Targeted Cancer Therapies: When Will They Come?

[Guest guest]

" Targeted cancer therapies will give doctors a better way

to tailor cancer

treatment. Eventually, treatments may be individualized

based on the unique

set of molecular targets produced by the patient's tumor.

Targeted cancer

therapies also hold the promise of being more selective,

thus harming fewer

normal cells, reducing side effects, and improving the

quality of life. "

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Targeted Cancer Therapies: Questions and Answers

Key Points

Targeted cancer therapies use drugs that block the growth

and spread of

cancer by interfering with specific molecules involved in

carcinogenesis

(the process by which normal cells become cancer cells) and

tumor growth

(see Questions 1, 2, and 3).

Because scientists call these molecules " molecular

targets, " therapies that

interfere with them are sometimes called

" molecular-targeted drugs, "

" molecularly targeted therapies, " or other similar names

(see Question 1).

The National Cancer Institute's Molecular Targets

Development Program is

working to identify and evaluate molecular targets (see

Question 6).

What are targeted cancer therapies?

Targeted cancer therapies use drugs that block the growth

and spread of

cancer. They interfere with specific molecules involved in

carcinogenesis

(the process by which normal cells become cancer cells) and

tumor growth.

Because scientists call these molecules " molecular

targets, " these therapies

are sometimes called " molecular-targeted drugs, "

" molecularly targeted

therapies, " or other similar names. By focusing on

molecular and cellular

changes that are specific to cancer, targeted cancer

therapies may be more

effective than current treatments and less harmful to

normal cells.

Most targeted cancer therapies are in preclinical testing

(research with

animals), but some are in clinical trials (research studies

with people), or

have been approved by the U.S. Food and Drug Administration

(FDA). Targeted

cancer therapies are being studied for use alone, in

combination with each

other, and in combination with other cancer treatments,

such as

chemotherapy.

What are some of the cellular changes that lead to cancer?

Normally, cells grow and divide to form new cells as the

body needs them.

When cells grow old, they die, and new cells take their

place. Sometimes

this orderly process goes wrong. New cells form when the

body does not need

them, and old cells do not die when they should. These

extra cells can form

a mass of tissue called a growth or tumor. The cells in

malignant

(cancerous) tumors are abnormal and divide without control

or order. They

can invade and damage nearby tissues and organs. Also,

cancer cells can

break away from a malignant tumor and spread to other parts

of the body.

Normal cell growth and division are largely under the

control of a network

of chemical and molecular signals that give instructions to

cells. Genetic

alterations (changes) can disrupt the signaling process so

that cells no

longer grow and divide normally, or no longer die when they

should.

Alterations in two types of genes can contribute to the

cancer process.

Proto-oncogenes are normal genes that are involved in cell

growth and

division. Changes in these genes lead to the development of

oncogenes, which

can promote or allow excessive and continuous cell growth

and division.

Tumor suppressor genes are normal genes that slow down cell

growth and

division. When a tumor suppressor gene does not work

properly, cells may be

unable to stop growing and dividing, which leads to tumor

growth.

To use the metaphor of a car, the presence of an oncogene

is like having a

gas pedal that is stuck to the floorboard, causing cells to

continually grow

and divide. Tumor suppressor genes act like a brake pedal.

The loss of a

functioning tumor suppressor gene is like having a brake

pedal that does not

work properly, allowing cells to continually grow and

divide.

Genetic changes that are not corrected by the cell can lead

to the

production of abnormal proteins. Normally, proteins

interact with each other

as a kind of relay team to carry out the work of the cell.

For example, when

molecules called growth factors (GFs) attach to their

corresponding growth

factor receptors (GFRs) on the surface of the cell, a

process carried out by

proteins signals the cell to divide. Damaged proteins may

not respond to

normal signals, may over-respond to normal signals, or

otherwise fail to

carry out their normal functions. Cancer develops when

abnormal proteins

inside a cell cause it to reproduce excessively and allow

that cell to live

longer than normal cells.

How do targeted cancer therapies work?

Targeted cancer therapies interfere with cancer cell growth

and division in

different ways and at various points during the

development, growth, and

spread of cancer. Many of these therapies focus on proteins

that are

involved in the signaling process. By blocking the signals

that tell cancer

cells to grow and divide uncontrollably, targeted cancer

therapies can help

to stop the growth and division of cancer cells.

What are some types of targeted cancer therapies?

Targeted cancer therapies include several types of drugs.

Some examples are

listed below:

" Small-molecule " drugs block specific enzymes and GFRs

involved in cancer

cell growth. These drugs are also called

signal-transduction inhibitors.

Gleevec® (STI-571 or imatinib mesylate) is a small-molecule

drug approved by

the FDA to treat gastrointestinal stromal tumor (a rare

cancer of the

gastrointestinal tract) and certain kinds of chronic

myeloid leukemia (1,

2).

Gleevec targets abnormal proteins, or enzymes, that form

inside cancer cells

and stimulate uncontrolled growth. Iressa® (ZD1839 or

gefitinib) is approved

by the FDA to treat advanced non-small cell lung cancer.

This drug targets

the epidermal growth factor receptor (EGFR), which is

overproduced by many

types of cancer cells. Other small-molecule drugs are being

studied in

clinical trials in the United States.

" Apoptosis-inducing " drugs cause cancer cells to undergo

apoptosis (cell

death) by interfering with proteins involved in the

process. Velcade®

(bortezomib) is approved by the FDA to treat multiple

myeloma that has not

responded to other treatments (3). Velcade causes cancer

cells to die by

blocking enzymes called proteasomes, which help to regulate

cell function

and growth.

Another apoptosis-inducing drug called GenasenseT

(oblimersen), which is

only available in clinical trials, is being studied to

treat leukemia,

non-Hodgkin's lymphoma, and solid tumors. Genasense blocks

the production of

a protein known as BCL-2, which promotes the survival of

tumor cells. By

blocking BCL-2, Genasense leaves the cancer cells more

vulnerable to

anticancer drugs.

Monoclonal antibodies, cancer vaccines, angiogenesis

inhibitors, and gene

therapy are considered by some to be targeted therapies

because they

interfere with the growth of cancer cells. Information

about these

treatments can be found in the following NCI fact sheets,

which are

available on the Internet or by calling the Cancer

Information Service (CIS)

(see below):

-Biological Therapies for Cancer: Questions and Answers

includes information

about monoclonal antibodies and cancer vaccines. This fact

sheet is

available at

http://www.cancer.gov/cancertopics/factsheet/Therapy/biological

on the Internet.

-Angiogenesis Inhibitors in the Treatment of Cancer is

available at

http://www.cancer.gov/cancertopics/factsheet/Therapy/angiogenesis-

inhibitors

on the Internet.

-Gene Therapy for Cancer: Questions and Answers can be

found at

http://www.cancer.gov/cancertopics/factsheet/Therapy/gene

on the Internet.

What impact will targeted therapies have on cancer

treatment?

Targeted cancer therapies will give doctors a better way to

tailor cancer

treatment. Eventually, treatments may be individualized

based on the unique

set of molecular targets produced by the patient's tumor.

Targeted cancer

therapies also hold the promise of being more selective,

thus harming fewer

normal cells, reducing side effects, and improving the

quality of life.

What are some resources for more information?

The NCI's Molecular Targets Development Program (MTDP) is

working to

identify and evaluate molecular targets that may be

candidates for drug

development. As part of the NCI's Center for Cancer

Research, the MTDP

provides research support for NCI-designated, high-priority

drug discovery,

development, and research focused on specific molecular

targets, pathways,

or processes. The MTDP's Web site is

http://home.ncifcrf.gov/mtdp/ on the

Internet.

Information about clinical trials is available from the CIS

(see below).

Information specialists at the CIS use PDQ®, the NCI's

cancer information

database, to identify and provide detailed information

about specific

ongoing clinical trials. PDQ includes all NCI-funded

clinical trials and

some studies conducted by independent investigators at

hospitals and medical

centers in the United States and other countries around the

world.

People also have the option of searching for clinical

trials on their own.

The clinical trials page of the NCI's Web site, located at

http://www.cancer.gov/clinicaltrials/ on the Internet,

provides information

about clinical trials and links to PDQ.

Selected References

Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and

safety of imatinib

mesylate in advanced gastrointestinal stromal tumors. New

England Journal of

Medicine 2002; 347(7):472-480.

Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and

cytogenetic

responses to imatinib mesylate in chronic myelogenous

leukemia. New England

Journal of Medicine 2002; 346(9):645-652.

PG, Barlogie B, Berenson J, et al. A phase 2

study of bortezomib

in relapsed, refractory myeloma. New England Journal of

Medicine 2003;

348(26):2609-2617.