Inhibition of PARP

In This Section:

PARP in Normal Cells

When a normal cell's DNA is damaged or mutated, several
cellular mechanisms can come into play to detect and repair
the alterations. If the DNA is repaired successfully, the cell survives.
However, if the DNA cannot be repaired, the cell will undergo
a form of cellular suicide called apoptosis rather than risk
passing on flawed genetic information to progeny cells.

On the left of the screen, a normal cell is shown with a red starburst in the nucleus. An arrow to the right leads to an icon labeled, 'damage,' and showing DNA with a single-strand break and a red starburst. Two arrows extend from the damage icon. The first is labeled 'Successful Repair and leads to a pink cell labeled 'Cell Survival.' The second arrow is labeled 'Failure to Repair' and leads to a group of gray spheres labeled 'Cell Suicide (Apoptosis).'

One protein involved in repairing damaged DNA is poly(ADP ribose)
polymerase 1, or PARP1. When a strand of DNA is broken, or nicked,
PARP1 moves to the site of damage and becomes activated. It then
recruits a team of DNA repair proteins that work together to mend the
broken strand of DNA.

A close-up view of a cell nucleus is shown. A group of proteins representing DNA repair proteins is shown interacting with the DNA. Screen text reads, 'PARP is important for DNA damage repair.'

A close-up view of a cell nucleus is shown. A group of proteins representing DNA repair proteins is shown interacting with the DNA. Screen text reads, 'PARP is important for DNA damage repair.'

PARP in Cancer Cells

Many standard cancer treatments, including many chemotherapy drugs
and radiation therapy, damage the DNA of rapidly dividing cancer cells.
If PARP is able to help repair the damage caused by these agents, tumor
cells may be more likely to survive and grow.

A cross-section of a cancer cell is shown. Screen text reads, 'Chemotherapy drugs and radiation therapies damage the DNA of rapidly dividing cancer cells.' A white haze entering the cell is labeled 'Radiation.' The DNA in the nucleus has been damaged and is labeled with the damage icon (a picture of DNA with a broken strand and a red starburst). A yellow protein representing PARP is in the nucleus.

A cross-section of a cancer cell is shown. Screen text reads, 'PARP may help cancer cells repair damage and survive.' Five DNA repair proteins are visible in the nucleus near the DNA. The DNA is intact, indicating that it has been repaired by PARP and the other DNA repair proteins.

Inhibiting PARP

However, preclinical studies suggest that standard therapies combined
with PARP inhibitors may be more effective than standard therapies alone.
If cancer cells are exposed to a PARP inhibitor, the protein will be unable to
respond when the cell's DNA is damaged by treatments such as chemotherapy.
The presence of unrepaired DNA damage will make the cell more
likely to undergo apoptosis.

A layer of pink normal cells is shown with a mass of green cancer cells in the middle. Small yellow dots near all of the cells represent standard chemotherapeutic drugs. A call-out bubble in the foreground shows the nucleus of a cancer cell containing damaged DNA. PARP is present in the nucleus and is associated with a PARP inhibitor.

A layer of pink normal cells is shown with a mass of green cancer cells in the middle. Small yellow dots near all of the cells represent standard chemotherapeutic drugs. A call-out bubble in the foreground shows the nucleus of a cancer cell containing damaged DNA. PARP is present in the nucleus and is associated with a PARP inhibitor.

Clinical trials studying PARP inhibitors in combination with standard
chemotherapeutic agents in breast cancer are currently under way.

This image is titled, 'PARP Inhibitors.' On the left side of the screen, there is a bulleted list that reads, 'Used in combination with standard therapies.' There are also three gray boxes labeled 'Phase 0,' 'Phase I,' and 'Phase II' and connected by arrows. On the right side of the screen is group of green female figures representing breast cancer patients.

This image is titled, 'PARP Inhibitors.' On the left side of the screen, there is a bulleted list that reads, 'Used in combination with standard therapies.' There are also three gray boxes labeled 'Phase 0,' 'Phase I,' and 'Phase II' and connected by arrows. On the right side of the screen is group of green female figures representing breast cancer patients.

It is also possible that PARP inhibitors could be effective as single
agents against tumors with inherent DNA repair defects, such as
breast tumors with mutations in the DNA repair proteins BRCA1 or
BRCA2. Preclinical studies have shown that breast tumor cells
carrying BRCA mutations undergo an arrest of the cell cycle and
apoptosis when exposed to PARP inhibitors, whereas cells with normal
BRCA proteins survive and continue to grow.

This is a split-screen image. A mass of cells on the left side is labeled 'Normal BRCA' and a mass on the right side is labeled 'Mutant BRCA' and has a mutation icon associated with it (DNA with starburst and labeled 'mutation'). Purple dots representing PARP inhibitors are circulating around both cell masses. The cells with mutant BRCA are undergoing apoptosis upon exposure to the PARP inhibitors, but the normal BRCA cells remain viable.

Several PARP inhibitors are currently being tested in clinical trials
involving women with BRCA mutation-associated breast cancer.

This image is titled, 'PARP Inhibitors.' On the left side of the screen, there is a bulleted list that reads, 'Tested in BRCA mutation-associated breast cancer.' There are also three gray boxes labeled 'Phase 0,' 'Phase I,' and 'Phase II' and connected by arrows. On the right side of the screen is group of green female figures representing breast cancer patients.

More Information

PARP

Several drugs that target PARP are currently being tested in clinical studies.

	Research Name	Generic Name	Trade Name	Drug Type
PARP inhibitors	ABT-888	n/a	n/a	Small molecule
	AG014699	n/a	n/a	Small molecule
	BSI-201	n/a	n/a	Small molecule
	AZD2281	n/a	n/a	Small molecule

For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview at http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies.

Self Test

Questions

Women whose breast tumors have mutations in BRCA1 or BRCA2 overexpress PARP.
1. True
2. False

Answers

Correct Answer: b
1. True - Incorrect.
  There is no evidence that BRCA-mutation-associated tumors have increased expression of PARP. However, it appears that cancer cells with BRCA1 or BRCA2 mutations are more sensitive to PARP inhibitors (i.e., more likely to undergo growth arrest and apoptosis) than cells with normal BRCA1 or BRCA2. This is most likely because the combination of inhibition of PARP and loss of BRCA1 or BRCA2 function results in inactivation of two major forms of DNA repair, making it more difficult for cells to maintain the integrity of their genome and leaving them more vulnerable to apoptosis.
2. False - Correct.
  There is no evidence that BRCA-mutation-associated tumors have increased expression of PARP. However, it appears that cancer cells with BRCA1 or BRCA2 mutations are more sensitive to PARP inhibitors (i.e., more likely to undergo growth arrest and apoptosis) than cells with normal BRCA1 or BRCA2. This is most likely because the combination of inhibition of PARP and loss of BRCA1 or BRCA2 function results in inactivation of two major forms of DNA repair, making it more difficult for cells to maintain the integrity of their genome and leaving them more vulnerable to apoptosis.

< Previous Section Next Section >