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The Lancet Oncology

Tuesday, June 23, 2009

PARP Inhibitors Show Promise for Hard-to-Treat (Breast) Cancers

Two studies, including one featured during the plenary session of the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), report promising data on a new class of targeted drugs called PARP inhibitors. The plenary study reports that women with hard-to-treat 'triple-negative' breast cancer who received the PARP inhibitor BSI-201 along with conventional chemotherapy had better outcomes than women who received chemotherapy alone. A second study reports that women with BRCA-deficient advanced breast cancer experienced tumor shrinkage after receiving the PARP inhibitor olaparib as a single agent.

The two new studies report results on the effect of a new class of targeted therapy called PARP inhibitors on traditionally difficult-to-treat breast cancers – so-called 'triple-negative' breast cancer and BRCA1- and BRCA2 deficient breast cancers.

PARP is short for ‘poly (ADP-ribose) polymerase.’ Cancer cells use the PARP enzyme to repair DNA damage, including the damage inflicted by chemotherapy drugs. Preclinical studies indicate that PARP inhibitors could enhance the efficacy of radiation therapy and chemotherapies such as alkylating agents and platinum-based drugs by preventing malignant cells from repairing damaged DNA, ultimately leading to impaired tumor growth and apoptosis.

PARP Concept
The concept is based on the fact that BRCA1 and BRCA2 are tumor suppressor genes that help control normal cell growth and cell death by regulating the repair of double strand breaks in DNA. Mutations in the BRCA1 and BRCA2 genes can impair this function, leaving cells unable to repair their own DNA, as well as causing the uncontrolled growth that is characteristic of cancer cells. Women who inherit mutations in the BRCA1 or BRCA2 genes have significantly higher risks for breast and ovarian cancer

Exploiting impaired DNA repair function
PARP inhibitors work by exploiting the impaired DNA repair function inherent in BRCA-associated cancers. In this case, inhibition of PARP leads to failure to repair DNA single strand breaks, which in turn, result in DNA double strand breaks. These effects are particularly detrimental to BRCA-associated cancer cells. Ultimately, failure to repair both DNA single strand breaks and double strand breaks, leads to cancer cell death.

Researchers interested in understanding how to exploit the DNA damage on tumor cells inflicting by anti-cancer agents, are now examining whether drugs that inhibit the PARP enzyme will indeed diminish the self-repair mechanism and make cancer cells more sensitive to treatment and promote cancer cell death.

Currently, a number of PARP inhibitors are studied in Phase I, II and III trials for a variety of cancer indications. These include:
  • ABT-888 in Metastatic melanoma (Abbott Laboratories). Preliminary trial results show that this drug candidate has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. Broad spectrum chemopotentiation and radiopotentiation makes this compound an attractive candidate for further clinical evaluation.
  • AG-014699 in Breast cancer, ovarian cancer and melanoma (Agouron/Pfizer Inc.). Preliminary results of a phase II trial of AG-014699 and temozolomide in patients with metastatic melanoma indicated that the addition of AG-14699 enhanced temozolomide-associated myelosuppression, and that the response rate for combination treatment was higher than for temozolomide alone.
  • Olaparib (AZD2281 / KU-0059436) in Breast cancer and ovarian cancer (AstraZeneca). Combination of AZD2281 with cisplatin or carboplatin increased the recurrence-free and overall survival, suggesting that AZD2281 potentiates the effect of these DNA-damaging agents. Preliminary results demonstrate in vivo sensitivity and efficacy of AZD2281, alone or in combination with cisplatin, and provide strong support for AZD2281 as a novel targeted therapeutic against BRCA-deficient cancers.
  • BSI-201 in Breast cancer, ovarian cancer, uterine cancerand glioblastoma multiforme (BiPar Sciences Inc.). Data from a Phase II trial of BSI-201 in metastatic breast cancer patients whose tumors were negative for three common breast cancer markers: estrogen receptor, progesterone receptor, and HER2, confirmed that the patients' tumors had significant upregulation of PARP, compared with normal breast tissue, supporting the targeting of this enzyme with BSI-201.

ASCO 2009 Abstracts

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