This talk covers the evolution of chemotherapy and the efforts that resulted in the discovery of targeted therapies.

1. Personalized Medicine in Oncology:
The Future Is Now
Bita Fakhri
04/07/2015

2. First Efforts
(1940-1952)
• German introduction of chemical warfare
during WWII
• A German air raid in Bari, Italy led to the
exposure of more than one thousand
people to the John Harvey’s secret cargo
composed of mustard gas bombs.
• Autopsies of the victims suggested
profound lymphoid and myeloid
suppression

3. First Efforts
(1940-1952)
• Set up an animal model - they established
lymphomas in mice
• Demonstrated they could treat them with
mustard agents.
• In collaboration with a thoracic surgeon,
Gustaf Lindskog, they injected nitrogen
mustard into a patient with NHL.
• They observed a dramatic reduction in
the patient's tumor masses. Although this
effect lasted only a few weeks, and the
patient had to return for another set of
treatment, this was the first step to the
realization that cancer could be treated
by pharmacological agents
Gustaf Lindskog

4. Antifolates (1948)
• Studied the effects of folic acid on leukemia
patients.
• Folic acid, a vitamin crucial for DNA
metabolism, had been discovered by Lucy
Wills, when she was working in India, in 1937.
• Folate seemed to stimulate the proliferation
of ALL cells when administered to children
with this cancer.
• Farber used folate analogues. These
analogues — first aminopterin and then
amethopterin (now methotrexate) were
antagonistic to folic acid, and blocked the
function of folate-requiring enzymes.
Sydney Farber – the father of modern chemotherapy

6. National Treatment Effort by the US (1955)
• 1955: The US congress created a
National Cancer Chemotherapy
Service Center (NCCSC) at the NCI in
response to early successes. This was
the first federal program to promote
drug discovery for cancer.
• 6-MP, Vinca alkaloids

7. First Solid Tumor To Be Treated with Chemotherpy (1958)
• When choriocarcinoma patients were being
treated with methotrexate, urine levels of the
hormone hCG dropped steadily.
• Li hypothesized that the patients' tumors were
secreting hCG, and as a result, that the level of
hCG in a patient's urine could be used to
measure the effectiveness of a particular
treatment.
• He concluded that a dose of 100–125 mg given
every day for four or five days was more
effective than a single, larger dose
• The NCI disapproved, feeling that by continuing
treatment Li was experimenting on his patients
and unnecessarily poisoning them with the
chemotherapy drug. In 1957, the NCI fired Li and
he returned to Sloan-Kettering.
Roy Hertz – Min Chiu Li

8. Combination Chemotherapy (1965)
• Hypothesized cancer chemotherapy
should follow the strategy of antibiotic
therapy for tuberculosis with
combinations of drugs, each with a
different mechanism of action. Cancer
cells could mutate to become resistant to
a single agent, but by using different
drugs concurrently it would be more
difficult for the tumor to develop
resistance to the combination.

9. Combination Chemotherapy (1965)
• POMP regimen — and induced long-term
remissions in children with ALL.
• This approach was extended to the
lymphomas by Vincent DeVita and George
Canellos at the NCI. In the late 1960s MOPP
regimen— could cure patients with HL and
NHL.
• Currently, nearly all successful cancer
chemotherapy regimens use this paradigm of
multiple drugs given simultaneously, called
combination chemotherapy or
polychemotherapy.
Dr. Vincent DeVita

10. Adjuvent Chemotherapy (1972-75)
• If the tumor burden could be reduced first by
surgery, then chemotherapy may be able to
clear away any remaining malignant cells. –
"adjuvant therapy“
• Emil Frei — high doses of methotrexate
prevented recurrence of osteosarcoma
following surgical removal of the primary
tumor.
• Emil Frie – 5-FU, an inhibitor of DNA
synthesis, was later shown to improve survival
when used as an adjuvant to surgery in
treating patients with colon cancer.

11. Adjuvant Chemotherapy (1972-75)
• The landmark trial of Bernard Fisher, chair of
the National Surgical Adjuvant Breast and
Bowel Project, proved adjuvant therapy after
complete surgical resection of breast tumors
significantly extended survival — particularly
in more advanced cancer.

13. Richard Nixon signs the National Cancer Act of 1971

14. Richard Nixon signs the National Cancer Act of 1971
• Create new cancer centers and manpower
training programs
• Appoint advisory committees, allowing the
director to explore new issues/opportunities.
• Expand the physical location at NIH and other
research facilities across the country.
• Award contracts for research
• Collaborate with other federal, state, or local
public agencies and private industry
• Conduct cancer control activities
• Establish an international cancer research
data bank that collects, catalogues, stores,
and disseminates results of cancer research
• Award research grants

15. New Drugs (1971-current)
Taxanes
• Paclitaxel (Taxol) - novel antimitotic agent: promoted microtubule assembly.
• obtained from the bark of the Pacific Yew Tree
• forced the NCI into the costly business of harvesting substantial quantities of yew trees from public lands.
• effective in ovarian cancer therapy.
Camptothecins
• derived from a Chinese ornamental tree
• inhibits topoisomerase I, an enzyme that allows DNA unwinding.
• the agent had little antitumor activity in early clinical trials
• dosing was limited by kidney toxicity.
• In 1996 a more stable analogue, irinotecan, won FDA approval for the treatment of colon cancer. Later, this
agent would also be used to treat lung and ovarian cancers.

16. New Drugs
The Pacific Yew - Original Source of
Taxol
Camptotheca, Happy Tree, Cancer Tree,
Tree Of Life

17. New Drugs (1971-current)
Platinum-based agents
• Cisplatin, was discovered by a Michigan State University researcher, Barnett Rosenberg, working under an NCI contract.
• Testicular cancer
• United Kingdom extended the clinical usefulness of the platinum compounds with their development of Carboplatin, a
cisplatin derivative with broad antitumor activity and comparatively less nephrotoxicity.
Nitrosoureas
• A second group with an NCI contract, led by John Montgomery at the Southern Research Institute
• synthesized nitrosureas, an alkylating agent which cross-links DNA.
• Fludarabine phosphate, a purine analogue which has become a mainstay in treatment of patients with CLL, was another
similar development by Montgomery.
Anthracyclines and epipodophyllotoxins
• both of which inhibited the action of topoisomerase II, an enzyme crucial for DNA synthesis.

18. The Birth of Targeted Therapies (1990s)
Brian Druker - Gleevec
Dennis Slamon - Herceptin

19. The Birth of Targeted Therapies (1990s)
• Trastuzumab is a mAb that interferes with the
HER2/neu Receptor.
• The HER proteins stimulate cell proliferation.
• In some cancers, notably certain types of
breast cancer, HER2 is over-expressed, and
causes cancer cells to reproduce
uncontrollably
Denis Slamon

20. The Birth of Targeted Therapies (1990s)
• For 12 years, Dr. Slamon and his colleagues conducted
the laboratory and clinical research that led to the
development of the new breast cancer drug
Herceptin, which targets a specific genetic alteration
found in about 25 percent of breast cancer patients.
• improved overall survival in late-stage (metastatic)
breast cancer from 20.3 to 25.1 months.
• In early stage breast cancer, reduces the risk of
cancer returning after surgery by an absolute risk of
9.5%
• Reduces the risk of death by an absolute risk of 3%
• however increases serious heart problems by an
absolute risk of 2.1% which may resolve if treatment
is stopped.

21. The Birth of Targeted Therapies (1990s)
• The biotech company Genentech
developed trastuzumab jointly
with UCLA and gained FDA
approval in September 1998.

22. The Birth of Targeted Therapies (1990s)
Janet Rowley,
the first geneticist
who identified
translocation
between
chromosomes:
• 9,22 (1970) 
Philadelphia
chromosome
• 8,21  AML
• 15, 17  APML

23. The Birth of Targeted Therapies (1990s)
• Collaboration between Novartis
and Brian Druker at OHSU.
• The first clinical trial of Gleevec
took place in 1998 and the drug
received FDA approval in May
2001.
Dr. Brian Druker

24. The Birth of Targeted Therapies (1990s)

25. The Birth of Targeted Therapies (1990s)

27. Targeted Therapies
• Drugs or other substances that block the growth and spread of cancer
by interfering with specific molecules ("molecular targets") 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," or
similar names.

28. The Differences between Targeted Therapies and Standard Chemotherapy
Targeted Therapies Standard 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
many standard chemotherapies were identified
because they kill cells
cytostatic (that is, they block tumor cell proliferation) cytotoxic (that is, they kill tumor cells)

29. How Are Targets for Targeted Therapies
Identified?
Compare the amount of individual proteins in cancer cells vs. normal cells
• Especially if they are known to be involved in cell growth and survival
• Her2/neu receptor
Determine whether cancer cells produce mutant proteins that drive cancer
progression
• BRAF  BRAF V600E in many melanomas
• Vemurafenib
Abnormalities in chromosomes that are present in cancer cells but not
normal cells
• Fusion proteins  drive cancer development
• Imatinib

30. Forms of Targeted Therapies
Monoclonal antibody drugs
• Man-made versions of large immune system proteins (called antibodies)
• Designed to attack a very specific target on cancer cells
• Referred to as biologics (made in living cells)
• The generic names for these drugs (as opposed to the brand names) all end in -
mab; for example, rituximab, panitumumab, etc.
Small-molecule drugs
• chemicals like most other types of drugs
• The generic names for most of these drugs end in -ib; for example, imatinib,
dasatinib, etc.

31. Types of Targeted Therapies
• Signal transduction inhibitors
• Angiogenesis inhibitors
• Apoptosis-inducing drugs
• Immunotherapy drugs
• Monoclonal antibody attached to toxin

32. Signal Transduction Inhibitors
• The cells in our bodies normally grow (or
stop growing) in response to chemical
signals they pick up from the area around
them.
• These signals are transmitted through
proteins to the cell’s control center, telling
it what to do.
• In cancer cells, these signals sometimes
get stuck in the “on” position, telling the
cell to grow even without it getting an
outside signal.

33. Signal Transduction Inhibitors
• EGFR inhibitors, such as cetuximab (Erbitux) and erlotinib (Tarceva), which are
used to treat some lung, colorectal, and other cancers.
• HER2 inhibitors, such as trastuzumab (Herceptin) and pertuzumab (Perjeta),
which are used to treat some breast, stomach, and other cancers.
• BCR-ABL inhibitors, such as imatinib (Gleevec) and dasatinib (Sprycel), which are
used to treat CML.
• BRAF inhibitors, such as vemurafenib (Zelboraf) and dabrafenib (Tafinlar), which
are used to treat some melanomas.

34. Angiogenesis Inhibitors
• Angiogenesis can help tumors grow by giving
them their own blood supply.
• Angiogenesis inhibitors stop tumors from
making new blood vessels, which greatly
limits how big they can grow.
• Many of these drugs work by blocking
vascular endothelial growth factor (VEGF)
proteins or the VEGF receptors.
• bevacizumab (Avastin) [GBM, NSCLC) and
sorafenib, sunitinib

35. Apoptosis-inducing Drugs
• change the proteins within the
cancer cells that cause the cells
to die
• bortezomib (Velcade) and
carfilzomib (Kyprolis)

36. Limitations of Targeted Therapies
Resistance
• the target itself changes through mutation
• the tumor finds a new pathway to achieve tumor growth that does
not depend on the target.
Solution
• Combination of targeted therapies (melanoma: dabrafenib +
trametinib)
• Combination of targeted therapies with traditional chemotherapy
(docetaxel + trastuzumab)

37. Limitations of Targeted Therapies
• some identified targets are difficult to develop because of the target’s
structure and/or the way its function is regulated in the cell.
• One example is Ras, a signaling protein that is mutated in as many as
one-quarter of all cancers (and in the majority of certain cancer types,
such as pancreatic cancer).

38. Conclusions
• Targeted therapy using mAbs or specific inhibitors of selected events
of cancer growth and progression has significantly expanded the
molecular treatment of malignancies.
• Moderate adverse effects
• The heterogeneity of the biologic processes underlying cancer
• The right selection of patients

39. Horizons
• Immune therapy
• Gene therapy

40. Cancer Patients
• “But the story of leukemia--the story of cancer--isn't the story of
doctors who struggle and survive, moving from institution to another.
It is the story of patients who struggle and survive, moving from one
embankment of illness to another. Resilience, inventiveness, and
survivorship--qualities often ascribed to great physicians--are
reflected qualities, emanating first from those who struggle with
illness and only then mirrored by those who treat them. If the history
of medicine is told through the stories of doctors, it is because their
contributions stand in place of the more substantive heroism of their
patients.”

41. Salute
Adam's sons are body limbs, to say;
For they're created of the same clay.
Should one organ be troubled by pain,
Others would suffer severe strain.
Thou, careless of people's suffering,
Deserve not the name, "human being".