Introduction and Overview of DNA Repair Targets: From Bench to Clinic - DNA Repair in Cancer Therapy - page 8

TABLE 1.4 PARP Inhibitors in Clinical Trialsdcont'd

Agent Company ROA Combo/Single therapy Indications Trial status

With gemictabine + cisplatin NSCLC Phase 2

With TMZ Glioblastoma Phase 1,2

Single agent Ovarian, fallopian, Primary peritoneal Phase 2

Olaparib (AZD2281,
KU-0059436)

Astra Zeneca Oral With paclitaxel Triple negative BC Phase 1

With paclitaxel Gastric Phase 2

With carboplatin Triple neg BC, cervical, ovarian,

breast, fallopian tube, endometrial,
carcinosarcoma, primary peritoneal

Phase 1

With carboplatin +/ Paclitaxel Advanced ovarian Phase 2

With topotecan Solid tumors Phase 1

With gemcitabine Pancreatic Phase 1

With dacarbazine Advanced melanoma Phase 1

With bevacizumab Solid tumors Phase 1

With cisplatin + gemcitabine Solid tumors Phase 1

Single agent Breast, triple neg BC, ovarian, prostate,

pancreatic, colorectal, advanced tumors

Phase 2

Single agent Solid tumors Phase 1

MK4827 Merck Oral Single agent Advanced solid Phase 1

Single agent BRCA ovarian Phase 1

Single agent Mantle cell lymphoma Phase 2

CEP-9722 Cephalon Oral With TMZ Advanced solid tumors Phase 1

E7016 Esai Oral With TMZ Solid tumors Phase 1

LT673 Biomarin Oral Solid tumors Phase 1

AG014699
(PF-01367338)

Pfizer IV With platinating agents

and other agents

Advanced solid tumors Phase 1

With TMZ Metastatic BC, advanced ovarian Phase 2

INO-1001 Inotek IV Single agent Angioplasty after AMI Phase 2

Abbreviations used: AMI acute myocardial infarction; BC breast cancer; CLL chronic lymphocytic leukemia; neg negative; NSCLC non-small-cell lung

¼ ¼ ¼ ¼ ¼

cancer; ROA route of administration; TMZ temozolomide.

¼ ¼

pathway. 23 Such possibilities of enhancing or inducing
“BRCA-ness” to create synthetic lethalities are tantalizing.

The hunt is underway to develop more biomarkers
that can reliably identify other “BRCA-like” tumors to
extend the benefit of PARP inhibitors. 18 In the quest to
find additional “drug-able” synthetic lethal targets,
EZH2 may be the next. EZH2 mediates proliferation in
breast cancer cell lines, and studies in mammals show
that it requires BRCA1 to do so. Although this relation-
ship is not yet fully elucidated, theoretically EZH2 inhi-
bition could be combined with PARP inhibition in
a “double synthetic lethal” strategy to treat BRCA1-
deficient breast cancers. 22
In similar fashion, silencing of XRCC1 (X-ray repair
cross-complementing group 1) has been demonstrated
to sensitize cells to PARP inhibition. XRCC1 is a substrate
of PARP, and it also has functionality in the NER

DNA DAMAGE CHECKPOINTS AND
THEIR INHIBITION

As DNA repair pathways began to be studied in more
depth, the working definition of “DNA repair”
expanded. DNA repair in its strictest sense means “bio-
logical processes during which alterations in the chem-
istry of DNA are removed and the integrity of the
genome is restored”. 2 Today's broader definition now
includes many biological responses to DNA damage,
including arrest of DNA synthesis in the presence or