Introduction and Overview of DNA Repair Targets: From Bench to Clinic - DNA Repair in Cancer Therapy - page 7

Damaged base

APE-1

DNA
DSB

DNA SSB

PARP

AT M AT R
H2AX BRCA1

XRCC1

Base
Excision
Repair

DNA pol β

Chk2 Chk1

Ligase III

Signaling
G2 arrest
to allow repair

Signaling
G1 arrest
to allow repair

KU 70/80
DNA-PK
XRCC4 Ligase IV

Rad51 BRCA2

ERCC1
XRCC3

RPA

Error free H2
Active in dividing cells

Error prone
NHEJ in G1

© 2010 American Association for Cancer Research

CCR Focus

FIGURE 1.3 Cross-pathway signaling and its influence on DNA repair. Simplified schematic of signaling and repair of SSBs and DSBs among
pathways. This knowledge can lead to potential rational inhibitor combinations. Damaged DNA bases are excised involving APE1, and a SSB
activates PARP, which recruits other BER proteins. In dividing cells or other circumstances where BER cannot be performed quickly enough, an
unrepaired SSB will become a DSB. The ATM/ATR pathways signal the presence of DSBs to arrest cell cycle progression and allow for repair. In
nondividing cells, G1 arrest is signaled via Chk2, and NHEJ pathways repair the break. In dividing cells, G2 arrest allows error-free repair using
HR. Adapted from Plummer R. Perspective on the pipeline of drugs being developed with modulation of DNA damage as a target. Clin Cancer Res 2010; 16:
4527-31 and reproduced with permission from the American Association for Cancer Research.

TABLE 1.4 PARP Inhibitors in Clinical Trials

Agent Company ROA Combo/Single therapy Indications Trial status

Veliparib (ABT-888) Abbott Oral With doxorubicin Metastatic BC Phase 1

With irinotecan Colorectal Phase 1

With TMZ Metastatic prostate, metastatic

melanoma

Phase 1

With TMZ Colorectal, metastatic BC Phase 2

With TMZ Recurrent CNS Phase 1

With topotecan Ovarian, peritoneal, solid tumors,

lymphoma, CLL

Phase 1,2

With carboplatin Ovarian Phase 1

With paclitaxel Peritoneal Phase 1

With bevacizumab Fallopian tube Phase 1

Single agent Ovarian Phase 2

Single agent Advanced solid tumors, hematologic

tumors

Phase 1

ER ,PR , and HER breast cancer Iniparib (SAR240550;

BSI-201)

Sanofi Aventis IV With inorectan Phase 2

With gemictabine + carboplatin Trible neg BC, recurrent ovarian Phase 2

With gemictabine + carboplatin Advanced solid tumors Phase 3

( Continued )