
Idec), was approved by the US FDA for the
treatment of B-cell non-Hodgkin's
lymphoma.
Rituximab targets CD20 found on B cells.
Trastuzumab (Herceptin; Genentech)
was approved by the US FDA for use in
patients with metastatic breast cancer in
1998.
genetically engineered anti-HER2
monoclonal antibody
HER2 protein is produced in excessive
amounts in 25-30% of patients with breast
cancer and is associated with aggressive
growth of tumor cells.
FDA-APPROVED “NAKED” (NON-
CONJUGATED) MOABS

16. Bevacizumab (Avastin; Genentech) approved by US FDA as a
first-line treatment for patients with metastatic colorectal cancer on
February 2004 .
Bevacizumab targets circulating VEGF ligand.
approved for use in the treatment of colon cancer, breast cancer,
non-small cell lung cancer, and is investigational in the treatment of
sarcoma.Use for the treatment of brain tumors has been
recommended.
Cetuximab (marketed as Erbitux) and Panitumumab target the
epidermal growth factor receptor (EGFR). They are used in the
treatment of colon cancer and non-small cell lung cancer.
MONOCLONAL ANTIBODIES AS TARGETED THERAPY
Ref:Kim. P. S, Perez-Gracia JL, Melero I, Gurpide A(2008).
Ref:Alfaro. C, , Suarez N, Gonzalez A, Erro L, Solano S, Dubrot J(2009).

17. Conjugated antibodies
currently approved—
CONJUGATED ANTIBODIES
Toxin-conjugated antibody
Gemtuzumab
ozogamicin
(Mylotarg)
Used against AML
Radio-conjugated
antibodies
Tositumomab
(Bexxar)
Ibritumomab
(Zevalin)
Both used against
refractory lymphomas

18. Limitations of targeted therapy
Resistant to targeted therapies
1. Target changes through mutation
2. Growth of tumour without the help
of target
Solution: targeted therapy in combination
with one or more traditional chemotherapy
drugs.
Eg: targeted therapy trastuzumab
(Herceptin®) + docetaxel,a traditional
chemotherapy drug treat
women with metastatic breast cancer
that overexpresses the protein
HER2/neu
Drugs are difficult to develop
because of the target’s
structure and/or the way its
function is regulated in the
cell.
Eg: Ras, a signaling protein
that is mutated in as many as
one-quarter of all cancers
Solution: No solution till date

19. Common side effects: diarrhea and liver problems, such as hepatitis and
elevated liver enzymes.
Others include:
i. Skin problems
ii. Problems with blood clotting and wound healing
iii. High blood pressure
iv. Gastrointestinal perforation
v. Immunosuppression and impaired sperm production
Certain side effects of some targeted therapies have been linked to better
patient outcomes…………
 patients who develop acneiform rash while being treated erlotinib (Tarceva®)
or gefitinib (Iressa®), have tended to respond better to these drugs than patients
who do not develop the rash.
Patients who develop high blood pressure while being treated with the
angiogenesis inhibitor bevacizumab generally have had better outcomes.
SIDE EFFECTS OF TARGETED CANCER THERAPIES

20. CONCLUSION
Significant advances have been made in the chemotherapeutic management of cancer.
Many new cytotoxic drugs that can potentially be used for the treatment of cancer, this
life-threatening disease still causes near 7 million deaths every year worldwide and the
number is growing.
Cancer chemotherapy is usually accompanied by severe side effects and acquired drug
resistance.
We anxiously await the development of target therapy that will allow greater tumor
specificity and less toxicity.
So, targeted therapies using small molecules or monoclonal antibodies gaing
importence due to its high specificity almost negligible effect on neighbouring cells.
Despite the promising clinical results from the agents that is highlighted, there is still
significant limitation to the concept of “pathway-specific” targeted therapies as that
most solid tumors are the result of numerous genetic mutations, and thus inhibiting a
single cellular pathway may not result in a significant therapeutic outcome.

21. REFERENCES
1. Press MF, Lenz HJ (2007). EGFR, HER2 and VEGF pathways: validated
targets for cancer treatment. Drugs 67: 2045-2075.
2. Drebin JA, Link VC, Weinberg RA, Greene MI (1986). Inhibition of tumor
growth by a monoclonal antibody reactive with an oncogene-encoded tumor
antigen. Proc. Natl. Acad. Sci. U.S.A. 83: 9129–9133.
3. Gibbs JB.(2000). Anticancer drug targets: growth factors and growth factor
signaling. J Clin Invest;105:9–13.
4. Druker, B. J, David A(2003). Karnofsky Award lecture. Imatinib as a paradigm
of targeted therapies. J. Clin. Oncol. 21, 239–245 .
5. Alfaro. C, , Suarez N, Gonzalez A, Erro L, Solano S, Dubrot J(2009). Influence
of bevacizumab, sunitinib and sorafenib as single agents or in combination on
the inhibitory effects of VEGF on human dendritic cell differentiation from
monocytes. Br. J. Cancer 100: 1111–1119 .
6. Katzel JA, Fanucchi MP, Li Z (2009).Recent advances of novel targeted
therapy in non-small cell lung cancer. J Hematol Oncol 2 : 2.
7. Kim P. S, Perez-Gracia JL, Melero I, Gurpide A(2008). Antibody association
with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice
through Fc-mediated activation of DCs. J. Clin. Invest. 118: 1700–1711.

22. Thanks to Dr. Subhasis Dutta, Principal, and Dr. Debojyoti
Chakrabarty, the Head of the P.G. Dept. of Zoology, Barasat Govt.
College for providing infrastructure facilities.
Sincere thanks to Dr. Debjani Sarkar for providing guidance and
important suggestions for this presentation .
Thanks to Dr. Tuhin Kumar Saha, Dr. Madhumita Manna,
Dr. Sanjay Podder, Dr.Tanaya Dey, Dr. Srikanta Guria,Prof.
Somaditya Dey for providing encouragements and various help
during the entire period of study.
Lastly, the co-operation received from the classmates is also
acknowledged.
ACKNOWLEDGEMENT