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

• O'Shaughnessy J, Osborne C, Pippen J, Yoffe M, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial. J Clin Oncol 27:18s, 2009 (suppl; abstr 3).

For more information, read these PubMed abstracts:

• Chalmers AJ. The potential role and application of PARP inhibitors in cancer treatment. Br Med Bull. 2009;89:23-40. Epub 2009 Feb 9.
• Dungey FA, Löser DA, Chalmers AJ. Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-Ribose) polymerase: mechanisms and therapeutic potential. Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1188-97.
• Chalmers AJ, Bentzen SM, Buffa FM. A general framework for quantifying the effects of DNA repair inhibitors on radiation sensitivity as a function of dose. Theor Biol Med Model. 2007 Jul 19;4:25.
• Kummar S, Kinders R, Gutierrez ME, Rubinstein L, et al. Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol. 2009 Jun 1;27(16):2705-11. Epub 2009 Apr 13.
• Donawho CK, Luo Y, Penning TD, Bauch JL, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007 May 1;13(9):2728-37
• Palma JP, Rodriguez LE, Bontcheva-Diaz VD, Bouska JJ, et al. The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and reduction in PARP activity in vivo. Anticancer Res. 2008 Sep-Oct;28(5A):2625-35
• Daniel RA, Rozanska AL, Thomas HD, Mulligan EA, et al. Inhibition of poly(ADP-ribose) polymerase-1 enhances temozolomide and topotecan activity against childhood neuroblastoma. Clin Cancer Res. 2009 Feb 15;15(4):1241-9. Epub 2009 Jan 27.
• Plummer R, Jones C, Middleton M, Wilson R, Evans J, et al. Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res. 2008 Dec 1;14(23):7917-23.
• Calvert AH, Plummer R. The development of phase I cancer trial methodologies: the use of pharmacokinetic and pharmacodynamic end points sets the scene for phase 0 cancer clinical trials. Clin Cancer Res. 2008 Jun 15;14(12):3664-9.

For more information:

• Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917-921 (14 April 2005) doi:10.1038/nature03445.
• Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913-917 (14 April 2005) doi:10.1038/nature03443.

Also read:

• Investigational BSI-201 plus Chemotherapy May Offer New Treatment Option for Triple-Negative Breast Cancer
• Olaparib Induces Tumor Response as Single Agent in BRCA-Deficient Breast Cancer.
• O’Shaughnessy J, Osborne C, Blum J, Pippen J, Yoffe M, et al. Triple Negative Metastatic Breast Cancer: A Phase 2, Multi-Center, Open-Label, Randomized Trial of Gemcitabine/Carboplatin (G/C) With or Without BSI-201, a PARP Inhibitor. SABCS Poster 2120, December 2008