Cancer Biology and Chemotherapy

Gene Terkoski
PharmD Candidate 2015

Objectives
At the conclusion of this presentation, the participants will be able to:

1

Describe what cancer is

2

Define the pathophysiology behind cancer

3

Identify factors that contribute to cancer development

4

Distinguish between different chemotherapy agents

5

Identify the MOA of chemotherapy agents

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What is Cancer?

 Comprises over 100 different diseases
 Cancer develops from a system break down that regulates cell
overgrowth and invasion of other tissues.
 Normally cells require special signaling to grow and divide. With
cancer cells the signaling to inhibit growth and division has no effect
on the cells due to changes within the cells.
 These abnormal cells begin to create their own mutations, proteins,
and genes that are unaffected by normal signaling.

* Place your footnotes here
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Pop Quiz

How many mutations does it take to develop cancer?

5-7

* Place your footnotes here
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What is Cancer?

Definitions
 If cells remain in their original location they are considered benign; if
they branch out and become invasive they are considered
malignant.
 Malignant tumor cells often metastasize, meaning they send rebel
cells to other parts of the body to grow and create new cancer
tumors throughout the body.

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What is Cancer?

 Alterations to our DNA may occur by mutation or the rearrangement
of genes in the chromosomes
 When our genes are mutated, cancerous genes may be formed.
These malfunctioning genes can be classified into three groups

- proto-oncogenes, tumor suppressors, and DNA repair
genes).

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Pop Quiz

How many genes are in the human genome?

21,000

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Cancer Pathophysiology

Brakes and
Accelerators

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Cancer Pathophysiology

Accelerators
 Proto-oncogenes regulate the speed of cell growth. If a proto-oncogene is mutated
and becomes an oncogene, cell growth may be unimpeded. Like an accelerator stuck
to the floor of a car, oncogenes produce uncontrolled cell growth.
 In normal cells, growth factors outside the cell transmit a signal and eventually
activate transcription factors which reach the DNA within the nucleus to promote cell
growth. Oncogenes don’t allow this process to ever stop.
 Two common proto-oncogenes are MYC and RAS. They are responsible for 70% of
cancers and 30% of tumors respectively.
 These oncogenes are considered a dominant mutation.
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Cancer Pathophysiology- Example

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Cancer Pathophysiology

Brakes
 Tumor Suppressor Genes inhibit cell growth, preventing tumor formation. Mutations
in these genes usually result in the loss of function. Like a defective brake pedal these
mutations make it difficult to stop cell growth.
 Such is the case with retinoblastoma, familial adenomatous polyposis, and hereditary
breast cancer.
 They are usually a recessive gene. Generally for both genes to be defective, an
individual inherits one and the other becomes mutated usually early in life.

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Cancer Pathophysiology

Bad
Mechanics
 DNA Repair Genes: repair damage to chromosomes minimizing mutations in the cell.
 When mutations happen to these genes it prevents DNA repair, allowing mutations to
remain unchecked and to accumulate in the cell. This is like a bad mechanic who
cannot fix faulty brakes or accelerators.

 Can be caused by environmental factors. (UV light, chemicals...)
 Some examples include Xeroderma pigmentosum where people are 1000 time more
likely to have skin cancer and Bloom syndrome that leads to lung disease, diabetes
and other cancers.
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Cancer Pathophysiology
Name

Examples of Cancer/Diseases

Type of Cancer
Gene

APC

Familial Adenomatous Polyposis

tumor suppressor

BCL2

Leukemia; Lymphoma

oncogene

BLM

Bloom Syndrome

DNA repair

BRCA1

Breast, Ovarian, Prostatic, & Colonic Neoplasms

tumor suppressor

BRCA2

Breast & Pancreatic Neoplasms; Leukemia

tumor suppressor

HER2

Breast, Ovarian Neoplasms

oncogene

MYC

Burkitt's Lymphoma, Hepatoblastoma

oncogene

P53

Colorectal Neoplasms; Li-Fraumeni Syndrome

tumor suppressor

RAS

Pancreatic, Colorectal, Bladder Breast, Kidney, &
Lung Neoplasms; Leukemia; Melanoma

oncogene

RB

Retinoblastoma

tumor suppressor

SIS

Dermatofibrosarcoma; Meningioma;
Skin Neoplasms

oncogene

XP
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Xeroderma pigmentosum

DNA repair

Cancer Pathophysiology
Other Factors that Influence Cancer

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Cancer Treatment

* Place your footnotes here
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Pop Quiz

What is the oldest and largest class of antineoplastic
agents?

Alkylating Agents

* Place your footnotes here
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Traditional Chemotherapy Agents

Purine and
Pyrimidine
Synthesis

Ribo and
Deoxyribo
nucleotides

DNA

Antimetabolites

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RNA

Proteins,
Enzymes,
and
microtubules

L-asparaginase

Alkylating Agents
Anthracyclines
Topoisomerase inhibitors

Vinca Alkaloids
Taxanes

Traditional Chemotherapy Agents

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Traditional Chemotherapy MOA
Cell Cycle Specific

Antimetabolites
- Folate antagonists- Inhibit dihydrofolate reductase (DHFR),
Inhibit de novo purine synthesis
- Ex: Methotrexate, Pemetrexed

- Purine analogs- incorporate into DNA/RNA and arrest
cellular development in the S phase
- Ex: 6-MP, Fludarabine *also enzyme inhibition

- Pyrimidine analogs-Inhibits DNA methyltransferase (DNMT),
Leads to hypomethylation of DNA apoptosis and
differentiation
- Ex: 5-FU, Cytarabine
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Traditional Chemotherapy MOA
Cell Cycle Specific

Vinca Alkaloids
- “Anti-Microtubule” Don’t allow assembly of microtubules
Cannot separate chromatids cell enters death pathway(s)
- Ex: Vincristine, Vinblastine

Taxanes
- “Anti-Microtubule”
- Ex: Paclitaxol, Docetaxol
- Require pvc-free tubing pre-meds due to cremaphor
vehicle

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Traditional Chemotherapy MOA
Cell Cycle Specific

Topoisomerase Inhibitors
- Inhibits Topo II leading to single-strand DNA breaks
- Etoposide, Teniposide
- Infusion reactions common due to polysorbate 80 vehicle

Page  21

Pop Quiz

Who developed the first chemotherapy?

Louis Goodman and Alfred Gilman in 1942
were recruited by the Department of Defense to
investigate therapeutic applications of chemical agents
used in warfare. Research spurred by observations
involving mustard gas exposure leading to
myelosuppression

* Place your footnotes here
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Traditional Chemotherapy MOA
Cell Cycle Non-Specific

Alkylating Agents
- Inhibition of DNA replication, DNA strand breaks, Crosslinking
- Cisplatin, Carboplatin, Cyclophosphamide, Ifosfamide, Busulfan,
Thiotepa, Procarbazine

Anthracyclines
- Free radical formation, DNA intercalation, and Topo II inhibitor
- Doxorubicin, Daunorubicin

L-asparaginase
- Depletes levels of asparagine. Immature leukemic blast cells do not
supply their own asparagine.

- Ex: L-asparaginase, Peg-asparaginase, Erwinia
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Cancer Treatment

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Chemotherapy
Traditional

Targeted

More Severe Side
Effects

Less Severe Side
Effects

Less Expensive

More Expensive

Methotrexate
 WAC- 25mg/mL (#10)

$11.17

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 Gleevec (imatinib)
 WAC- 400mg (#30)

 $8380.87

Biologic Chemotherapy MOA

Immune modulators
Cytokines
- Increases cytotoxic T and B cells, recognize and destroy
malignant cells via apoptosis
- Interleukin-2, Interleukin Alpha

Antiangiogenesis
- Inhibition of basic fibroblast growth factors (FGF), reduced
angiogenesis, degradation of TNF- α, increases IL-2 levels
- Thalidomide, lenalidomide

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Biologic Chemotherapy MOA

Proteasome Inhibitors
- Inhibits the enzymes that regulate protein homeostasis
within the cell
- Bortezomib (Velcade®), Carfilzomib (Kyprolis®)

Tyrosine Kinase Inhibitors (TKIs)
- Prevent cellular signaling and interfere with growth and
proliferation
- Imatanib, Dasatinib, Sorafenib

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Biologic Chemotherapy MOA

 mTOR Inhibitors
- Reduces protein synthesis by binding FKBP-12 and forming a
complex that inhibits mTOR kinase activity
- Everolimus (Afinitor®), Temsirolimus (Torisel®)

 Monoclonal Antibodies
- Antibody-dependent cellular lysis, Complement activation,
Angiogenesis inhibitition
- Rituximab, Alemtuzumab, Trastuzumab

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Summary
We discussed and are now able to:

1

Describe what cancer is

2

Define the pathophysiology behind cancer

3

Identify factors that contribute to cancer development

4

Distinguish between different chemotherapy agents

5

Identify the MOA of chemotherapy agents

Page  29

Any Questions?

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